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Infant Gut Microbiome Associated With Cognitive Development.
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Infant Gut Microbiome Associated With Cognitive Development.

Biol Psychiatry. 2017 Jun 27;:

Authors: Carlson AL, Xia K, Azcarate-Peril MA, Goldman BD, Ahn M, Styner MA, Thompson AL, Geng X, Gilmore JH, Knickmeyer RC

Abstract
BACKGROUND: Studies in rodents provide compelling evidence that microorganisms inhabiting the gut influence neurodevelopment. In particular, experimental manipulations that alter intestinal microbiota impact exploratory and communicative behaviors and cognitive performance. In humans, the first years of life are a dynamic time in gut colonization and brain development, but little is known about the relationship between these two processes.
METHODS: We tested whether microbial composition at 1 year of age is associated with cognitive outcomes using the Mullen Scales of Early Learning and with global and regional brain volumes using structural magnetic resonance imaging at 1 and 2 years of age. Fecal samples were collected from 89 typically developing 1-year-olds. 16S ribosomal RNA amplicon sequencing was used for identification and relative quantification of bacterial taxa.
RESULTS: Cluster analysis identified 3 groups of infants defined by their bacterial composition. Mullen scores at 2 years of age differed significantly between clusters. In addition, higher alpha diversity was associated with lower scores on the overall composite score, visual reception scale, and expressive language scale at 2 years of age. Exploratory analyses of neuroimaging data suggest the gut microbiome has minimal effects on regional brain volumes at 1 and 2 years of age.
CONCLUSIONS: This is the first study to demonstrate associations between the gut microbiota and cognition in human infants. As such, it represents an essential first step in translating animal data into the clinic.

PMID: 28793975 [PubMed - as supplied by publisher]




Corticotropin-Releasing Factor Receptor 1 Antagonism Is Ineffective for Women With Posttraumatic Stress Disorder.
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Corticotropin-Releasing Factor Receptor 1 Antagonism Is Ineffective for Women With Posttraumatic Stress Disorder.

Biol Psychiatry. 2017 Jul 04;:

Authors: Dunlop BW, Binder EB, Iosifescu D, Mathew SJ, Neylan TC, Pape JC, Carrillo-Roa T, Green C, Kinkead B, Grigoriadis D, Rothbaum BO, Nemeroff CB, Mayberg HS

Abstract
BACKGROUND: Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD.
METHODS: We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor 1 (CRF1 receptor) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the 6-week treatment period.
RESULTS: In both the intent-to-treat and completer samples, GSK561679 failed to show superiority over placebo on the primary outcome of change in Clinician-Administered PTSD Scale total score. Adverse event frequencies did not significantly differ between GSK561679- and placebo-treated subjects. Exploration of the CRF1 receptor single nucleotide polymorphism rs110402 found that response to GSK561679 and placebo did not significantly differ by genotype alone. However, subjects who had experienced a moderate or severe history of childhood abuse and who were also GG homozygotes for rs110402 showed significant improvement after treatment with GSK561679 (n = 6) but not with placebo (n = 7) on the PTSD Symptom Scale-Self-Report.
CONCLUSIONS: The results of this trial, the first evaluating a CRF1 receptor antagonist for the treatment of PTSD, combined with other negative trials of CRF1 receptor antagonists for major depressive disorder, generalized anxiety disorder, and social anxiety disorder, suggest that CRF1 receptor antagonists lack efficacy as monotherapy agents for these conditions.

PMID: 28793974 [PubMed - as supplied by publisher]




Autoimmunity, Autoantibodies, and Autism Spectrum Disorder.
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Autoimmunity, Autoantibodies, and Autism Spectrum Disorder.

Biol Psychiatry. 2017 Mar 01;81(5):383-390

Authors: Edmiston E, Ashwood P, Van de Water J

Abstract
Auism spectrum disorder (ASD) now affects one in 68 births in the United States and is the fastest growing neurodevelopmental disability worldwide. Alarmingly, for the majority of cases, the causes of ASD are largely unknown, but it is becoming increasingly accepted that ASD is no longer defined simply as a behavioral disorder, but rather as a highly complex and heterogeneous biological disorder. Although research has focused on the identification of genetic abnormalities, emerging studies increasingly suggest that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in ASD. This review summarizes the investigations implicating autoimmunity and autoantibodies in ASD.

PMID: 28340985 [PubMed - indexed for MEDLINE]




Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.
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Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

Biol Psychiatry. 2017 May 01;81(9):778-788

Authors: Charbogne P, Gardon O, Martín-García E, Keyworth HL, Matsui A, Mechling AE, Bienert T, Nasseef T, Robé A, Moquin L, Darcq E, Ben Hamida S, Robledo P, Matifas A, Befort K, Gavériaux-Ruff C, Harsan LA, von Elverfeldt D, Hennig J, Gratton A, Kitchen I, Bailey A, Alvarez VA, Maldonado R, Kieffer BL

Abstract
BACKGROUND: Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward.
METHODS: We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food.
RESULTS: Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures.
CONCLUSIONS: Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.

PMID: 28185645 [PubMed - indexed for MEDLINE]




Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates.
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Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates.

Biol Psychiatry. 2017 Mar 01;81(5):391-401

Authors: Careaga M, Murai T, Bauman MD

Abstract
A subset of women who are exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental or neuropsychiatric disorder. Although epidemiology studies have primarily focused on the association between maternal infection and an increased risk of offspring schizophrenia, mounting evidence indicates that maternal infection may also increase the risk of autism spectrum disorder. A number of factors, including genetic susceptibility, the intensity and timing of the infection, and exposure to additional aversive postnatal events, may influence the extent to which maternal infection alters fetal brain development and which disease phenotype (autism spectrum disorder, schizophrenia, other neurodevelopmental disorders) is expressed. Preclinical animal models provide a test bed to systematically evaluate the effects of maternal infection on fetal brain development, determine the relevance to human central nervous system disorders, and to evaluate novel preventive and therapeutic strategies. Maternal immune activation models in mice, rats, and nonhuman primates suggest that the maternal immune response is the critical link between exposure to infection during pregnancy and subsequent changes in brain and behavioral development of offspring. However, differences in the type, severity, and timing of prenatal immune challenge paired with inconsistencies in behavioral phenotyping approaches have hindered the translation of preclinical results to human studies. Here we highlight the promises and limitations of the maternal immune activation model as a preclinical tool to study prenatal risk factors for autism spectrum disorder, and suggest specific changes to improve reproducibility and maximize translational potential.

PMID: 28137374 [PubMed - indexed for MEDLINE]




A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Nucleus Accumbens Neuron Subtypes in Cocaine Action.
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A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Nucleus Accumbens Neuron Subtypes in Cocaine Action.

Biol Psychiatry. 2017 Apr 01;81(7):564-572

Authors: Chandra R, Engeln M, Francis TC, Konkalmatt P, Patel D, Lobo MK

Abstract
BACKGROUND: Molecules critically involved in cocaine behavioral plasticity are known to regulate and interact with peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). In addition, the PGC-1α promoter has binding sites for early growth response 3 (Egr3), which plays a dynamic role in cocaine action in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor D1 (D1-MSN) versus D2 (D2-MSN). However, the role of PGC-1α in NAc in cocaine action is unknown.
METHODS: PGC-1α messenger RNA and protein were examined in NAc after repeated cocaine exposure. Binding of Egr3 to and histone methylation at the PGC-1α promoter was examined in NAc using chromatin immunoprecipitation after repeated cocaine. PGC-1α ribosome-associated messenger RNA in MSN subtypes was assessed after repeated cocaine using D1-Cre-RiboTag and D2-Cre-RiboTag lines. Finally, PGC-1α was expressed in NAc D1-MSNs versus D2-MSNs using a Cre-inducible adeno-associated virus and Cre lines during cocaine conditioned place preference and cocaine-induced locomotion.
RESULTS: Repeated cocaine increased PGC-1α levels and increased Egr3 binding and H3K4me3 at the PGC-1α promoter in NAc. Increased PGC-1α occurred in D1-MSNs, while D2-MSNs showed reduced levels. Viral-mediated expression of PGC-1α in D1-MSNs enhanced behavioral responses to cocaine, while expression in D2-MSNs blunted these behaviors.
CONCLUSIONS: We demonstrate a novel role for PGC-1α in NAc in cocaine action. PGC-1α is enhanced in NAc D1-MSNs, specifically after cocaine exposure. These data are consistent with increased active methylation and Egr3 binding at the PGC-1α promoter. Finally, we demonstrate a bidirectional role for PGC-1α in mediating behavioral plasticity to cocaine through D1-MSNs versus D2-MSNs.

PMID: 27939396 [PubMed - indexed for MEDLINE]




Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating.
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Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating.

Biol Psychiatry. 2017 May 01;81(9):757-769

Authors: Kirkpatrick SL, Goldberg LR, Yazdani N, Babbs RK, Wu J, Reed ER, Jenkins DF, Bolgioni AF, Landaverde KI, Luttik KP, Mitchell KS, Kumar V, Johnson WE, Mulligan MK, Cottone P, Bryant CD

Abstract
BACKGROUND: Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions.
METHODS: We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2 cross to identify quantitative trait loci associated with binge eating. We used gene targeting to validate candidate genetic factors. Finally, we used transcriptome analysis of the striatum via messenger RNA sequencing to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment.
RESULTS: C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant quantitative trait locus on chromosome 11 (logarithm of the odds = 7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms morphine addiction and retrograde endocannabinoid signaling, whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression.
CONCLUSIONS: We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.

PMID: 27914629 [PubMed - indexed for MEDLINE]




The Eating-Disorder Associated HDAC4(A778T) Mutation Alters Feeding Behaviors in Female Mice.
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The Eating-Disorder Associated HDAC4(A778T) Mutation Alters Feeding Behaviors in Female Mice.

Biol Psychiatry. 2017 May 01;81(9):770-777

Authors: Lutter M, Khan MZ, Satio K, Davis KC, Kidder IJ, McDaniel L, Darbro BW, Pieper AA, Cui H

Abstract
BACKGROUND: While eating disorders (EDs) are thought to result from a combination of environmental and psychological stressors superimposed on genetic vulnerability, the neurobiological basis of EDs remains incompletely understood. We recently reported that a rare missense mutation in the gene for the transcriptional repressor histone deacetylase 4 (HDAC4) is associated with the risk of developing an ED in humans.
METHODS: To understand the biological consequences of this missense mutation, we created transgenic mice carrying this mutation by introducing the alanine to threonine mutation at position 778 of mouse Hdac4 (corresponding to position 786 of the human protein). Bioinformatic analysis to identify Hdac4-regulated genes was performed using available databases.
RESULTS: Male mice heterozygous for HDAC4(A778T) did not show any metabolic or behavioral differences. In contrast, female mice heterozygous for HDAC4(A778T) display several ED-related feeding and behavioral deficits depending on housing condition. Individually housed HDAC4(A778T) female mice exhibit reduced effortful responding for high-fat diet and compulsive grooming, whereas group-housed female mice display increased weight gain on high-fat diet, reduced behavioral despair, and increased anxiety-like behaviors. Bioinformatic analysis identifies mitochondrial biogenesis including synthesis of glutamate/gamma-aminobutyric acid as a potential transcriptional target of HDAC4(A778T) activity relevant to the behavioral deficits identified in this new mouse model of disordered eating.
CONCLUSIONS: The HDAC4(A778T) mouse line is a novel model of ED-related behaviors and identifies mitochondrial biogenesis as a potential molecular pathway contributing to behavioral deficits.

PMID: 27884425 [PubMed - indexed for MEDLINE]




Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder.
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Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder.

Biol Psychiatry. 2017 Mar 01;81(5):402-410

Authors: McCarthy MM, Wright CL

Abstract
The male bias in autism spectrum disorder incidence is among the most extreme of all neuropsychiatric disorders, yet the origins of the sex difference remain obscure. Developmentally, males are exposed to high levels of testosterone and its byproduct, estradiol. Together these steroids modify the course of brain development by altering neurogenesis, cell death, migration, differentiation, dendritic and axonal growth, synaptogenesis, and synaptic pruning, all of which can be deleteriously impacted during the course of developmental neuropsychiatric disorders. Elucidating the cellular mechanisms by which steroids modulate brain development provides valuable insights into how these processes may go awry. An emerging theme is the role of inflammatory signaling molecules and the innate immune system in directing brain masculinization, the evidence for which we review here. Evidence is also emerging that the neuroimmune system is overactivated in individuals with autism spectrum disorder. These combined observations lead us to propose that the natural process of brain masculinization puts males at risk by moving them closer to a vulnerability threshold that could more easily be breached by inflammation during critical periods of brain development. Two brain regions are highlighted: the preoptic area and the cerebellum. Both are developmentally regulated by the inflammatory prostaglandin E2, but in different ways. Microglia, innate immune cells of the brain, and astrocytes are also critical contributors to masculinization and illustrate the importance of nonneuronal cells to the health of the developing brain.

PMID: 27871670 [PubMed - indexed for MEDLINE]




Induction and Blockade of Adolescent Cocaine-Induced Habits.
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Induction and Blockade of Adolescent Cocaine-Induced Habits.

Biol Psychiatry. 2017 Apr 01;81(7):595-605

Authors: DePoy LM, Zimmermann KS, Marvar PJ, Gourley SL

Abstract
BACKGROUND: Cocaine use during adolescence increases vulnerability to drug dependence and decreases the likelihood that individuals will seek treatment as adults. Understanding how early-life cocaine exposure influences decision-making processes in adulthood is thus critically important.
METHODS: Adolescent or adult mice were exposed to subchronic cocaine, then behavioral sensitivity to changes in the predictive relationship between actions and their consequences was tested. Dendritic spines on the principal pyramidal neurons of the orbitofrontal prefrontal cortex (oPFC) were also imaged and enumerated. To determine whether cytoskeletal regulatory systems in the oPFC influenced decision-making strategies, we then inhibited the activity of Abl family and Rho kinases as well as NR2B-containing N-methyl-D-aspartate receptors. We also attempted to block the reinstatement of cocaine seeking in cocaine self-administering mice.
RESULTS: Adult mice with a history of subchronic cocaine exposure in adolescence engaged habit-based response strategies at the expense of goal-directed decision-making strategies and had fewer dendritic spines in the oPFC. Inhibition of the cytoskeletal regulatory Abl family kinases in the oPFC recapitulated these neurobehavioral deficiencies, whereas Rho kinase inhibition corrected response strategies. Additionally, the NR2B-selective N-methyl-D-aspartate receptor antagonists ifenprodil and CP-101,606 blocked cocaine-induced habits; this was dependent on Abl family signaling in the oPFC. Ifenprodil also mitigated cue-induced reinstatement of cocaine seeking in mice self-administering cocaine.
CONCLUSIONS: We suggest that adolescent cocaine exposure confers a bias toward habit-based behavior in adulthood via long-term cellular structural modifications in the oPFC. Treatments aimed at mitigating the durable consequences of early-life cocaine use may benefit from targeting cytoskeletal regulatory systems.

PMID: 27871669 [PubMed - indexed for MEDLINE]




CYP2A6 Genetic Variation Alters Striatal-Cingulate Circuits, Network Hubs, and Executive Processing in Smokers.
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CYP2A6 Genetic Variation Alters Striatal-Cingulate Circuits, Network Hubs, and Executive Processing in Smokers.

Biol Psychiatry. 2017 Apr 01;81(7):554-563

Authors: Li S, Yang Y, Hoffmann E, Tyndale RF, Stein EA

Abstract
BACKGROUND: Variation in the CYP2A6 gene alters the rate of nicotine metabolic inactivation and is associated with smoking behaviors and cessation success rates. The underlying neurobiological mechanisms of this genetic influence are unknown.
METHODS: Intrinsic functional connectivity strength, a whole-brain, data-driven, graph theory-based method, was applied to resting-state functional magnetic resonance imaging data in 66 smokers and 92 nonsmokers. A subset of subjects (n = 23/20; smokers/nonsmokers) performed the monetary incentive delay task, probing reward anticipation, and a go/no-go task, probing response inhibition, on two occasions, in the presence and absence of a nicotine patch.
RESULTS: A significant CYP2A6 genotype × smoking effect was found in the dorsal anterior cingulate cortex and ventral striatum, such that the normal (vs. slow) genotype individuals showed greater functional connectivity strength among smokers but not nonsmokers. Functional connectivity strength was negatively associated with severity of nicotine dependence in slow metabolizers. Both hubs were biased by inputs from the insula identified from seed-based connectivity. Similar gene × environment interactions were seen in ventral striatum during smoking abstinence when subjects performed the monetary incentive delay task and in dorsal anterior cingulate cortex when they performed the go/no-go task; both reductions were "normalized" in smokers (and increased in nonsmokers) after acute nicotine administration.
CONCLUSIONS: Because the CYP2A6 effect was seen only in smokers, these data suggest that the rate of nicotine metabolism-and thus the concentration of nicotine presented to the brain over the course of nicotine addiction-shapes brain circuits that, among other functions, compute reward and impulsivity processes.

PMID: 27865452 [PubMed - indexed for MEDLINE]




Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target.
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Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target.

Biol Psychiatry. 2017 Apr 01;81(7):585-594

Authors: Egervari G, Landry J, Callens J, Fullard JF, Roussos P, Keller E, Hurd YL

Abstract
BACKGROUND: Opiate abuse and overdose reached epidemic levels in the United States. However, despite significant advances in animal and in vitro models, little knowledge has been directly accrued regarding the neurobiology of the opiate-addicted human brain.
METHODS: We used postmortem human brain specimens from a homogeneous European Caucasian population of heroin users for transcriptional and epigenetic profiling, as well as direct assessment of chromatin accessibility in the striatum, a brain region central to reward and emotion. A rat heroin self-administration model was used to obtain translational molecular and behavioral insights.
RESULTS: Our transcriptome approach revealed marked impairments related to glutamatergic neurotransmission and chromatin remodeling in the human striatum. A series of biochemical experiments tracked the specific location of the epigenetic disturbances to hyperacetylation of lysine 27 of histone H3, showing dynamic correlations with heroin use history and acute opiate toxicology. Targeted investigation of GRIA1, a glutamatergic gene implicated in drug-seeking behavior, verified the increased enrichment of lysine-27 acetylated histone H3 at discrete loci, accompanied by enhanced chromatin accessibility at hyperacetylated regions in the gene body. Analogous epigenetic impairments were detected in the striatum of heroin self-administering rats. Using this translational model, we showed that bromodomain inhibitor JQ1, which blocks the functional readout of acetylated lysines, reduced heroin self-administration and cue-induced drug-seeking behavior.
CONCLUSIONS: Overall, our data suggest that heroin-related histone H3 hyperacetylation contributes to glutamatergic transcriptional changes that underlie addiction behavior and identify JQ1 as a promising candidate for targeted clinical interventions in heroin use disorder.

PMID: 27863698 [PubMed - indexed for MEDLINE]




The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism.
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The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism.

Biol Psychiatry. 2017 Mar 01;81(5):424-433

Authors: Eagleson KL, Xie Z, Levitt P

Abstract
People with autism spectrum disorder and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy-the influence of one gene on distinct phenotypes-raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multifunctional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with autism spectrum disorder, reduces transcription and disrupts socially relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways and has a complex protein interactome that is enriched in autism spectrum disorder and other NDD candidates. The interactome is coregulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, affecting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms.

PMID: 27837921 [PubMed - indexed for MEDLINE]




Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking.
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Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking.

Biol Psychiatry. 2017 Apr 01;81(7):616-624

Authors: Spencer S, Garcia-Keller C, Roberts-Wolfe D, Heinsbroek JA, Mulvaney M, Sorrell A, Kalivas PW

Abstract
BACKGROUND: Relapse is a two-component process consisting of a highly motivated drug-seeking phase that, if successful, is followed by a drug-using phase resulting in temporary satiation. In rodents, cue-induced drug seeking requires transient synaptic potentiation (t-SP) of cortical glutamatergic synapses on nucleus accumbens core medium spiny neurons, but it is unknown how achieving drug use affects this plasticity. We modeled the two phases of relapse after extinction from cocaine self-administration to assess how cocaine use affects t-SP associated with cue-induced drug seeking.
METHODS: Rats were trained to self-administer cocaine (n = 96) or were used as yoked-saline control animals (n = 21). After extinction, reinstatement was initiated by 10 minutes of cue-induced drug seeking, followed by 45 minutes with contingent cocaine access, after which cocaine was discontinued and unreinforced lever pressing ensued. Three measures of t-SP were assayed during reinstatement: dendritic spine morphology, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to N-methyl-D-aspartate (NMDA) ratios, and matrix metalloproteinase activity.
RESULTS: We found that cocaine use for 10 minutes collapsed all three measures of cue-potentiated t-SP back to baseline. Moreover, when cocaine use was discontinued 45 minutes later, dendritic spine morphology and AMPA to NMDA ratios were restored as animals became motivated to engage unrewarded lever pressing. Nonreinforced drug seeking was positively correlated with changes in spine morphology, and cocaine access reversed this relationship.
CONCLUSIONS: Using a novel modification of the reinstatement paradigm, we show that achieving cocaine use reversed the synaptic plasticity underpinning the motivation to seek the drug.

PMID: 27837917 [PubMed - indexed for MEDLINE]




New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy.
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New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy.

Biol Psychiatry. 2017 Jan 01;81(1):78-85

Authors: Urs NM, Peterson SM, Caron MG

Abstract
The dopamine D2 receptor (D2R) is a G protein-coupled receptor that is a common target for antipsychotic drugs. Antagonism of D2R signaling in the striatum is thought to be the primary mode of action of antipsychotic drugs in alleviating psychotic symptoms. However, antipsychotic drugs are not clinically effective at reversing cortical-related symptoms, such as cognitive deficits in schizophrenia. While the exact mechanistic underpinnings of these cognitive deficits are largely unknown, deficits in cortical dopamine function likely play a contributing role. It is now recognized that similar to most G protein-coupled receptors, D2Rs signal not only through canonical G protein pathways but also through noncanonical beta-arrestin2-dependent pathways. We review the current mechanistic bases for this dual signaling mode of D2Rs and how these new concepts might be leveraged for therapeutic gain to target both cortical and striatal dysfunction in dopamine neurotransmission and hence have the potential to correct both positive and cognitive symptoms of schizophrenia.

PMID: 27832841 [PubMed - indexed for MEDLINE]




Prefrontal Structure Varies as a Function of Pain Symptoms in Chronic Fatigue Syndrome.
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Prefrontal Structure Varies as a Function of Pain Symptoms in Chronic Fatigue Syndrome.

Biol Psychiatry. 2017 Feb 15;81(4):358-365

Authors: van der Schaaf ME, De Lange FP, Schmits IC, Geurts DE, Roelofs K, van der Meer JW, Toni I, Knoop H

Abstract
BACKGROUND: Chronic fatigue syndrome (CFS) is characterized by severe fatigue persisting for ≥6 months and leading to considerable impairment in daily functioning. Neuroimaging studies of patients with CFS have revealed alterations in prefrontal brain morphology. However, it remains to be determined whether these alterations are specific for fatigue or whether they relate to other common CFS symptoms (e.g., chronic pain, lower psychomotor speed, and reduced physical activity).
METHODS: We used magnetic resonance imaging to quantify gray matter volume (GMV) and the N-acetylaspartate and N-acetylaspartylglutamate/creatine ratio (NAA/Cr) in a group of 89 women with CFS. Building on previous reports, we tested whether GMV and NAA/Cr in the dorsolateral prefrontal cortex are associated with fatigue severity, pain, psychomotor speed, and physical activity, while controlling for depressive symptoms. We also considered GMV and NAA/Cr differences between patients with CFS and 26 sex-, age-, and education-matched healthy controls.
RESULTS: The presence of pain symptoms was the main predictor of both GMV and NAA/Cr in the left dorsolateral prefrontal cortex of patients with CFS. More pain was associated with reduced GMVs and NAA/Cr, over and above the effects of fatigue, depressive symptoms, physical activity, and psychomotor speed. In contrast to previous reports and despite a large representative sample, global GMV did not differ between the CFS and healthy control groups.
CONCLUSIONS: CFS, as diagnosed by Centers for Disease Control and Prevention criteria, is not a clinical entity reliably associated with reduced GMV. Individual variation in the presence of pain, rather than fatigue, is associated with neuronal alterations in the dorsolateral prefrontal cortex of patients with CFS.

PMID: 27817843 [PubMed - indexed for MEDLINE]




It's All in the Brain: A Review of Available Functional Genomic Annotations.
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It's All in the Brain: A Review of Available Functional Genomic Annotations.

Biol Psychiatry. 2017 Mar 15;81(6):478-483

Authors: Gagliano SA

Abstract
What makes the molecular study of psychiatric and other neurological conditions particularly challenging compared with other complex traits is the difficulty of accessing the relevant tissue. The Encyclopedia of DNA Elements (ENCODE) project was one of the earliest producers of brain-derived epigenetic functional genomic data, albeit initially from only two cancerous brain cell lines for a limited number of epigenetic marks. It has only been in very recent years that such data from human brain tissue have been made available from various sources. Yet, these data are scattered throughout the literature with no central organization. This review summarizes the availability and accessibility of brain epigenetic and functional genomic data as a single resource to allow investigators to easily access available brain annotations and thus incorporate this wealth of information into their research to make important advances in the field of neuroscience.

PMID: 27788914 [PubMed - indexed for MEDLINE]




Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder.
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Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder.

Biol Psychiatry. 2017 Mar 01;81(5):411-423

Authors: Vuong HE, Hsiao EY

Abstract
Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder that affects one in 45 children in the United States, with a similarly striking prevalence in countries around the world. However, mechanisms underlying its etiology and manifestations remain poorly understood. Although ASD is diagnosed based on the presence and severity of impaired social communication and repetitive behavior, immune dysregulation and gastrointestinal issues are common comorbidities. The microbiome is an integral part of human physiology; recent studies show that changes in the gut microbiota can modulate gastrointestinal physiology, immune function, and even behavior. Links between particular bacteria from the indigenous gut microbiota and phenotypes relevant to ASD raise the important question of whether microbial dysbiosis plays a role in the development or presentation of ASD symptoms. Here we review reports of microbial dysbiosis in ASD. We further discuss potential effects of the microbiota on ASD-associated symptoms, drawing on signaling mechanisms for reciprocal interactions among the microbiota, immunity, gut function, and behavior. In addition, we discuss recent findings supporting a role for the microbiome as an interface between environmental and genetic risk factors that are associated with ASD. These studies highlight the integration of pathways across multiple body systems that together can impact brain and behavior and suggest that changes in the microbiome may contribute to symptoms of neurodevelopmental disease.

PMID: 27773355 [PubMed - indexed for MEDLINE]




DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218.
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DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218.

Biol Psychiatry. 2017 Feb 15;81(4):306-315

Authors: Torres-Berrío A, Lopez JP, Bagot RC, Nouel D, Dal Bo G, Cuesta S, Zhu L, Manitt C, Eng C, Cooper HM, Storch KF, Turecki G, Nestler EJ, Flores C

Abstract
BACKGROUD: Variations in the expression of the Netrin-1 guidance cue receptor DCC (deleted in colorectal cancer) appear to confer resilience or susceptibility to psychopathologies involving prefrontal cortex (PFC) dysfunction.
METHODS: With the use of postmortem brain tissue, mouse models of defeat stress, and in vitro analysis, we assessed microRNA (miRNA) regulation of DCC and whether changes in DCC levels in the PFC lead to vulnerability to depression-like behaviors.
RESULTS: We identified miR-218 as a posttranscriptional repressor of DCC and detected coexpression of DCC and miR-218 in pyramidal neurons of human and mouse PFC. We found that exaggerated expression of DCC and reduced levels of miR-218 in the PFC are consistent traits of mice susceptible to chronic stress and of major depressive disorder in humans. Remarkably, upregulation of Dcc in mouse PFC pyramidal neurons causes vulnerability to stress-induced social avoidance and anhedonia.
CONCLUSIONS: These data are the first demonstration of microRNA regulation of DCC and suggest that, by regulating DCC, miR-218 may be a switch of susceptibility versus resilience to stress-related disorders.

PMID: 27773352 [PubMed - indexed for MEDLINE]




Genome-wide DNA Methylation Changes in a Mouse Model of Infection-Mediated Neurodevelopmental Disorders.
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Genome-wide DNA Methylation Changes in a Mouse Model of Infection-Mediated Neurodevelopmental Disorders.

Biol Psychiatry. 2017 Feb 01;81(3):265-276

Authors: Richetto J, Massart R, Weber-Stadlbauer U, Szyf M, Riva MA, Meyer U

Abstract
BACKGROUND: Prenatal exposure to infectious or inflammatory insults increases the risk of neurodevelopmental disorders. Using a well-established mouse model of prenatal viral-like immune activation, we examined whether this pathological association involves genome-wide DNA methylation differences at single nucleotide resolution.
METHODS: Prenatal immune activation was induced by maternal treatment with the viral mimetic polyriboinosinic-polyribocytidylic acid in middle or late gestation. Following behavioral and cognitive characterization of the adult offspring (n = 12 per group), unbiased capture array bisulfite sequencing was combined with subsequent matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and quantitative real-time polymerase chain reaction analyses to quantify DNA methylation changes and transcriptional abnormalities in the medial prefrontal cortex of immune-challenged and control offspring. Gene ontology term enrichment analysis was used to explore shared functional pathways of genes with differential DNA methylation.
RESULTS: Adult offspring of immune-challenged mothers displayed hyper- and hypomethylated CpGs at numerous loci and at distinct genomic regions, including genes relevant for gamma-aminobutyric acidergic differentiation and signaling (e.g., Dlx1, Lhx5, Lhx8), Wnt signaling (Wnt3, Wnt8a, Wnt7b), and neural development (e.g., Efnb3, Mid1, Nlgn1, Nrxn2). Altered DNA methylation was associated with transcriptional changes of the corresponding genes. The epigenetic and transcriptional effects were dependent on the offspring's age and were markedly influenced by the precise timing of prenatal immune activation.
CONCLUSIONS: Prenatal viral-like immune activation is capable of inducing stable DNA methylation changes in the medial prefrontal cortex. These long-term epigenetic modifications are a plausible mechanism underlying the disruption of prefrontal gene transcription and behavioral functions in subjects with prenatal infectious histories.

PMID: 27769567 [PubMed - indexed for MEDLINE]




An Examination of Polygenic Score Risk Prediction in Individuals With First-Episode Psychosis.
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An Examination of Polygenic Score Risk Prediction in Individuals With First-Episode Psychosis.

Biol Psychiatry. 2017 Mar 15;81(6):470-477

Authors: Vassos E, Di Forti M, Coleman J, Iyegbe C, Prata D, Euesden J, O'Reilly P, Curtis C, Kolliakou A, Patel H, Newhouse S, Traylor M, Ajnakina O, Mondelli V, Marques TR, Gardner-Sood P, Aitchison KJ, Powell J, Atakan Z, Greenwood KE, Smith S, Ismail K, Pariante C, Gaughran F, Dazzan P, Markus HS, David AS, Lewis CM, Murray RM, Breen G

Abstract
BACKGROUND: Polygenic risk scores (PRSs) have successfully summarized genome-wide effects of genetic variants in schizophrenia with significant predictive power. In a clinical sample of first-episode psychosis (FEP) patients, we estimated the ability of PRSs to discriminate case-control status and to predict the development of schizophrenia as opposed to other psychoses.
METHODS: The sample (445 case and 265 control subjects) was genotyped on the Illumina HumanCore Exome BeadChip with an additional 828 control subjects of African ancestry genotyped on the Illumina Multi-Ethnic Genotyping Array. To calculate PRSs, we used the results from the latest Psychiatric Genomics Consortium schizophrenia meta-analysis. We examined the association of PRSs with case-control status and with schizophrenia versus other psychoses in European and African ancestry FEP patients and in a second sample of 248 case subjects with chronic psychosis.
RESULTS: PRS had good discriminative ability of case-control status in FEP European ancestry individuals (9.4% of the variance explained, p < 10(-6)), but lower in individuals of African ancestry (R(2) = 1.1%, p = .004). Furthermore, PRS distinguished European ancestry case subjects who went on to acquire a schizophrenia diagnosis from those who developed other psychotic disorders (R(2) = 9.2%, p = .002).
CONCLUSIONS: PRS was a powerful predictor of case-control status in a European sample of patients with FEP, even though a large proportion did not have an established diagnosis of schizophrenia at the time of assessment. PRS was significantly different between those case subjects who developed schizophrenia from those who did not, although the discriminative accuracy may not yet be sufficient for clinical utility in FEP.

PMID: 27765268 [PubMed - indexed for MEDLINE]




CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.
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CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.

Biol Psychiatry. 2017 Apr 01;81(7):625-634

Authors: Saravia R, Flores Á, Plaza-Zabala A, Busquets-Garcia A, Pastor A, de la Torre R, Di Marzo V, Marsicano G, Ozaita A, Maldonado R, Berrendero F

Abstract
BACKGROUND: Tobacco withdrawal is associated with deficits in cognitive function, including attention, working memory, and episodic memory. Understanding the neurobiological mechanisms involved in these effects is crucial because cognitive deficits during nicotine withdrawal may predict relapse in humans.
METHODS: We investigated in mice the role of CB1 cannabinoid receptors (CB1Rs) in memory impairment and spine density changes induced by nicotine withdrawal precipitated by the nicotinic antagonist mecamylamine. Drugs acting on the endocannabinoid system and genetically modified mice were used.
RESULTS: Memory impairment during nicotine withdrawal was blocked by the CB1R antagonist rimonabant or the genetic deletion of CB1R in forebrain gamma-aminobutyric acidergic (GABAergic) neurons (GABA-CB1R). An increase of 2-arachidonoylglycerol (2-AG), but not anandamide, was observed during nicotine withdrawal. The selective inhibitor of 2-AG biosynthesis O7460 abolished cognitive deficits of nicotine abstinence, whereas the inhibitor of 2-AG enzymatic degradation JZL184 did not produce any effect in cognitive impairment. Moreover, memory impairment was prevented by the selective mammalian target of rapamycin inhibitor temsirolimus and the protein synthesis inhibitor anisomycin. Mature dendritic spines on CA1 pyramidal hippocampal neurons decreased 4 days after the precipitation of nicotine withdrawal, when the cognitive deficits were still present. Indeed, a correlation between memory performance and mature spine density was found. Interestingly, these structural plasticity alterations were normalized in GABA-CB1R conditional knockout mice and after subchronic treatment with rimonabant.
CONCLUSIONS: These findings underline the interest of CB1R as a target to improve cognitive performance during early nicotine withdrawal. Cognitive deficits in early abstinence are associated with increased relapse risk.

PMID: 27737762 [PubMed - indexed for MEDLINE]




Insights About Striatal Circuit Function and Schizophrenia From a Mouse Model of Dopamine D2 Receptor Upregulation.
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Insights About Striatal Circuit Function and Schizophrenia From a Mouse Model of Dopamine D2 Receptor Upregulation.

Biol Psychiatry. 2017 Jan 01;81(1):21-30

Authors: Simpson EH, Kellendonk C

Abstract
The dopamine hypothesis of schizophrenia is supported by a large number of imaging studies that have identified an increase in dopamine binding at the D2 receptor selectively in the striatum. We review a decade of work using a regionally restricted and temporally regulated transgenic mouse model to investigate the behavioral, molecular, electrophysiological, and anatomical consequences of selective D2 receptor upregulation in the striatum. These studies have identified new and potentially important biomarkers at the circuit and molecular level that can now be explored in patients with schizophrenia. They provide an example of how animal models and their detailed level of neurobiological analysis allow a deepening of our understanding of the relationship between neuronal circuit function and symptoms of schizophrenia, and as a consequence generate new hypotheses that are testable in patients.

PMID: 27720388 [PubMed - indexed for MEDLINE]




Connectome Disconnectivity and Cortical Gene Expression in Patients With Schizophrenia.
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Connectome Disconnectivity and Cortical Gene Expression in Patients With Schizophrenia.

Biol Psychiatry. 2017 Mar 15;81(6):495-502

Authors: Romme IA, de Reus MA, Ophoff RA, Kahn RS, van den Heuvel MP

Abstract
BACKGROUND: Genome-wide association studies have identified several common risk loci for schizophrenia (SCZ). In parallel, neuroimaging studies have shown consistent findings of widespread white matter disconnectivity in patients with SCZ.
METHODS: We examined the role of genes in brain connectivity in patients with SCZ by combining transcriptional profiles of 43 SCZ risk genes identified by the recent genome-wide association study of the Schizophrenia Working Group of the Psychiatric Genomics Consortium with data on macroscale connectivity reductions in patients with SCZ. Expression profiles of 43 Psychiatric Genomics Consortium SCZ risk genes were extracted from the Allen Human Brain Atlas, and their average profile across the cortex was correlated to the pattern of cortical disconnectivity as derived from diffusion-weighted magnetic resonance imaging data of patients with SCZ (n = 48) and matched healthy controls (n = 43).
RESULTS: The expression profile of SCZ risk genes across cortical regions was significantly correlated with the regional macroscale disconnectivity (r = .588; p = .017). In addition, effects were found to be potentially specific to SCZ, with transcriptional profiles not related to cortical disconnectivity in patients with bipolar I disorder (diffusion-weighted magnetic resonance imaging data; 216 patients, 144 controls). Further examination of correlations across all 20,737 genes present in the Allen Human Brain Atlas showed the set of top 100 strongest correlating genes to display significant enrichment for the disorder, potentially identifying new genes involved in the pathophysiology of SCZ.
CONCLUSIONS: Our results suggest that under disease conditions, cortical areas with pronounced expression of risk genes implicated in SCZ form central areas for white matter disconnectivity.

PMID: 27720199 [PubMed - indexed for MEDLINE]




The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.
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The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.

Biol Psychiatry. 2017 Jan 01;81(1):9-20

Authors: Howes OD, McCutcheon R, Owen MJ, Murray RM

Abstract
The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients.

PMID: 27720198 [PubMed - indexed for MEDLINE]




Parsing Heterogeneity in the Brain Connectivity of Depressed and Healthy Adults During Positive Mood.
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Parsing Heterogeneity in the Brain Connectivity of Depressed and Healthy Adults During Positive Mood.

Biol Psychiatry. 2017 Feb 15;81(4):347-357

Authors: Price RB, Lane S, Gates K, Kraynak TE, Horner MS, Thase ME, Siegle GJ

Abstract
BACKGROUND: There is well-known heterogeneity in affective mechanisms in depression that may extend to positive affect. We used data-driven parsing of neural connectivity to reveal subgroups present across depressed and healthy individuals during positive processing, informing targets for mechanistic intervention.
METHODS: Ninety-two individuals (68 depressed patients, 24 never-depressed control subjects) completed a sustained positive mood induction during functional magnetic resonance imaging. Directed functional connectivity paths within a depression-relevant network were characterized using Group Iterative Multiple Model Estimation (GIMME), a method shown to accurately recover the direction and presence of connectivity paths in individual participants. During model selection, individuals were clustered using community detection on neural connectivity estimates. Subgroups were externally tested across multiple levels of analysis.
RESULTS: Two connectivity-based subgroups emerged: subgroup A, characterized by weaker connectivity overall, and subgroup B, exhibiting hyperconnectivity (relative to subgroup A), particularly among ventral affective regions. Subgroup predicted diagnostic status (subgroup B contained 81% of patients; 50% of control subjects; χ(2) = 8.6, p = .003) and default mode network connectivity during a separate resting-state task. Among patients, subgroup B members had higher self-reported symptoms, lower sustained positive mood during the induction, and higher negative bias on a reaction-time task. Symptom-based depression subgroups did not predict these external variables.
CONCLUSIONS: Neural connectivity-based categorization travels with diagnostic category and is clinically predictive, but not clinically deterministic. Both patients and control subjects showed heterogeneous, and overlapping, profiles. The larger and more severely affected patient subgroup was characterized by ventrally driven hyperconnectivity during positive processing. Data-driven parsing suggests heterogeneous substrates of depression and possible resilience in control subjects in spite of biological overlap.

PMID: 27712830 [PubMed - indexed for MEDLINE]




Epigenetic Aging and Immune Senescence in Women With Insomnia Symptoms: Findings From the Women's Health Initiative Study.
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Epigenetic Aging and Immune Senescence in Women With Insomnia Symptoms: Findings From the Women's Health Initiative Study.

Biol Psychiatry. 2017 Jan 15;81(2):136-144

Authors: Carroll JE, Irwin MR, Levine M, Seeman TE, Absher D, Assimes T, Horvath S

Abstract
BACKGROUND: Insomnia symptoms are associated with vulnerability to age-related morbidity and mortality. Cross-sectional data suggest that accelerated biological aging may be a mechanism through which sleep influences risk. A novel method for determining age acceleration using epigenetic methylation to DNA has demonstrated predictive utility as an epigenetic clock and prognostic of age-related morbidity and mortality.
METHODS: We examined the association of epigenetic age and immune cell aging with sleep in the Women's Health Initiative study (N = 2078; mean 64.5 ± 7.1 years of age) with assessment of insomnia symptoms (restlessness, difficulty falling asleep, waking at night, trouble getting back to sleep, and early awakenings), sleep duration (short sleep 5 hours or less; long sleep greater than 8 hours), epigenetic age, naive T cell (CD8+CD45RA+CCR7+), and late differentiated T cells (CD8+CD28-CD45RA-).
RESULTS: Insomnia symptoms were related to advanced epigenetic age (β ± SE = 1.02 ± 0.37, p = .005) after adjustments for covariates. Insomnia symptoms were also associated with more late differentiated T cells (β ± SE = 0.59 ± 0.21, p = .006), but not with naive T cells. Self-reported short and long sleep duration were unrelated to epigenetic age. Short sleep, but not long sleep, was associated with fewer naive T cells (p < .005) and neither was related to late differentiated T cells.
CONCLUSIONS: Symptoms of insomnia were associated with increased epigenetic age of blood tissue and were associated with higher counts of late differentiated CD8+ T cells. Short sleep was unrelated to epigenetic age and late differentiated cell counts, but was related to a decline in naive T cells. In this large population-based study of women in the United States, insomnia symptoms are implicated in accelerated aging.

PMID: 27702440 [PubMed - indexed for MEDLINE]




Heterogeneity in Dopamine Neuron Synaptic Actions Across the Striatum and Its Relevance for Schizophrenia.
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Heterogeneity in Dopamine Neuron Synaptic Actions Across the Striatum and Its Relevance for Schizophrenia.

Biol Psychiatry. 2017 Jan 01;81(1):43-51

Authors: Chuhma N, Mingote S, Kalmbach A, Yetnikoff L, Rayport S

Abstract
Brain imaging has revealed alterations in dopamine uptake, release, and receptor levels in patients with schizophrenia that have been resolved on the scale of striatal subregions. However, the underlying synaptic mechanisms are on a finer scale. Dopamine neuron synaptic actions vary across the striatum, involving variations not only in dopamine release but also in dopamine neuron connectivity, cotransmission, modulation, and activity. Optogenetic studies have revealed that dopamine neurons release dopamine in a synaptic signal mode, and that the neurons also release glutamate and gamma-aminobutyric acid as cotransmitters, with striking regional variation. Fast glutamate and gamma-aminobutyric acid cotransmission convey discrete patterns of dopamine neuron activity to striatal neurons. Glutamate may function not only in a signaling role at a subset of dopamine neuron synapses, but also in mediating vesicular synergy, contributing to regional differences in loading of dopamine into synaptic vesicles. Regional differences in dopamine neuron signaling are likely to be differentially involved in the schizophrenia disease process and likely determine the subregional specificity of the action of psychostimulants that exacerbate the disorder, and antipsychotics that ameliorate the disorder. Elucidating dopamine neuron synaptic signaling offers the potential for achieving greater pharmacological specificity through intersectional pharmacological actions targeting subsets of dopamine neuron synapses.

PMID: 27692238 [PubMed - indexed for MEDLINE]




Data-Driven Phenotypic Categorization for Neurobiological Analyses: Beyond DSM-5 Labels.
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Data-Driven Phenotypic Categorization for Neurobiological Analyses: Beyond DSM-5 Labels.

Biol Psychiatry. 2017 Mar 15;81(6):484-494

Authors: Van Dam NT, O'Connor D, Marcelle ET, Ho EJ, Cameron Craddock R, Tobe RH, Gabbay V, Hudziak JJ, Xavier Castellanos F, Leventhal BL, Milham MP

Abstract
BACKGROUND: Data-driven approaches can capture behavioral and biological variation currently unaccounted for by contemporary diagnostic categories, thereby enhancing the ability of neurobiological studies to characterize brain-behavior relationships.
METHODS: A community-ascertained sample of individuals (N = 347, 18-59 years of age) completed a battery of behavioral measures, psychiatric assessment, and resting-state functional magnetic resonance imaging in a cross-sectional design. Bootstrap-based exploratory factor analysis was applied to 49 phenotypic subscales from 10 measures. Hybrid hierarchical clustering was applied to resultant factor scores to identify nested groups. Adjacent groups were compared via independent samples t tests and chi-square tests of factor scores, syndrome scores, and psychiatric prevalence. Multivariate distance matrix regression examined functional connectome differences between adjacent groups.
RESULTS: Reduction yielded six factors, which explained 77.8% and 65.4% of the variance in exploratory and constrained exploratory models, respectively. Hybrid hierarchical clustering of these six factors identified two, four, and eight nested groups (i.e., phenotypic communities). At the highest clustering level, the algorithm differentiated functionally adaptive and maladaptive groups. At the middle clustering level, groups were separated by problem type (maladaptive groups; internalizing vs. externalizing problems) and behavioral type (adaptive groups; sensation-seeking vs. extraverted/emotionally stable). Unique phenotypic profiles were also evident at the lowest clustering level. Group comparisons exhibited significant differences in intrinsic functional connectivity at the highest clustering level in somatomotor, thalamic, basal ganglia, and limbic networks.
CONCLUSIONS: Data-driven approaches for identifying homogenous subgroups, spanning typical function to dysfunction, not only yielded clinically meaningful groups, but also captured behavioral and neurobiological variation among healthy individuals.

PMID: 27667698 [PubMed - indexed for MEDLINE]




Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia.
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Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia.

Biol Psychiatry. 2017 Mar 15;81(6):514-524

Authors: Kort NS, Ford JM, Roach BJ, Gunduz-Bruce H, Krystal JH, Jaeger J, Reinhart RM, Mathalon DH

Abstract
BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia.
METHODS: In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared.
RESULTS: N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen's d = 1.14) and schizophrenia (Cohen's d = .85).
CONCLUSIONS: Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.

PMID: 27647218 [PubMed - indexed for MEDLINE]




Impaired Communication Between the Motor and Somatosensory Homunculus Is Associated With Poor Manual Dexterity in Autism Spectrum Disorder.
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Impaired Communication Between the Motor and Somatosensory Homunculus Is Associated With Poor Manual Dexterity in Autism Spectrum Disorder.

Biol Psychiatry. 2017 Feb 01;81(3):211-219

Authors: Thompson A, Murphy D, Dell'Acqua F, Ecker C, McAlonan G, Howells H, Baron-Cohen S, Lai MC, Lombardo MV, MRC AIMS Consortium, and Marco Catani

Abstract
BACKGROUND: Fine motor skill impairments are common in autism spectrum disorder (ASD), significantly affecting quality of life. Sensory inputs reaching the primary motor cortex (M1) from the somatosensory cortex (S1) are likely involved in fine motor skill and specifically motor learning. However, the role of these connections has not been directly investigated in humans. This study aimed to investigate, for the first time, the role of the S1-M1 connections in healthy subjects in vivo and whether microstructural alterations are associated with motor impairment in ASD.
METHODS: Sixty right-handed neurotypical adult men aged 18 to 45 years, and 60 right-handed age- and sex-matched subjects diagnosed with ASD underwent fine motor skill assessment and scanning with diffusion tensor imaging (DTI). The streamlines of the hand region connecting S1-M1 of the motor-sensory homunculus were virtually dissected using TrackVis, and diffusion properties were extracted. The face/tongue region connections were used as control tracts.
RESULTS: The ASD group displayed lower motor performances and altered DTI measurements of the hand-region connection. Behavioral performance correlated with hand-region DTI measures in both groups, but not with the face/tongue connections, indicating anatomical specificity. There was a left-hemisphere association of motor ability in the control group and an atypical rightward shift in the ASD group.
CONCLUSIONS: These findings suggest that direct interaction between S1 and M1 may contribute to the human ability to precisely interact with and manipulate the environment. Because electrophysiological evidence indicates that these connections may underpin long-term potentiation in M1, our findings may lead to novel therapeutic treatments for motor skill disorders.

PMID: 27639500 [PubMed - indexed for MEDLINE]




Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies.
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Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies.

Biol Psychiatry. 2017 Feb 01;81(3):179-192

Authors: Papale A, d'Isa R, Menna E, Cerovic M, Solari N, Hardingham N, Cambiaghi M, Cursi M, Barbacid M, Leocani L, Fasano S, Matteoli M, Brambilla R

Abstract
BACKGROUND: Dysregulation of Ras-extracellular signal-related kinase (ERK) signaling gives rise to RASopathies, a class of neurodevelopmental syndromes associated with intellectual disability. Recently, much attention has been directed at models bearing mild forms of RASopathies whose behavioral impairments can be attenuated by inhibiting the Ras-ERK cascade in the adult. Little is known about the brain mechanisms in severe forms of these disorders.
METHODS: We performed an extensive characterization of a new brain-specific model of severe forms of RASopathies, the KRAS(12V) mutant mouse.
RESULTS: The KRAS(12V) mutation results in a severe form of intellectual disability, which parallels mental deficits found in patients bearing mutations in this gene. KRAS(12V) mice show a severe impairment of both short- and long-term memory in a number of behavioral tasks. At the cellular level, an upregulation of ERK signaling during early phases of postnatal development, but not in the adult state, results in a selective enhancement of synaptogenesis in gamma-aminobutyric acidergic interneurons. The enhancement of ERK activity in interneurons at this critical postnatal time leads to a permanent increase in the inhibitory tone throughout the brain, manifesting in reduced synaptic transmission and long-term plasticity in the hippocampus. In the adult, the behavioral and electrophysiological phenotypes in KRAS(12V) mice can be temporarily reverted by inhibiting gamma-aminobutyric acid signaling but not by a Ras-ERK blockade. Importantly, the synaptogenesis phenotype can be rescued by a treatment at the developmental stage with Ras-ERK inhibitors.
CONCLUSIONS: These data demonstrate a novel mechanism underlying inhibitory synaptogenesis and provide new insights in understanding mental dysfunctions associated to RASopathies.

PMID: 27587266 [PubMed - indexed for MEDLINE]




CRTC1 Function During Memory Encoding Is Disrupted in Neurodegeneration.
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CRTC1 Function During Memory Encoding Is Disrupted in Neurodegeneration.

Biol Psychiatry. 2017 Jan 15;81(2):111-123

Authors: Parra-Damas A, Chen M, Enriquez-Barreto L, Ortega L, Acosta S, Perna JC, Fullana MN, Aguilera J, Rodríguez-Alvarez J, Saura CA

Abstract
BACKGROUND: Associative memory impairment is an early clinical feature of dementia patients, but the molecular and cellular mechanisms underlying these deficits are largely unknown. In this study, we investigated the functional regulation of the cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) by associative learning in physiological and neurodegenerative conditions.
METHODS: We evaluated the activation of CRTC1 in the hippocampus of control mice and mice lacking the Alzheimer's disease-linked presenilin genes (presenilin conditional double knockout [PS cDKO]) after one-trial contextual fear conditioning by using biochemical, immunohistochemical, and gene expression analyses. PS cDKO mice display classical features of neurodegeneration occurring in Alzheimer's disease including age-dependent cortical atrophy, neuron loss, dendritic degeneration, and memory deficits.
RESULTS: Context-associative learning, but not single context or unconditioned stimuli, induces rapid dephosphorylation (Ser151) and translocation of CRTC1 from the cytosol/dendrites to the nucleus of hippocampal neurons in the mouse brain. Accordingly, context-associative learning induces differential CRTC1-dependent transcription of c-fos and the nuclear receptor subfamily 4 (Nr4a) genes Nr4a1-3 in the hippocampus through a mechanism that involves CRTC1 recruitment to CRE promoters. Deregulation of CRTC1 dephosphorylation, nuclear translocation, and transcriptional function are associated with long-term contextual memory deficits in PS cDKO mice. Importantly, CRTC1 gene therapy in the hippocampus ameliorates context memory and transcriptional deficits and dendritic degeneration despite ongoing cortical degeneration in this neurodegeneration mouse model.
CONCLUSIONS: These findings reveal a critical role of CRTC1 in the hippocampus during associative memory, and provide evidence that CRTC1 deregulation underlies memory deficits during neurodegeneration.

PMID: 27587263 [PubMed - indexed for MEDLINE]




Using Clinical Characteristics to Identify Which Patients With Major Depressive Disorder Have a Higher Genetic Load for Three Psychiatric Disorders.
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Using Clinical Characteristics to Identify Which Patients With Major Depressive Disorder Have a Higher Genetic Load for Three Psychiatric Disorders.

Biol Psychiatry. 2017 Feb 15;81(4):316-324

Authors: Verduijn J, Milaneschi Y, Peyrot WJ, Hottenga JJ, Abdellaoui A, de Geus EJ, Smit JH, Breen G, Lewis CM, Boomsma DI, Beekman AT, Penninx BW

Abstract
BACKGROUND: Limited successes of gene finding for major depressive disorder (MDD) may be partly due to phenotypic heterogeneity. We tested whether the genetic load for MDD, bipolar disorder, and schizophrenia (SCZ) is increased in phenotypically more homogenous MDD patients identified by specific clinical characteristics.
METHODS: Patients (n = 1539) with a DSM-IV MDD diagnosis and control subjects (n = 1792) were from two large cohort studies (Netherlands Study of Depression and Anxiety and Netherlands Twin Register). Genomic profile risk scores (GPRSs) for MDD, bipolar disorder, and SCZ were based on meta-analysis results of the Psychiatric Genomics Consortium. Regression analyses (adjusted for year of birth, sex, three principal components) examined the association between GPRSs with characteristics and GPRSs with MDD subgroups stratified according to the most relevant characteristics. The proportion of liability variance explained by GPRSs for each MDD subgroup was estimated.
RESULTS: GPRS-MDD explained 1.0% (p = 4.19e(-09)) of MDD variance, and 1.5% (p = 4.23e(-09)) for MDD endorsing nine DSM symptoms. GPRS-bipolar disorder explained 0.6% (p = 2.97e(-05)) of MDD variance and 1.1% (p = 1.30e(-05)) for MDD with age at onset <18 years. GPRS-SCZ explained 2.0% (p = 6.15e(-16)) of MDD variance, 2.6% (p = 2.88e(-10)) for MDD with higher symptom severity, and 2.3% (p = 2.26e(-13)) for MDD endorsing nine DSM symptoms. An independent sample replicated the same pattern of stronger associations between cases with more DSM symptoms, as compared to overall MDD, and GPRS-SCZ.
CONCLUSIONS: MDD patients with early age at onset and higher symptom severity have an increased genetic risk for three major psychiatric disorders, suggesting that it is useful to create phenotypically more homogenous groups when searching for genes associated with MDD.

PMID: 27576130 [PubMed - indexed for MEDLINE]




Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles.
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Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles.

Biol Psychiatry. 2017 Feb 15;81(4):285-295

Authors: Bagot RC, Cates HM, Purushothaman I, Vialou V, Heller EA, Yieh L, LaBonté B, Peña CJ, Shen L, Wittenberg GM, Nestler EJ

Abstract
BACKGROUND: Examining transcriptional regulation by antidepressants in key neural circuits implicated in depression and understanding the relation to transcriptional mechanisms of susceptibility and natural resilience may help in the search for new therapeutic agents. Given the heterogeneity of treatment response in human populations, examining both treatment response and nonresponse is critical.
METHODS: We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine, and a rapidly acting, non-monoamine-based antidepressant, ketamine, in mice subjected to chronic social defeat stress, a validated depression model, and used RNA sequencing to analyze transcriptional profiles associated with susceptibility, resilience, and antidepressant response and nonresponse in the prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala.
RESULTS: We identified similar numbers of responders and nonresponders after ketamine or imipramine treatment. Ketamine induced more expression changes in the hippocampus; imipramine induced more expression changes in the nucleus accumbens and amygdala. Transcriptional profiles in treatment responders were most similar in the PFC. Nonresponse reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptibility-associated transcriptional changes and induced resilience-associated transcription in the PFC.
CONCLUSIONS: We generated a uniquely large resource of gene expression data in four interconnected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by antidepressant drugs and in both reversing susceptibility- and inducing resilience-associated molecular adaptations. In addition, we found region-specific effects of each drug, suggesting both common and unique effects of imipramine versus ketamine.

PMID: 27569543 [PubMed - indexed for MEDLINE]




Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene.
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Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene.

Biol Psychiatry. 2017 Feb 01;81(3):193-202

Authors: Schoch H, Kreibich AS, Ferri SL, White RS, Bohorquez D, Banerjee A, Port RG, Dow HC, Cordero L, Pallathra AA, Kim H, Li H, Bilker WB, Hirano S, Schultz RT, Borgmann-Winter K, Hahn CG, Feldmeyer D, Carlson GC, Abel T, Brodkin ES

Abstract
BACKGROUND: Behavioral symptoms in individuals with autism spectrum disorder (ASD) have been attributed to abnormal neuronal connectivity, but the molecular bases of these behavioral and brain phenotypes are largely unknown. Human genetic studies have implicated PCDH10, a member of the δ2 subfamily of nonclustered protocadherin genes, in ASD. PCDH10 expression is enriched in the basolateral amygdala, a brain region implicated in the social deficits of ASD. Previous reports indicate that Pcdh10 plays a role in axon outgrowth and glutamatergic synapse elimination, but its roles in social behaviors and amygdala neuronal connectivity are unknown. We hypothesized that haploinsufficiency of Pcdh10 would reduce social approach behavior and alter the structure and function of amygdala circuits.
METHODS: Mice lacking one copy of Pcdh10 (Pcdh10(+/-)) and wild-type littermates were assessed for social approach and other behaviors. The lateral/basolateral amygdala was assessed for dendritic spine number and morphology, and amygdala circuit function was studied using voltage-sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was assessed in postsynaptic density fractions of the amygdala.
RESULTS: Male Pcdh10(+/-) mice have reduced social approach behavior, as well as impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in the amygdala. Social approach deficits in Pcdh10(+/-) male mice were rescued with acute treatment with the NMDAR partial agonist d-cycloserine.
CONCLUSIONS: Our studies reveal that male Pcdh10(+/-) mice have synaptic and behavioral deficits, and establish Pcdh10(+/-) mice as a novel genetic model for investigating neural circuitry and behavioral changes relevant to ASD.

PMID: 27567313 [PubMed - indexed for MEDLINE]




Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats.
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Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats.

Biol Psychiatry. 2017 Apr 01;81(7):606-615

Authors: Schmeichel BE, Herman MA, Roberto M, Koob GF

Abstract
BACKGROUND: Cocaine addiction is characterized by patterns of compulsive drug-taking, including preoccupation with obtaining cocaine and loss of control over drug intake. The lateral hypothalamic hypocretin/orexin (HCRT) system has been implicated in drug-taking and the reinstatement of drug-seeking. Evidence suggests that HCRT may drive drug-seeking through activation of specific brain regions implicated in stress system dysfunction, including the central amygdala (CeA). The role of HCRT in the persistence of compulsive-like cocaine-taking has yet to be fully elucidated.
METHODS: Systemic and intra-CeA microinfusions of the HCRT-receptor 1 antagonist, SB-334867, were administered to rats allowed either short (1 hour; ShA) or long (6 hours; LgA) access to cocaine self-administration. Animals were tested for fixed and progressive ratio responding for cocaine and stress-induced reinstatement of drug-seeking. In addition, using electrophysiological techniques on in vitro slices, we investigated gamma-aminobutyric acidergic (GABAergic) neurotransmission in the medial CeA and the sensitivity of GABAergic synapses to modulation of the HCRT system in ShA or LgA rats.
RESULTS: We found systemic administration of SB-334867 (0, 7.5, 15, 30 mg/kg) dose dependently decreased cocaine intake specifically in LgA rats but not in ShA rats. Microinjections of SB-334867 (20 nmol) bilaterally into the CeA significantly reduced cocaine intake in LgA rats. We also observed a significant attenuation of yohimbine-induced reinstatement of cocaine-seeking after intra-CeA SB-334867 (10 nmol) administration. Finally, electrophysiological data indicated enhanced GABAergic neurotransmission within the medial CeA in LgA rats, which was blocked with SB-334867 (10 μmol/L).
CONCLUSIONS: These findings suggest that HCRT neurotransmission within the CeA is implicated in compulsive-like cocaine-seeking.

PMID: 27567312 [PubMed - indexed for MEDLINE]




Activity-Regulated Cytoskeleton-Associated Protein Accumulates in the Nucleus in Response to Cocaine and Acts as a Brake on Chromatin Remodeling and Long-Term Behavioral Alterations.
Related Articles Activity-Regulated Cytoskeleton-Associated Protein Accumulates in the Nucleus in Response to Cocaine and Acts as a Brake on Chromatin Remodeling and Long-Term Behavioral Alterations. Biol Psychiatry. 2017 Apr 01;81(7):573-584 Authors: Salery M, Dos Santos M, Saint-Jour E, Moumné L, Pagès C, Kappès V, Parnaudeau S, Caboche J, Vanhoutte P Abstract BACKGROUND: Addiction relies on persistent alterations of neuronal properties, which depends on gene regulation. Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates neuronal plasticity underlying learning and memory. Its role in cocaine-induced neuronal and behavioral adaptations remains elusive. METHODS: Acute cocaine-treated mice were used for quantitative reverse-transcriptase polymerase chain reaction, immunocytochemistry, and confocal imaging from striatum. Live imaging and transfection assays for Arc overexpression were performed from primary cultures. Molecular and behavioral adaptations to cocaine were studied from Arc-deficient mice and their wild-type littermates. RESULTS: Arc messenger RNA and proteins are rapidly induced in the striatum after acute cocaine administration, via an extracellular-signal regulated kinase-dependent de novo protein synthesis. Although detected in dendrites, Arc accumulates in the nucleus in active zones of transcription, where it colocalizes with phospho-Ser10-histone H3, an important component of nucleosomal response. In vitro, Arc overexpression downregulates phospho-Ser10-histone H3 without modifying extracellular-signal regulated kinase phosphorylation in the nucleus. In vivo, Arc-deficient mice display decreased heterochromatin domains, a high RNA-polymerase II activity and enhanced c-Fos expression. These mice presented an exacerbated psychomotor sensitization and conditioned place preference induced by low doses of cocaine. CONCLUSIONS: Cocaine induces the rapid induction of Arc and its nuclear accumulation in striatal neurons. Locally, it alters the nucleosomal response, and acts as a brake on chromatin remodeling and gene regulation. These original observations posit Arc as a major homeostatic modulator of molecular and behavioral responses to cocaine. Thus, modulating Arc levels may provide promising therapeutic approaches in drug addiction. PMID: 27567310 [PubMed - indexed for MEDLINE] [...]



Translating the Habenula-From Rodents to Humans.
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Translating the Habenula-From Rodents to Humans.

Biol Psychiatry. 2017 Feb 15;81(4):296-305

Authors: Boulos LJ, Darcq E, Kieffer BL

Abstract
The habenula (Hb) is a central structure connecting forebrain to midbrain regions. This microstructure regulates monoaminergic systems, notably dopamine and serotonin, and integrates cognitive with emotional and sensory processing. Early preclinical data have described Hb as a brain nucleus activated in anticipation of aversive outcomes. Evidence has now accumulated to show that the Hb encodes both rewarding and aversive aspects of external stimuli, thus driving motivated behaviors and decision making. Human Hb research is still nascent but develops rapidly, alongside with the growth of neuroimaging and deep brain stimulation techniques. Not surprisingly, Hb dysfunction has been associated with psychiatric disorders, and studies in patients have established evidence for Hb involvement in major depression, addiction, and schizophrenia, as well as in pain and analgesia. Here, we summarize current knowledge from animal research and overview the existing human literature on anatomy and function of the Hb. We also discuss challenges and future directions in targeting this small brain structure in both rodents and humans. By combining animal data and human experimental studies, this review addresses the translational potential of preclinical Hb research.

PMID: 27527822 [PubMed - indexed for MEDLINE]




Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.
Related Articles Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Biol Psychiatry. 2017 Feb 15;81(4):325-335 Authors: Power RA, Tansey KE, Buttenschøn HN, Cohen-Woods S, Bigdeli T, Hall LS, Kutalik Z, Lee SH, Ripke S, Steinberg S, Teumer A, Viktorin A, Wray NR, Arolt V, Baune BT, Boomsma DI, Børglum AD, Byrne EM, Castelao E, Craddock N, Craig IW, Dannlowski U, Deary IJ, Degenhardt F, Forstner AJ, Gordon SD, Grabe HJ, Grove J, Hamilton SP, Hayward C, Heath AC, Hocking LJ, Homuth G, Hottenga JJ, Kloiber S, Krogh J, Landén M, Lang M, Levinson DF, Lichtenstein P, Lucae S, MacIntyre DJ, Madden P, Magnusson PK, Martin NG, McIntosh AM, Middeldorp CM, Milaneschi Y, Montgomery GW, Mors O, Müller-Myhsok B, Nyholt DR, Oskarsson H, Owen MJ, Padmanabhan S, Penninx BW, Pergadia ML, Porteous DJ, Potash JB, Preisig M, Rivera M, Shi J, Shyn SI, Sigurdsson E, Smit JH, Smith BH, Stefansson H, Stefansson K, Strohmaier J, Sullivan PF, Thomson P, Thorgeirsson TE, Van der Auwera S, Weissman MM, CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium, Breen G, Lewis CM Abstract BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap wi[...]



Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice.
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Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice.

Biol Psychiatry. 2017 May 01;81(9):737-747

Authors: Xu P, He Y, Cao X, Valencia-Torres L, Yan X, Saito K, Wang C, Yang Y, Hinton A, Zhu L, Shu G, Myers MG, Wu Q, Tong Q, Heisler LK, Xu Y

Abstract
BACKGROUND: Neural networks that regulate binge eating remain to be identified, and effective treatments for binge eating are limited.
METHODS: We combined neuroanatomic, pharmacologic, electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of 5-hydroxytryptamine (5-HT) 2C receptor (5-HT2CR) expressed by dopamine (DA) neurons in the regulation of binge-like eating behavior in mice.
RESULTS: We showed that 5-HT stimulates DA neural activity through a 5-HT2CR-mediated mechanism, and activation of this midbrain 5-HT→DA neural circuit effectively inhibits binge-like eating behavior in mice. Notably, 5-HT medications, including fluoxetine, d-fenfluramine, and lorcaserin (a selective 5-HT2CR agonist), act on 5-HT2CRs expressed by DA neurons to inhibit binge-like eating in mice.
CONCLUSIONS: We identified the 5-HT2CR population in DA neurons as one potential target for antibinge therapies, and provided preclinical evidence that 5-HT2CR agonists could be used to treat binge eating.

PMID: 27516377 [PubMed - indexed for MEDLINE]




12/15-Lipoxygenase Inhibition Reverses Cognitive Impairment, Brain Amyloidosis, and Tau Pathology by Stimulating Autophagy in Aged Triple Transgenic Mice.
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12/15-Lipoxygenase Inhibition Reverses Cognitive Impairment, Brain Amyloidosis, and Tau Pathology by Stimulating Autophagy in Aged Triple Transgenic Mice.

Biol Psychiatry. 2017 Jan 15;81(2):92-100

Authors: Di Meco A, Li JG, Blass BE, Abou-Gharbia M, Lauretti E, Praticò D

Abstract
BACKGROUND: The 12/15-lipoxygenase (12/15-LO) enzyme is upregulated in the brains of patients with Alzheimer's disease (AD), and its expression levels influence the onset of the AD-like phenotype in mouse models. However, whether targeting this pathway after the neuropathology and behavioral impairments have been established remains to be investigated.
METHODS: Triple transgenic (3xTg) mice received either PD146176-a selective and specific pharmacological inhibitor of 12/15-LO-or placebo starting at 12 months of age for 12 weeks. They were then assessed for the effect of the treatment on neuropathologies and behavioral impairments.
RESULTS: At the end of the study, mice in the control group showed a worsening of memory and learning abilities, whereas mice receiving PD146176 were undistinguishable from wild-type mice. The same group also had significantly lower amyloid beta levels and deposition, less tau neuropathology, increased synaptic integrity, and autophagy activation. Ex vivo and in vitro genetic and pharmacological studies found that the mechanism involved in these effects was the activation of neuronal autophagy.
CONCLUSIONS: Our findings provide new insights into the disease-modifying action of 12/15-LO pharmacological inhibition and establish it as a viable therapeutic approach for patients with AD.

PMID: 27499089 [PubMed - indexed for MEDLINE]




An Integrative Perspective on the Role of Dopamine in Schizophrenia.
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An Integrative Perspective on the Role of Dopamine in Schizophrenia.

Biol Psychiatry. 2017 Jan 01;81(1):52-66

Authors: Maia TV, Frank MJ

Abstract
We propose that schizophrenia involves a combination of decreased phasic dopamine responses for relevant stimuli and increased spontaneous phasic dopamine release. Using insights from computational reinforcement-learning models and basic-science studies of the dopamine system, we show that each of these two disturbances contributes to a specific symptom domain and explains a large set of experimental findings associated with that domain. Reduced phasic responses for relevant stimuli help to explain negative symptoms and provide a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with negative symptoms: reduced learning from rewards; blunted activation of the ventral striatum, midbrain, and other limbic regions for rewards and positive prediction errors; blunted activation of the ventral striatum during reward anticipation; blunted autonomic responding for relevant stimuli; blunted neural activation for aversive outcomes and aversive prediction errors; reduced willingness to expend effort for rewards; and psychomotor slowing. Increased spontaneous phasic dopamine release helps to explain positive symptoms and provides a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with positive symptoms: aberrant learning for neutral cues (assessed with behavioral and autonomic responses), and aberrant, increased activation of the ventral striatum, midbrain, and other limbic regions for neutral cues, neutral outcomes, and neutral prediction errors. Taken together, then, these two disturbances explain many findings in schizophrenia. We review evidence supporting their co-occurrence and consider their differential implications for the treatment of positive and negative symptoms.

PMID: 27452791 [PubMed - indexed for MEDLINE]




Hypofrontality and Posterior Hyperactivity in Early Schizophrenia: Imaging and Behavior in a Preclinical Model.
Related Articles Hypofrontality and Posterior Hyperactivity in Early Schizophrenia: Imaging and Behavior in a Preclinical Model. Biol Psychiatry. 2017 Mar 15;81(6):503-513 Authors: Kaneko G, Sanganahalli BG, Groman SM, Wang H, Coman D, Rao J, Herman P, Jiang L, Rich K, de Graaf RA, Taylor JR, Hyder F Abstract BACKGROUND: Schizophrenia is a debilitating neuropsychiatric disorder typically diagnosed from late adolescence to adulthood. Subthreshold behavioral symptoms (e.g., cognitive deficits and substance abuse) often precede the clinical diagnosis of schizophrenia. However, these prodromal symptoms have not been consistently associated with structural and functional brain biomarkers, limiting the chance of early diagnosis of schizophrenia. METHODS: Using an extensively multimodal range of magnetic resonance methods (for anatomy, metabolism, and function), we screened early biomarkers in a methylazoxymethanol acetate (MAM) rat model of schizophrenia and saline-treated control (SHAM) rats, in conjunction with immunohistochemistry, myelin staining, and a novel three-choice, reversal-learning task to identify early behavioral markers corresponding the subthreshold symptoms. RESULTS: MAM (vs. SHAM) rats had lower/higher structural connectivity in anterior/posterior corpus callosum. The orbitofrontal cortex of MAM rats showed lower resting-state functional magnetic resonance imaging functional connectivity in conjunction with lower neuronal density, lower glucose oxidation, and attenuated neurotransmission (hypofrontality). In contrast, these measures were all higher in visual cortex of MAM rats (posterior hyperactivity), which might parallel perceptual problems in schizophrenia. In behavioral studies, MAM (vs. SHAM) rats displayed abnormal orbitofrontal cortex-mediated decision-making processes, resulting in a novel reward-sensitive hyperflexible phenotype, which might reflect vulnerability of prodromal patients to substance abuse. CONCLUSIONS: We identified two novel biomarkers of early schizophrenia in a preclinical rat model: hypofrontality associated with the hyperflexible phenotype, and posterior hyperactivity. Because each of these magnetic resonance methods is clinically translatable, these markers could contribute to early diagnosis and the development of novel therapies of schizophrenia. PMID: 27450031 [PubMed - indexed for MEDLINE] [...]



Bidirectional Modulation of Extinction of Drug Seeking by Deep Brain Stimulation of the Ventral Striatum.
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Bidirectional Modulation of Extinction of Drug Seeking by Deep Brain Stimulation of the Ventral Striatum.

Biol Psychiatry. 2016 Nov 01;80(9):682-690

Authors: Martínez-Rivera FJ, Rodriguez-Romaguera J, Lloret-Torres ME, Do Monte FH, Quirk GJ, Barreto-Estrada JL

Abstract
BACKGROUND: Recent research in humans and rodents has explored the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VS) as a possible treatment for drug addiction. However, the optimum electrode placement and optimum DBS parameters have not been thoroughly studied. Here we varied stimulation sites and frequencies to determine whether DBS of the VS could facilitate the extinction of morphine-induced conditioned place preference in rats.
METHODS: Rats were implanted with DBS electrodes in the dorsal or ventral subregions of the VS and trained to the morphine conditioned place preference. Subsequently, rats received extinction sessions over 9 days, combined with 60 min of either high- (130 Hz) or low- (20 Hz) frequency DBS. To study circuit-wide activations after DBS of the VS, c-fos immunohistochemistry was performed in regions involved in the extinction of drug-seeking behaviors.
RESULTS: High-frequency DBS of the dorsal-VS impaired both extinction training and extinction memory, whereas high-frequency DBS of the ventral-VS had no effect. In contrast, low-frequency DBS of the dorsal-VS strengthened extinction memory when tested 2 or 9 days after the cessation of stimulation. Both DBS frequencies increased c-fos expression in the infralimbic prefrontal cortex, but only low-frequency DBS increased c-fos expression in the basal amygdala and the medial portion of the central amygdala.
CONCLUSIONS: Our results suggest that low-frequency (rather than high-frequency) DBS of the dorsal-VS strengthens extinction memory and may be a potential adjunct for extinction-based therapies for treatment-refractory opioid addiction.

PMID: 27449798 [PubMed - indexed for MEDLINE]




A Combined Pathway and Regional Heritability Analysis Indicates NETRIN1 Pathway Is Associated With Major Depressive Disorder.
Related Articles A Combined Pathway and Regional Heritability Analysis Indicates NETRIN1 Pathway Is Associated With Major Depressive Disorder. Biol Psychiatry. 2017 Feb 15;81(4):336-346 Authors: Zeng Y, Navarro P, Fernandez-Pujals AM, Hall LS, Clarke TK, Thomson PA, Smith BH, Hocking LJ, Padmanabhan S, Hayward C, MacIntyre DJ, Wray NR, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Deary IJ, Porteous DJ, Haley CS, McIntosh AM Abstract BACKGROUND: Genome-wide association studies (GWASs) of major depressive disorder (MDD) have identified few significant associations. Testing the aggregation of genetic variants, in particular biological pathways, may be more powerful. Regional heritability analysis can be used to detect genomic regions that contribute to disease risk. METHODS: We integrated pathway analysis and multilevel regional heritability analyses in a pipeline designed to identify MDD-associated pathways. The pipeline was applied to two independent GWAS samples [Generation Scotland: The Scottish Family Health Study (GS:SFHS, N = 6455) and Psychiatric Genomics Consortium (PGC:MDD) (N = 18,759)]. A polygenic risk score (PRS) composed of single nucleotide polymorphisms from the pathway most consistently associated with MDD was created, and its accuracy to predict MDD, using area under the curve, logistic regression, and linear mixed model analyses, was tested. RESULTS: In GS:SFHS, four pathways were significantly associated with MDD, and two of these explained a significant amount of pathway-level regional heritability. In PGC:MDD, one pathway was significantly associated with MDD. Pathway-level regional heritability was significant in this pathway in one subset of PGC:MDD. For both samples the regional heritabilities were further localized to the gene and subregion levels. The NETRIN1 signaling pathway showed the most consistent association with MDD across the two samples. PRSs from this pathway showed competitive predictive accuracy compared with the whole-genome PRSs when using area under the curve statistics, logistic regression, and linear mixed model. CONCLUSIONS: These post-GWAS analyses highlight the value of combining multiple methods on multiple GWAS data for the identification of risk pathways for MDD. The NETRIN1 signaling pathway is identified as a candidate pathway for MDD and should be explored in further large population studies. PMID: 27422368 [PubMed - indexed for MEDLINE] [...]



BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior.
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BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior.

Biol Psychiatry. 2016 Nov 01;80(9):652-660

Authors: Wang ZJ, Martin JA, Mueller LE, Caccamise A, Werner CT, Neve RL, Gancarz AM, Li JX, Dietz DM

Abstract
BACKGROUND: Drug addiction is defined as a chronic disease characterized by compulsive drug seeking and episodes of relapse despite prolonged periods of drug abstinence. Neurobiological adaptations, including transcriptional and epigenetic alterations in the nucleus accumbens, are thought to contribute to this life-long disease state. We previously demonstrated that the transcription factor SMAD3 is increased after 7 days of withdrawal from cocaine self-administration. However, it is still unknown which additional factors participate in the process of chromatin remodeling and facilitate the binding of SMAD3 to promoter regions of target genes. Here, we examined the possible interaction of BRG1-also known as SMARCA4, an adenosine triphosphatase-containing chromatin remodeler-and SMAD3 in response to cocaine exposure.
METHODS: The expression of BRG1, as well as its binding to SMAD3 and target gene promoter regions, was evaluated in the nucleus accumbens and dorsal striatum of rats using western blotting, co-immunoprecipitation, and chromatin immunoprecipitation following abstinence from cocaine self-administration. Rats were assessed for cocaine-seeking behaviors after either intra-accumbal injections of the BRG1 inhibitor PFI3 or viral-mediated overexpression of BRG1.
RESULTS: After withdrawal from cocaine self-administration, BRG1 expression and complex formation with SMAD3 are increased in the nucleus accumbens, resulting in increased binding of BRG1 to the promoter regions of Ctnnb1, Mef2d, and Dbn1. Intra-accumbal infusion of PFI3 attenuated, whereas viral overexpression of Brg1 enhanced, cocaine-reinstatement behavior.
CONCLUSIONS: BRG1 is a key mediator of the SMAD3-dependent regulation of cellular and behavioral plasticity that mediates cocaine seeking after a period of withdrawal.

PMID: 27422367 [PubMed - indexed for MEDLINE]




Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [(11)C]CURB.
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Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [(11)C]CURB.

Biol Psychiatry. 2016 Nov 01;80(9):691-701

Authors: Boileau I, Mansouri E, Williams B, Le Foll B, Rusjan P, Mizrahi R, Tyndale RF, Huestis MA, Payer DE, Wilson AA, Houle S, Kish SJ, Tong J

Abstract
BACKGROUND: One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown.
METHODS: Brain FAAH binding was measured with positron emission tomography and [(11)C]CURB in 22 healthy control subjects and ten chronic cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine, and hair levels of cannabinoids and metabolites were determined.
RESULTS: In cannabis users, FAAH binding was significantly lower by 14%-20% across the brain regions examined than in matched control subjects (overall Cohen's d = 0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness.
CONCLUSIONS: Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.

PMID: 27345297 [PubMed - indexed for MEDLINE]




7T Proton Magnetic Resonance Spectroscopy of Gamma-Aminobutyric Acid, Glutamate, and Glutamine Reveals Altered Concentrations in Patients With Schizophrenia and Healthy Siblings.
Related Articles 7T Proton Magnetic Resonance Spectroscopy of Gamma-Aminobutyric Acid, Glutamate, and Glutamine Reveals Altered Concentrations in Patients With Schizophrenia and Healthy Siblings. Biol Psychiatry. 2017 Mar 15;81(6):525-535 Authors: Thakkar KN, Rösler L, Wijnen JP, Boer VO, Klomp DW, Cahn W, Kahn RS, Neggers SF Abstract BACKGROUND: The N-methyl-D-aspartate receptor hypofunction model of schizophrenia predicts dysfunction in both glutamatergic and gamma-aminobutyric acidergic (GABAergic) transmission. We addressed this hypothesis by measuring GABA, glutamate, glutamine, and the sum of glutamine plus glutamate concentrations in vivo in patients with schizophrenia using proton magnetic resonance spectroscopy at 7T, which allows separation of metabolites that would otherwise overlap at lower field strengths. In addition, we investigated whether altered levels of GABA, glutamate, glutamine, and the sum of glutamine plus glutamate reflect genetic vulnerability to schizophrenia by including healthy first-degree relatives. METHODS: Proton magnetic resonance spectroscopy at 7T was performed in 21 patients with chronic schizophrenia who were taking medication, 23 healthy first-degree relatives of patients with schizophrenia, and 24 healthy nonrelatives. Glutamate, glutamine, and GABA were measured cortically and subcortically in bilateral basal ganglia and occipital cortex. RESULTS: Patients with schizophrenia had reduced cortical GABA compared with healthy relatives and the combined sample of healthy relatives and healthy nonrelatives, suggesting that altered GABAergic systems in schizophrenia are associated with either disease state or medication effects. Reduced cortical glutamine relative to healthy control subjects was observed in patients with schizophrenia and the combined sample of healthy relatives and patients with schizophrenia, suggesting that altered glutamatergic metabolite levels are associated with illness liability. No group differences were found in the basal ganglia. CONCLUSIONS: Taken together, these findings are consistent with alterations in GABAergic and glutamatergic systems in patients with schizophrenia and provide novel insights into these systems in healthy relatives. PMID: 27316853 [PubMed - indexed for MEDLINE] [...]



AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving.
Related Articles AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving. Biol Psychiatry. 2016 Nov 01;80(9):661-670 Authors: Scheyer AF, Loweth JA, Christian DT, Uejima J, Rabei R, Le T, Dolubizno H, Stefanik MT, Murray CH, Sakas C, Wolf ME Abstract BACKGROUND: The incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (CP-AMPARs). Through metabotropic glutamate receptor 1 (mGluR1)-mediated synaptic depression, mGluR1 positive allosteric modulators remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving. METHODS: Rats self-administered saline or methamphetamine under extended-access conditions. Cue-induced seeking tests demonstrated incubation of methamphetamine craving. After withdrawal periods ranging from 1 to >40 days, rats underwent one of the following procedures: 1) whole-cell patch clamp recordings to characterize AMPAR transmission, 2) intra-NAc core injection of the CP-AMPAR antagonist 1-naphthyl acetyl spermine followed by a seeking test, or 3) systemic administration of a mGluR1 positive allosteric modulator followed by a seeking test. RESULTS: Incubation of methamphetamine craving was associated with CP-AMPAR accumulation in NAc core, and both effects were maximal after ~1 week of withdrawal. Expression of incubated craving was decreased by intra-NAc core 1-naphthyl acetyl spermine injection or systemic mGluR1 positive allosteric modulator administration. CONCLUSIONS: These results are the first to demonstrate a role for the NAc in the incubation of methamphetamine craving and describe adaptations in synaptic transmission associated with this model. They establish that incubation of craving and associated CP-AMPAR plasticity occur much more rapidly during withdrawal from methamphetamine compared with cocaine. However, a common mGluR1-based therapeutic strategy may be helpful for recovering cocaine and methamphetamine addicts. PMID: 27264310 [PubMed - indexed for MEDLINE] [...]



Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms.
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Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms.

Biol Psychiatry. 2017 Mar 15;81(6):536-547

Authors: Pantazopoulos H, Wiseman JT, Markota M, Ehrenfeld L, Berretta S

Abstract
BACKGROUND: Growing evidence points to a key role for somatostatin (SST) in schizophrenia (SZ) and bipolar disorder (BD). In the amygdala, neurons expressing SST play an important role in the regulation of anxiety, which is often comorbid in these disorders. We tested the hypothesis that SST-immunoreactive (IR) neurons are decreased in the amygdala of subjects with SZ and BD. Evidence for circadian SST expression in the amygdala and disrupted circadian rhythms and rhythmic peaks of anxiety in BD suggest a disruption of rhythmic expression of SST in this disorder.
METHODS: Amygdala sections from 12 SZ, 15 BD, and 15 control subjects were processed for immunocytochemistry for SST and neuropeptide Y, a neuropeptide partially coexpressed in SST-IR neurons. Total numbers (Nt) of IR neurons were measured. Time of death was used to test associations with circadian rhythms.
RESULTS: SST-IR neurons were decreased in the lateral amygdala nucleus in BD (Nt, p = .003) and SZ (Nt, p = .02). In normal control subjects, Nt of SST-IR neurons varied according to time of death. This pattern was altered in BD subjects, characterized by decreases of SST-IR neurons selectively in subjects with time of death corresponding to the day (6:00 am to 5:59 pm). Numbers of neuropeptide Y-IR neurons were not affected.
CONCLUSIONS: Decreased SST-IR neurons in the amygdala of patients with SZ and BD, interpreted here as decreased SST expression, may disrupt responses to fear and anxiety regulation in these individuals. In BD, our findings raise the possibility that morning peaks of anxiety depend on a disruption of circadian regulation of SST expression in the amygdala.

PMID: 27259817 [PubMed - indexed for MEDLINE]




Genetically Induced Retrograde Amnesia of Associative Memories After Neuroplastin Ablation.
Related Articles Genetically Induced Retrograde Amnesia of Associative Memories After Neuroplastin Ablation. Biol Psychiatry. 2017 Jan 15;81(2):124-135 Authors: Bhattacharya S, Herrera-Molina R, Sabanov V, Ahmed T, Iscru E, Stöber F, Richter K, Fischer KD, Angenstein F, Goldschmidt J, Beesley PW, Balschun D, Smalla KH, Gundelfinger ED, Montag D Abstract BACKGROUND: Neuroplastin cell recognition molecules have been implicated in synaptic plasticity. Polymorphisms in the regulatory region of the human neuroplastin gene (NPTN) are correlated with cortical thickness and intellectual abilities in adolescents and in individuals with schizophrenia. METHODS: We characterized behavioral and functional changes in inducible conditional neuroplastin-deficient mice. RESULTS: We demonstrate that neuroplastins are required for associative learning in conditioning paradigms, e.g., two-way active avoidance and fear conditioning. Retrograde amnesia of learned associative memories is elicited by inducible neuron-specific ablation of Nptn gene expression in adult mice, which shows that neuroplastins are indispensable for the availability of previously acquired associative memories. Using single-photon emission computed tomography imaging in awake mice, we identified brain structures activated during memory recall. Constitutive neuroplastin deficiency or Nptn gene ablation in adult mice causes substantial electrophysiologic deficits such as reduced long-term potentiation. In addition, neuroplastin-deficient mice reveal profound physiologic and behavioral deficits, some of which are related to depression and schizophrenia, which illustrate neuroplastin's essential functions. CONCLUSIONS: Neuroplastins are essential for learning and memory. Retrograde amnesia after an associative learning task can be induced by ablation of the neuroplastin gene. The inducible neuroplastin-deficient mouse model provides a new and unique means to analyze the molecular and cellular mechanisms underlying retrograde amnesia and memory. PMID: 27215477 [PubMed - indexed for MEDLINE] [...]



Cocaine Experience Enhances Thalamo-Accumbens N-Methyl-D-Aspartate Receptor Function.
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Cocaine Experience Enhances Thalamo-Accumbens N-Methyl-D-Aspartate Receptor Function.

Biol Psychiatry. 2016 Nov 01;80(9):671-681

Authors: Joffe ME, Grueter BA

Abstract
BACKGROUND: Excitatory synaptic transmission in the nucleus accumbens (NAc) is a key biological substrate underlying behavioral responses to psychostimulants and susceptibility to relapse. Studies have demonstrated that cocaine induces changes in glutamatergic signaling at distinct inputs to the NAc. However, consequences of cocaine experience on synaptic transmission from the midline nuclei of the thalamus (mThal) to the NAc have yet to be reported.
METHODS: To examine synapses from specific NAc core inputs, we recorded light-evoked excitatory postsynaptic currents following viral-mediated expression of channelrhodopsin-2 in the mThal, prefrontal cortex (PFC), or basolateral amygdala from acute brain slices. To identify NAc medium spiny neuron subtypes, we used mice expressing tdTomato driven by the promoter for dopamine receptor subtype 1 (D1). We recorded N-methyl-D-aspartate receptor (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) properties to evaluate synaptic adaptations induced by cocaine experience, a 5-day cocaine exposure followed by 2 weeks of abstinence.
RESULTS: Excitatory inputs to the NAc core displayed differential NMDAR properties, and cocaine experience uniquely altered AMPAR and NMDAR properties at mThal-D1(+), mThal-D1(-), and PFC-D1(+) synapses, but not at PFC-D1(-) synapses. Finally, at mThal-D1(+) synapses, cocaine enhanced GluN2C/D function and NMDAR-dependent synaptic plasticity.
CONCLUSIONS: Our results identify contrasting cocaine-induced AMPAR and NMDAR modifications at mThal-NAc and PFC-NAc core synapses. These changes include an enhancement of NMDAR function and plasticity at mThal-D1(+) synapses. Incorporation of GluN2C/D-containing NMDARs most likely underlies these phenomena and represents a potential therapeutic target for psychostimulant use disorders.

PMID: 27209241 [PubMed - indexed for MEDLINE]




Pathway-Specific Dopamine Abnormalities in Schizophrenia.
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Pathway-Specific Dopamine Abnormalities in Schizophrenia.

Biol Psychiatry. 2017 Jan 01;81(1):31-42

Authors: Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A

Abstract
In light of the clinical evidence implicating dopamine in schizophrenia and the prominent hypotheses put forth regarding alterations in dopaminergic transmission in this disease, molecular imaging has been used to examine multiple aspects of the dopaminergic system. We review the imaging methods used and compare the findings across the different molecular targets. Findings have converged to suggest early dysregulation in the striatum, especially in the rostral caudate, manifesting as excess synthesis and release. Recent data showed deficit extending to most cortical regions and even to other extrastriatal subcortical regions not previously considered to be "hypodopaminergic" in schizophrenia. These findings yield a new topography for the dopaminergic dysregulation in schizophrenia. We discuss the dopaminergic innervation within the individual projection fields to provide a topographical map of this dual dysregulation and explore potential cellular and circuit-based mechanisms for brain region-dependent alterations in dopaminergic parameters. This refined knowledge is essential to better guide translational studies and efforts in early drug development.

PMID: 27206569 [PubMed - indexed for MEDLINE]




Higher C-Reactive Protein Levels Predict Postoperative Delirium in Older Patients Undergoing Major Elective Surgery: A Longitudinal Nested Case-Control Study.
Related Articles Higher C-Reactive Protein Levels Predict Postoperative Delirium in Older Patients Undergoing Major Elective Surgery: A Longitudinal Nested Case-Control Study. Biol Psychiatry. 2017 Jan 15;81(2):145-153 Authors: Dillon ST, Vasunilashorn SM, Ngo L, Otu HH, Inouye SK, Jones RN, Alsop DC, Kuchel GA, Metzger ED, Arnold SE, Marcantonio ER, Libermann TA Abstract BACKGROUND: Delirium is a common, morbid, and costly postoperative complication. We aimed to identify blood-based postoperative delirium markers in a nested case-control study of older surgical patients using a proteomics approach followed by enzyme-linked immunosorbent assay (ELISA) validation. METHODS: The Successful Aging after Elective Surgery study enrolled dementia-free adults ≥70 years old undergoing major scheduled noncardiac surgery (N = 566; 24% delirium). Plasma was collected at four time points: preoperative, postanesthesia care unit, postoperative day 2, and 1 month postoperative. Matched pairs were selected for the independent discovery (39 pairs) and replication cohorts (36 pairs), which were subsequently combined into the pooled cohort (75 pairs). Isobaric tags for relative and absolute quantitation-based relative quantitation mass spectrometry proteomics were performed to identify the strongest delirium-related protein, which was selected for ELISA validation. Using the ELISA results, statistical analyses using nonparametric signed rank tests were performed in all cohorts examining the association between the identified protein and delirium. RESULTS: C-reactive protein emerged from the proteomics analysis as the strongest delirium-related protein. Validation by ELISA confirmed that compared with controls, cases had significantly higher C-reactive protein levels in the discovery, replication, and pooled cohorts at the preoperative (median paired difference [MPD] 1.97 mg/L [p < .05], 0.29 mg/L, 1.56 mg/L [p < .01]), postanesthesia care unit (MPD 2.83 mg/L, 2.22 mg/L [p < .05], 2.53 mg/L [p < .01]) and postoperative day 2 (MPD 71.97 mg/L [p < .01], 35.18 mg/L [p < .05], 63.76 mg/L [p < .01]) time points, but not 1 month postoperative (MPD 2.72 mg/L, -0.66 mg/L, 1.10 mg/L). CONCLUSIONS: Elevated preoperative and postoperative plasma levels of C-reactive protein were associated with delirium, suggesting that a preinflammatory state and heightened inflammatory response to surgery are potential pathophysiologic mechanisms of delirium. PMID: 27160518 [PubMed - indexed for MEDLINE] [...]



Multimodal Brain Imaging Reveals Structural Differences in Alzheimer's Disease Polygenic Risk Carriers: A Study in Healthy Young Adults.
Related Articles Multimodal Brain Imaging Reveals Structural Differences in Alzheimer's Disease Polygenic Risk Carriers: A Study in Healthy Young Adults. Biol Psychiatry. 2017 Jan 15;81(2):154-161 Authors: Foley SF, Tansey KE, Caseras X, Lancaster T, Bracht T, Parker G, Hall J, Williams J, Linden DE Abstract BACKGROUND: Recent genome-wide association studies have identified genetic loci that jointly make a considerable contribution to risk of developing Alzheimer's disease (AD). Because neuropathological features of AD can be present several decades before disease onset, we investigated whether effects of polygenic risk are detectable by neuroimaging in young adults. We hypothesized that higher polygenic risk scores (PRSs) for AD would be associated with reduced volume of the hippocampus and other limbic and paralimbic areas. We further hypothesized that AD PRSs would affect the microstructure of fiber tracts connecting the hippocampus with other brain areas. METHODS: We analyzed the association between AD PRSs and brain imaging parameters using T1-weighted structural (n = 272) and diffusion-weighted scans (n = 197). RESULTS: We found a significant association between AD PRSs and left hippocampal volume, with higher risk associated with lower left hippocampal volume (p = .001). This effect remained when the APOE gene was excluded (p = .031), suggesting that the relationship between hippocampal volume and AD is the result of multiple genetic factors and not exclusively variability in the APOE gene. The diffusion tensor imaging analysis revealed that fractional anisotropy of the right cingulum was inversely correlated with AD PRSs (p = .009). We thus show that polygenic effects of AD risk variants on brain structure can already be detected in young adults. CONCLUSIONS: This finding paves the way for further investigation of the effects of AD risk variants and may become useful for efforts to combine genotypic and phenotypic data for risk prediction and to enrich future prevention trials of AD. PMID: 27157680 [PubMed - indexed for MEDLINE] [...]



Fibroblast Growth Factor 2 Modulates Hypothalamic Pituitary Axis Activity and Anxiety Behavior Through Glucocorticoid Receptors.
Related Articles Fibroblast Growth Factor 2 Modulates Hypothalamic Pituitary Axis Activity and Anxiety Behavior Through Glucocorticoid Receptors. Biol Psychiatry. 2016 Sep 15;80(6):479-89 Authors: Salmaso N, Stevens HE, McNeill J, ElSayed M, Ren Q, Maragnoli ME, Schwartz ML, Tomasi S, Sapolsky RM, Duman R, Vaccarino FM Abstract BACKGROUND: Despite strong evidence linking fibroblast growth factor 2 (FGF2) with anxiety and depression in both rodents and humans, the molecular mechanisms linking FGF2 with anxiety are not understood. METHODS: We compare 1) mice that lack a functional Fgf2 gene (Fgf2 knockout [KO]), 2) wild-type mice, and 3) Fgf2 KO with adult rescue by FGF2 administration on measures of anxiety, depression, and motor behavior, and further investigate the mechanisms of this behavior by cellular, molecular, and neuroendocrine studies. RESULTS: We demonstrate that Fgf2 KO mice have increased anxiety, decreased hippocampal glucocorticoid receptor (GR) expression, and increased hypothalamic-pituitary-adrenal axis activity. FGF2 administration in adulthood was sufficient to rescue the entire phenotype. Blockade of GR in adult mice treated with FGF2 precluded the therapeutic effects of FGF2 on anxiety behavior, suggesting that GR is necessary for FGF2 to regulate anxiety behavior. The level of Egr-1/NGFI-A was decreased in Fgf2 KO mice and was reestablished with FGF2 treatment. By chromatin immunoprecipitation studies, we found decreased binding of EGR-1 to the GR promoter region in Fgf2 KO mice. Finally, we examined anxiety behavior in FGF receptor (FGFR) KO mice; however, FGFR1, FGFR2, and FGFR3 KO mice did not mimic the phenotype of Fgf2 KO mice, suggesting a role for other receptor subtypes (i.e., FGFR5). CONCLUSIONS: These data suggest that FGF2 levels are critically related to anxiety behavior and hypothalamic-pituitary-adrenal axis activity, likely through modulation of hippocampal glucocorticoid receptor expression, an effect that is likely receptor mediated, albeit not by FGFR1, FGFR2, and FGFR3. PMID: 27133954 [PubMed - indexed for MEDLINE] [...]



Neurochemical Mediation of Affiliation and Aggression Associated With Pair-Bonding.
Related Articles Neurochemical Mediation of Affiliation and Aggression Associated With Pair-Bonding. Biol Psychiatry. 2017 Feb 01;81(3):231-242 Authors: Gobrogge KL, Jia X, Liu Y, Wang Z Abstract BACKGROUND: The neuropeptides vasopressin and corticotropin-releasing factor facilitate, while serotonin inhibits, aggression. How the brain is wired to coordinate interactions between these functionally opposed neurotransmitters to control behavioral states is poorly understood. METHODS: Pair-bonded male prairie voles (Microtus ochrogaster) were infused with a retrograde tracer, Fluoro-Gold, and tested for affiliation and aggression toward a female partner or novel female subject. Subsequent immunocytochemical experiments examined neuronal activation using Fos and neurochemical/neuroreceptor profiles on brain areas involved in these social behaviors. Finally, a series of behavioral pharmacologic and real-time in vivo brain microdialysis experiments were performed on male prairie voles displaying affiliation or aggression. RESULTS: We localized a subpopulation of excitatory vasopressin neurons in the anterior hypothalamus that may gate corticotropin-releasing factor output from the amygdala to the anterior hypothalamus and then the lateral septum to modulate aggression associated with mate guarding. Conversely, we identified a subset of inhibitory serotonergic projection neurons in the dorsal raphe that project to the anterior hypothalamus and may mediate the spatiotemporal release of neuropeptides and their interactions in modulating aggression and affiliation. CONCLUSIONS: Together, this study establishes the medial extended amygdala as a major neural substrate regulating the switch between positive and negative affective states, wherein several neurochemicals converge and interact to coordinate divergent social behaviors. PMID: 27129413 [PubMed - indexed for MEDLINE] [...]



Practical Guidelines for High-Resolution Epigenomic Profiling of Nucleosomal Histones in Postmortem Human Brain Tissue.
Related Articles Practical Guidelines for High-Resolution Epigenomic Profiling of Nucleosomal Histones in Postmortem Human Brain Tissue. Biol Psychiatry. 2017 Jan 15;81(2):162-170 Authors: Kundakovic M, Jiang Y, Kavanagh DH, Dincer A, Brown L, Pothula V, Zharovsky E, Park R, Jacobov R, Magro I, Kassim B, Wiseman J, Dang K, Sieberts SK, Roussos P, Fromer M, Harris B, Lipska BK, Peters MA, Sklar P, Akbarian S Abstract BACKGROUND: The nervous system may include more than 100 residue-specific posttranslational modifications of histones forming the nucleosome core that are often regulated in cell-type-specific manner. On a genome-wide scale, some of the histone posttranslational modification landscapes show significant overlap with the genetic risk architecture for several psychiatric disorders, fueling PsychENCODE and other large-scale efforts to comprehensively map neuronal and nonneuronal epigenomes in hundreds of specimens. However, practical guidelines for efficient generation of histone chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) datasets from postmortem brains are needed. METHODS: Protocols and quality controls are given for the following: 1) extraction, purification, and NeuN neuronal marker immunotagging of nuclei from adult human cerebral cortex; 2) fluorescence-activated nuclei sorting; 3) preparation of chromatin by micrococcal nuclease digest; 4) ChIP for open chromatin-associated histone methylation and acetylation; and 5) generation and sequencing of ChIP-seq libraries. RESULTS: We present a ChIP-seq pipeline for epigenome mapping in the neuronal and nonneuronal nuclei from the postmortem brain. This includes a stepwise system of quality controls and user-friendly data presentation platforms. CONCLUSIONS: Our practical guidelines will be useful for projects aimed at histone posttranslational modification mapping in chromatin extracted from hundreds of postmortem brain samples in cell-type-specific manner. PMID: 27113501 [PubMed - indexed for MEDLINE] [...]



A Comprehensive Analysis of Cell Type-Specific Nuclear RNA From Neurons and Glia of the Brain.
Related Articles A Comprehensive Analysis of Cell Type-Specific Nuclear RNA From Neurons and Glia of the Brain. Biol Psychiatry. 2017 Feb 01;81(3):252-264 Authors: Reddy AS, O'Brien D, Pisat N, Weichselbaum CT, Sakers K, Lisci M, Dalal JS, Dougherty JD Abstract BACKGROUND: Studies in psychiatric genetics have identified >100 loci associated with disease risk, yet many of these loci are distant from protein coding genes. Recent characterization of the transcriptional landscape of cell lines and whole tissues has suggested widespread transcription in both coding and noncoding regions of the genome, including differential expression from loci that produce regulatory noncoding RNAs that function within the nucleus; however, the nuclear transcriptome of specific cell types in the brain has not been previously investigated. METHODS: We defined the nuclear transcriptional landscape of the three major cellular divisions of the nervous system using flow sorting of genetically labeled nuclei from bacTRAP mouse lines. Next, we characterized the unique expression of coding, noncoding, and intergenic RNAs in the mature mouse brain with RNA-Seq and validation with independent methods. RESULTS: We found diverse expression across the cell types of all classes of RNAs, including long noncoding RNAs, several of which were confirmed as highly enriched in the nuclei of specific cell types using anatomic methods. We also discovered several examples of cell type-specific expression of tandem gene fusions, and we report the first cell type-specific expression of circular RNAs-a neuron-specific and nuclear-enriched RNA arising from the gene Hnrnpu. CONCLUSIONS: These data provide an important resource for studies evaluating the function of various noncoding RNAs in the brain, including noncoding RNAs that may play a role in psychiatric disease. PMID: 27113499 [PubMed - indexed for MEDLINE] [...]



Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment.
Related Articles Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment. Biol Psychiatry. 2016 Sep 15;80(6):457-68 Authors: Ren Z, Pribiag H, Jefferson SJ, Shorey M, Fuchs T, Stellwagen D, Luscher B Abstract BACKGROUND: Major depressive disorder is increasingly recognized to involve functional deficits in both gamma-aminobutyric acid (GABA)ergic and glutamatergic synaptic transmission. To elucidate the relationship between these phenotypes, we used GABAA receptor γ2 subunit heterozygous (γ2(+/-)) mice, which we previously characterized as a model animal with construct, face, and predictive validity for major depressive disorder. METHODS: To assess possible consequences of GABAergic deficits on glutamatergic transmission, we quantitated the cell surface expression of N-methyl-D-aspartate (NMDA)-type and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors and the function of synapses in the hippocampus and medial prefrontal cortex of γ2(+/-) mice. We also analyzed the effects of an acute dose of the experimental antidepressant ketamine on all these parameters in γ2(+/-) versus wild-type mice. RESULTS: Modest defects in GABAergic synaptic transmission of γ2(+/-) mice resulted in a strikingly prominent homeostatic-like reduction in the cell surface expression of NMDA-type and AMPA-type glutamate receptors, along with prominent functional impairment of glutamatergic synapses in the hippocampus and medial prefrontal cortex. A single subanesthetic dose of ketamine normalized glutamate receptor expression and synaptic function of γ2(+/-) mice to wild-type levels for a prolonged period, along with antidepressant-like behavioral consequences selectively in γ2(+/-) mice. The GABAergic synapses of γ2(+/-) mice were potentiated by ketamine in parallel but only in the medial prefrontal cortex. CONCLUSIONS: Depressive-like brain states that are caused by GABAergic deficits involve a homeostatic-like reduction of glutamatergic transmission that is reversible by an acute, subanesthetic dose of ketamine, along with regionally selective potentiation of GABAergic synapses. The data merge the GABAergic and glutamatergic deficit hypotheses of major depressive disorder. PMID: 27062563 [PubMed - indexed for MEDLINE] [...]



Neural Correlates of Exposure to Cocaine Cues in Rhesus Monkeys: Modulation by the Dopamine Transporter.
Related Articles Neural Correlates of Exposure to Cocaine Cues in Rhesus Monkeys: Modulation by the Dopamine Transporter. Biol Psychiatry. 2016 Nov 01;80(9):702-710 Authors: Porrino LJ, Miller MD, Smith HR, Nader SH, Nader MA Abstract BACKGROUND: A major goal of treatments for cocaine addiction is to reduce relapse-associated cravings, which are typically induced by environmental stimuli associated with cocaine use and related to changes in dopamine neurotransmission. METHODS: The present study used an animal model of cocaine seeking to determine functional consequences of cue exposure using fluorodeoxyglucose positron emission tomography and to relate findings to juvenile levels of dopamine transporter and D2-like receptor availabilities determined before any drug exposure. Adult male rhesus monkeys (N = 11) self-administered cocaine (0.2 mg/kg per injection) under a second-order schedule of reinforcement, in which responding was maintained by conditioned reinforcers. Positron emission tomography scans assessing glucose utilization, a marker of functional activation, were conducted during cocaine-cue responding and food-reinforced responding in a context where cocaine was never available. RESULTS: Compared with the noncocaine condition, we found significant functional activation in the medial prefrontal cortex, anterior cingulate, precuneus region of the parietal cortex, and striatum-findings similar to those reported in humans who abuse cocaine. Furthermore, these functional activations in the prefrontal, cingulate, and parietal cortex measured during cocaine-cue responding were significantly correlated with juvenile measures of dopamine transporter availability, whereas no significant relationship with prior D2-like receptor availability was observed in any brain region. CONCLUSIONS: The similarity between the present findings and findings in humans who use cocaine supports the use of this model for examination of factors that affect the development and intensity of cue-induced drug seeking and provides evidence for potential biomarkers for the evaluation of potential treatments (behavioral and pharmacologic) for cocaine abuse. PMID: 27059874 [PubMed - indexed for MEDLINE] [...]



Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development.
Related Articles Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development. Biol Psychiatry. 2017 Feb 01;81(3):220-230 Authors: Usui N, Co M, Harper M, Rieger MA, Dougherty JD, Konopka G Abstract BACKGROUND: Mutations in the gene encoding the transcription factor forkhead box P2 (FOXP2) result in brain developmental abnormalities, including reduced gray matter in both human patients and rodent models and speech and language deficits. However, neither the region-specific function of FOXP2 in the brain, in particular the cerebellum, nor the effects of any posttranslational modifications of FOXP2 in the brain and disorders have been explored. METHODS: We characterized sumoylation of FOXP2 biochemically and analyzed the region-specific function and sumoylation of FOXP2 in the developing mouse cerebellum. Using in utero electroporation to manipulate the sumoylation state of FOXP2 as well as Foxp2 expression levels in Purkinje cells of the cerebellum in vivo, we reduced Foxp2 expression approximately 40% in the mouse cerebellum. Such a reduction approximates the haploinsufficiency observed in human patients who demonstrate speech and language impairments. RESULTS: We identified sumoylation of FOXP2 at K674 (K673 in mice) in the cerebellum of neonates. In vitro co-immunoprecipitation and in vivo colocalization experiments suggest that PIAS3 acts as the small ubiquitin-like modifier E3 ligase for FOXP2 sumoylation. This sumoylation modifies transcriptional regulation by FOXP2. We demonstrated that FOXP2 sumoylation is required for regulation of cerebellar motor function and vocal communication, likely through dendritic outgrowth and arborization of Purkinje cells in the mouse cerebellum. CONCLUSIONS: Sumoylation of FOXP2 in neonatal mouse cerebellum regulates Purkinje cell development and motor functions and vocal communication, demonstrating evidence for sumoylation in regulating mammalian behaviors. PMID: 27009683 [PubMed - indexed for MEDLINE] [...]



Limbic Activity Modulation Guided by Functional Magnetic Resonance Imaging-Inspired Electroencephalography Improves Implicit Emotion Regulation.
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Limbic Activity Modulation Guided by Functional Magnetic Resonance Imaging-Inspired Electroencephalography Improves Implicit Emotion Regulation.

Biol Psychiatry. 2016 Sep 15;80(6):490-6

Authors: Keynan JN, Meir-Hasson Y, Gilam G, Cohen A, Jackont G, Kinreich S, Ikar L, Or-Borichev A, Etkin A, Gyurak A, Klovatch I, Intrator N, Hendler T

Abstract
The amygdala has a pivotal role in processing traumatic stress; hence, gaining control over its activity could facilitate adaptive mechanism and recovery. To date, amygdala volitional regulation could be obtained only via real-time functional magnetic resonance imaging (fMRI), a highly inaccessible procedure. The current article presents high-impact neurobehavioral implications of a novel imaging approach that enables bedside monitoring of amygdala activity using fMRI-inspired electroencephalography (EEG), hereafter termed amygdala-electrical fingerprint (amyg-EFP). Simultaneous EEG/fMRI indicated that the amyg-EFP reliably predicts amygdala-blood oxygen level-dependent activity. Implementing the amyg-EFP in neurofeedback demonstrated that learned downregulation of the amyg-EFP facilitated volitional downregulation of amygdala-blood oxygen level-dependent activity via real-time fMRI and manifested as reduced amygdala reactivity to visual stimuli. Behavioral evidence further emphasized the therapeutic potential of this approach by showing improved implicit emotion regulation following amyg-EFP neurofeedback. Additional EFP models denoting different brain regions could provide a library of localized activity for low-cost and highly accessible brain-based diagnosis and treatment.

PMID: 26996601 [PubMed - indexed for MEDLINE]




Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats.
Related Articles Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats. Biol Psychiatry. 2016 Sep 15;80(6):448-56 Authors: Sarkar A, Kabbaj M Abstract BACKGROUND: The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats. METHODS: We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in male rats and female rats in diestrus. Medial prefrontal cortex spine density was also examined in male rats and female rats that received ketamine during either the diestrus or the proestrus phase of their estrous cycle. RESULTS: Male rats showed anhedonia and depression-like behavior after 8 weeks of IS, concomitant with decreases in spine density and levels of synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in the medial prefrontal cortex; these changes were reversed by a single injection of ketamine (5 mg/kg). After 11 weeks of IS, female rats showed depression-like behavior but no signs of anhedonia. Although both doses of ketamine rescued depression-like behavior in female rats, the decline observed in synaptic proteins and spine density in IS and in diestrus female rats could not be reversed by ketamine. Spine density was higher in female rats during proestrus than in diestrus. CONCLUSIONS: Our findings implicate a role for synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 and medial prefrontal cortex spine density in the antidepressant effects of ketamine in male rats subjected to IS but not in female rats subjected to IS, suggesting dissimilar underlying mechanisms for efficacy of ketamine in the two sexes. PMID: 26957131 [PubMed - indexed for MEDLINE] [...]



Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia.
Related Articles Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. Biol Psychiatry. 2017 Jan 01;81(1):67-77 Authors: Arnsten AF, Girgis RR, Gray DL, Mailman RB Abstract Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D1 receptors (D1R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D1R stimulation. D1R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D1 agonists, e.g., the first full D1 agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D1 agonists with better pharmacokinetics, functionally selective D1 ligands, and D1R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D1R stimulation in the dlPFC that can be translated into clinical practice. PMID: 26946382 [PubMed - indexed for MEDLINE] [...]



Essential Role of Mesolimbic Brain-Derived Neurotrophic Factor in Chronic Social Stress-Induced Depressive Behaviors.
Related Articles Essential Role of Mesolimbic Brain-Derived Neurotrophic Factor in Chronic Social Stress-Induced Depressive Behaviors. Biol Psychiatry. 2016 Sep 15;80(6):469-78 Authors: Wook Koo J, Labonté B, Engmann O, Calipari ES, Juarez B, Lorsch Z, Walsh JJ, Friedman AK, Yorgason JT, Han MH, Nestler EJ Abstract BACKGROUND: Previous work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine (DA) neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical, as increased DA signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress is unknown. METHODS: We used CSDS with repeated optogenetic activation and pharmacologic manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. We measured BDNF protein expression and DA release in this model. RESULTS: Pharmacologic blockade of BDNF-tyrosine receptor kinase B (TrkB) signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated behavioral deficits induced by phasic stimulation of the VTA-NAc pathway were blocked as well by local knockdown of BDNF in VTA. CONCLUSIONS: These findings show that BDNF-TrkB signaling, rather than DA signaling, in the VTA-NAc circuit is crucial for facilitating depressive-like outcomes after CSDS and they establish BDNF-TrkB signaling as a pathologic mechanism during periods of chronic stress. PMID: 26858215 [PubMed - indexed for MEDLINE] [...]



A Common Polymorphism in a Williams Syndrome Gene Predicts Amygdala Reactivity and Extraversion in Healthy Adults.
Related Articles A Common Polymorphism in a Williams Syndrome Gene Predicts Amygdala Reactivity and Extraversion in Healthy Adults. Biol Psychiatry. 2017 Feb 01;81(3):203-210 Authors: Swartz JR, Waller R, Bogdan R, Knodt AR, Sabhlok A, Hyde LW, Hariri AR Abstract BACKGROUND: Williams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms would help advance our understanding not only of this specific genetic association but also of the broader neurogenetic mechanisms of variability in socioemotional behavior. METHODS: Through an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional magnetic resonance imaging, assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students. RESULTS: The GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men. CONCLUSIONS: A common polymorphism in the WS gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. These results are consistent with reduced threat-related amygdala reactivity in WS and suggest that common variation in GTF2I contributes to broader variability in socioemotional brain function and behavior, with implications for understanding the neurogenetic bases of WS as well as social anxiety. PMID: 26853120 [PubMed - i[...]



Addiction-like Synaptic Impairments in Diet-Induced Obesity.
Related Articles Addiction-like Synaptic Impairments in Diet-Induced Obesity. Biol Psychiatry. 2017 May 01;81(9):797-806 Authors: Brown RM, Kupchik YM, Spencer S, Garcia-Keller C, Spanswick DC, Lawrence AJ, Simonds SE, Schwartz DJ, Jordan KA, Jhou TC, Kalivas PW Abstract BACKGROUND: There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core considered hallmarks of addiction. METHODS: Sprague Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed ratio 1, 3, and 5 and progressive ratio schedules. Subsequently, nucleus accumbens brain slices were prepared, and we tested for changes in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate currents and the ability to exhibit long-term depression. RESULTS: We found that propensity to develop DIO is linked to deficits in the ability to induce long-term depression in the nucleus accumbens, as well as increased potentiation at these synapses as measured by AMPA/N-methyl-D-aspartate currents. Consistent with these impairments, we observed addictive-like behavior in DIO-prone rats, including 1) heightened motivation for palatable food; 2) excessive intake; and 3) increased food seeking when food was unavailable. CONCLUSIONS: Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction. PMID: 26826876 [PubMed - indexed for MEDLINE] [...]



Effects of Creatine Monohydrate Augmentation on Brain Metabolic and Network Outcome Measures in Women With Major Depressive Disorder.
Related Articles Effects of Creatine Monohydrate Augmentation on Brain Metabolic and Network Outcome Measures in Women With Major Depressive Disorder. Biol Psychiatry. 2016 Sep 15;80(6):439-47 Authors: Yoon S, Kim JE, Hwang J, Kim TS, Kang HJ, Namgung E, Ban S, Oh S, Yang J, Renshaw PF, Lyoo IK Abstract BACKGROUND: Creatine monohydrate (creatine) augmentation has the potential to accelerate the clinical responses to and enhance the overall efficacy of selective serotonin reuptake inhibitor treatment in women with major depressive disorder (MDD). Although it has been suggested that creatine augmentation may involve the restoration of brain energy metabolism, the mechanisms underlying its antidepressant efficacy are unknown. METHODS: In a randomized, double-blind, placebo-controlled trial, 52 women with MDD were assigned to receive either creatine augmentation or placebo augmentation of escitalopram; 34 subjects participated in multimodal neuroimaging assessments at baseline and week 8. Age-matched healthy women (n = 39) were also assessed twice at the same intervals. Metabolic and network outcomes were measured for changes in prefrontal N-acetylaspartate and changes in rich club hub connections of the structural brain network using proton magnetic resonance spectroscopy and diffusion tensor imaging, respectively. RESULTS: We found MDD-related metabolic and network dysfunction at baseline. Improvement in depressive symptoms was greater in patients receiving creatine augmentation relative to placebo augmentation. After 8 weeks of treatment, prefrontal N-acetylaspartate levels increased significantly in the creatine augmentation group compared with the placebo augmentation group. Increment in rich club hub connections was also greater in the creatine augmentation group than in the placebo augmentation group. CONCLUSIONS: N-acetylaspartate levels and rich club connections increased after creatine augmentation of selective serotonin reuptake inhibitor treatment. Effects of creatine administration on brain energy metabolism and network organization may partly underlie its efficacy in treating women with[...]



Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases.
Related Articles Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases. Biol Psychiatry. 2017 Mar 01;81(5):452-459 Authors: Instanes JT, Halmøy A, Engeland A, Haavik J, Furu K, Klungsøyr K Abstract BACKGROUND: Prenatal inflammatory mechanisms may play a role in the pathogenesis of psychiatric disorders and could be relevant for attention-deficit/hyperactivity disorder (ADHD). We investigated maternal chronic somatic diseases with immune components as possible risk factors for ADHD in offspring. METHODS: We performed a population-based nested case-control study by linking data from longitudinal Norwegian registers. We included all individuals born during the period 1967-2008 and alive at record linkage (2012). Individuals receiving ADHD medication during the years 2004-2012 were defined as patients with ADHD (N = 47,944), and all remaining individuals (N = 2,274,713) were defined as control subjects. The associations between maternal diseases and ADHD in offspring were analyzed using logistic regression models. RESULTS: The following chronic diseases with immune components were related to ADHD in offspring: multiple sclerosis (adjusted odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.2-2.5), rheumatoid arthritis (adjusted OR = 1.7; 95% CI = 1.5-1.9), type 1 diabetes (adjusted OR = 1.6; 95% CI = 1.3-2.0), asthma (adjusted OR = 1.5; 95% CI = 1.4-1.6), and hypothyroidism (adjusted OR = 1.2; 95% CI = 1.1-1.4). In contrast, chronic hypertension and type 2 diabetes showed no significant associations. Estimates were almost unchanged with additional adjustment for parental ADHD, infant birth weight, and gestational age. Although point estimates for male and female offspring were different for some diseases (e.g., maternal asthma [adjusted OR = 1.7; 95% CI = 1.5-1.8 for female offspring and adjusted OR = 1.5; 95% CI = 1.4-1.6 for male offspring]), none of the associations differed significantly by offspring sex. CONCLUSIONS: Several maternal somatic diseases with immune components were found to increase the risk of[...]



Ventral and Dorsal Striatum Networks in Obesity: Link to Food Craving and Weight Gain.
Related Articles Ventral and Dorsal Striatum Networks in Obesity: Link to Food Craving and Weight Gain. Biol Psychiatry. 2017 May 01;81(9):789-796 Authors: Contreras-Rodríguez O, Martín-Pérez C, Vilar-López R, Verdejo-Garcia A Abstract BACKGROUND: The food addiction model proposes that obesity overlaps with addiction in terms of neurobiological alterations in the striatum and related clinical manifestations (i.e., craving and persistence of unhealthy habits). Therefore, we aimed to examine the functional connectivity of the striatum in excess-weight versus normal-weight subjects and to determine the extent of the association between striatum connectivity and individual differences in food craving and changes in body mass index (BMI). METHODS: Forty-two excess-weight participants (BMI > 25) and 39 normal-weight participants enrolled in the study. Functional connectivity in the ventral and dorsal striatum was indicated by seed-based analyses on resting-state data. Food craving was indicated with subjective ratings of visual cues of high-calorie food. Changes in BMI between baseline and 12 weeks follow-up were assessed in 28 excess-weight participants. Measures of connectivity in the ventral striatum and dorsal striatum were compared between groups and correlated with craving and BMI change. RESULTS: Participants with excess weight displayed increased functional connectivity between the ventral striatum and the medial prefrontal and parietal cortices and between the dorsal striatum and the somatosensory cortex. Dorsal striatum connectivity correlated with food craving and predicted BMI gains. CONCLUSIONS: Obesity is linked to alterations in the functional connectivity of dorsal striatal networks relevant to food craving and weight gain. These neural alterations are associated with habit learning and thus compatible with the food addiction model of obesity. PMID: 26809248 [PubMed - indexed for MEDLINE] [...]



Activation of Supraoptic Oxytocin Neurons by Secretin Facilitates Social Recognition.
Related Articles Activation of Supraoptic Oxytocin Neurons by Secretin Facilitates Social Recognition. Biol Psychiatry. 2017 Feb 01;81(3):243-251 Authors: Takayanagi Y, Yoshida M, Takashima A, Takanami K, Yoshida S, Nishimori K, Nishijima I, Sakamoto H, Yamagata T, Onaka T Abstract BACKGROUND: Social recognition underlies social behavior in animals, and patients with psychiatric disorders associated with social deficits show abnormalities in social recognition. Oxytocin is implicated in social behavior and has received attention as an effective treatment for sociobehavioral deficits. Secretin receptor-deficient mice show deficits in social behavior. The relationship between oxytocin and secretin concerning social behavior remains to be determined. METHODS: Expression of c-Fos in oxytocin neurons and release of oxytocin from their dendrites after secretin application were investigated. Social recognition was examined after intracerebroventricular or local injection of secretin, oxytocin, or an oxytocin receptor antagonist in rats, oxytocin receptor-deficient mice, and secretin receptor-deficient mice. Electron and light microscopic immunohistochemical analysis was also performed to determine whether oxytocin neurons extend their dendrites into the medial amygdala. RESULTS: Supraoptic oxytocin neurons expressed the secretin receptor. Secretin activated supraoptic oxytocin neurons and facilitated oxytocin release from dendrites. Secretin increased acquisition of social recognition in an oxytocin receptor-dependent manner. Local application of secretin into the supraoptic nucleus facilitated social recognition, and this facilitation was blocked by an oxytocin receptor antagonist injected into, but not outside of, the medial amygdala. In the medial amygdala, dendrite-like thick oxytocin processes were found to extend from the supraoptic nucleus. Furthermore, oxytocin treatment restored deficits of social recognition in secretin receptor-deficient mice. CONCLUSIONS: The results of our study demonstrate that secretin-indu[...]



The Potential Role of Amygdaloid MicroRNA-494 in Alcohol-Induced Anxiolysis.
Related Articles The Potential Role of Amygdaloid MicroRNA-494 in Alcohol-Induced Anxiolysis. Biol Psychiatry. 2016 Nov 01;80(9):711-719 Authors: Teppen TL, Krishnan HR, Zhang H, Sakharkar AJ, Pandey SC Abstract BACKGROUND: The antianxiety effects of ethanol appear to be a crucial factor in promoting alcohol intake. Regulation of gene expression by microRNA (miRNA) is an important epigenetic mechanism that affects neuronal pathways and behaviors. We investigated the role of miRNAs underlying the mechanisms of ethanol-induced anxiolysis. METHODS: Acute ethanol-induced anxiolysis was measured in adult rats, and amygdaloid tissues were used for miRNA profiling by microarray analysis. The expression of miR-494 and its target genes in the amygdala was measured using real-time quantitative polymerase chain reaction. The direct role of miR-494 in the anxiety phenotype was also investigated via infusion of a miR-494 antagomir into the central nucleus of amygdala. RESULTS: Microarray profiling of miRNAs in the amygdala showed significant alteration of several miRNA expression levels by acute ethanol exposure. Expression of miR-494 was significantly decreased, whereas expression of the binding protein of cyclic adenosine monophosphate response element binding protein (CBP), p300, and Cbp/p300-interacting transactivator 2 (Cited2) was increased in the amygdala during ethanol-induced anxiolysis. Inhibition of miR-494 in the central nucleus of amygdala, through infusion of a specific antagomir, provoked anxiolysis, mimicking the action of ethanol. Also, expression of Cited2, CBP, and p300 as well as histone H3-lysine 9 acetylation was significantly increased by miR-494 antagomir infusion, indicating their regulation by miR-494 in the amygdala. CONCLUSIONS: These novel results suggest that acute ethanol-induced reduction in miR-494 expression in the amygdala can serve as a key regulatory mechanism for chromatin remodeling possibly leading to anxiolysis. PMID: 26786313 [PubMed - indexed for MEDLIN[...]



Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor.
Related Articles Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor. Biol Psychiatry. 2017 Feb 15;81(4):366-377 Authors: Zimmermann KS, Yamin JA, Rainnie DG, Ressler KJ, Gourley SL Abstract BACKGROUND: Distinguishing between actions that are more likely or less likely to be rewarded is a critical aspect of goal-directed decision making. However, neuroanatomic and molecular mechanisms are not fully understood. METHODS: We used anterograde tracing, viral-mediated gene silencing, functional disconnection strategies, pharmacologic rescue, and designer receptors exclusively activated by designer drugs (DREADDs) to determine the anatomic and functional connectivity between the orbitofrontal cortex (OFC) and the amygdala in mice. In particular, we knocked down brain-derived neurotrophic factor (Bdnf) bilaterally in the OFC or generated an OFC-amygdala "disconnection" by pairing unilateral OFC Bdnf knockdown with lesions of the contralateral amygdala. We characterized decision-making strategies using a task in which mice selected actions based on the likelihood that they would be reinforced. Additionally, we assessed the effects of DREADD-mediated OFC inhibition on the consolidation of action-outcome conditioning. RESULTS: As in other species, the OFC projects to the basolateral amygdala and dorsal striatum in mice. Bilateral Bdnf knockdown within the ventrolateral OFC and unilateral Bdnf knockdown accompanied by lesions of the contralateral amygdala impede goal-directed response selection, implicating BDNF-expressing OFC projection neurons in selecting actions based on their consequences. The tyrosine receptor kinase B agonist 7,8-dihydroxyflavone rescues action selection and increases dendritic spine density on excitatory neurons in the OFC. Rho-kinase inhibition also rescues goal-directed response strategies, linking neural remodeling with outcome-based decision making. Finally, DREADD-mediated O[...]



Online Effects of Transcranial Direct Current Stimulation in Real Time on Human Prefrontal and Striatal Metabolites.
Related Articles Online Effects of Transcranial Direct Current Stimulation in Real Time on Human Prefrontal and Striatal Metabolites. Biol Psychiatry. 2016 Sep 15;80(6):432-8 Authors: Hone-Blanchet A, Edden RA, Fecteau S Abstract BACKGROUND: Studies have reported that transcranial direct current stimulation (tDCS) can modulate human behaviors, symptoms, and neural activity; however, the neural effects during stimulation are unknown. Most studies compared the effects of tDCS before and after stimulation. The objective of our study was to measure the neurobiological effect of a single tDCS dose during stimulation. METHODS: We conducted an online and offline protocol combining tDCS and magnetic resonance spectroscopy (MRS) in 17 healthy participants. We applied anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) and cathodal tDCS over the right DLPFC for 30 minutes, one of the most common montages used with tDCS. We collected MRS measurements in the left DLPFC and left striatum during tDCS and an additional MRS measurement in the left DLPFC immediately after the end of stimulation. RESULTS: During stimulation, active tDCS, as compared with sham tDCS, elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine but did not induce significant differences in prefrontal or striatal gamma-aminobutyric acid level. Immediately after stimulation, active tDCS, as compared with sham tDCS, did not significantly induce differences in glutamate + glutamine, N-acetylaspartate, or gamma-aminobutyric acid levels in the left DLPFC. CONCLUSIONS: These observations indicate that tDCS over the DLPFC has fast excitatory effects, acting on prefrontal and striatal transmissions, and these effects are short lived. One may postulate that repeated sessions of tDCS might induce similar longer lasting effects of elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine levels, which may contribute to its behavioral and clinica[...]



Leptin Dysregulation Is Specifically Associated With Major Depression With Atypical Features: Evidence for a Mechanism Connecting Obesity and Depression.
Related Articles Leptin Dysregulation Is Specifically Associated With Major Depression With Atypical Features: Evidence for a Mechanism Connecting Obesity and Depression. Biol Psychiatry. 2017 May 01;81(9):807-814 Authors: Milaneschi Y, Lamers F, Bot M, Drent ML, Penninx BW Abstract BACKGROUND: Obesity-related dysregulation of leptin signaling (e.g., hyperleptinemia due to central functional resistance) may affect mood. However, evidence for leptin dysregulation in major depressive disorder (MDD) is conflicting. Inconclusive findings may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the relationship of leptin with MDD, its common subtypes (typical and atypical), and clinical features. METHODS: The sample consisted of participants (aged 18 to 65 years) from the Netherlands Study of Depression and Anxiety with current (n = 1062) or remitted (n = 711) MDD and healthy control subjects (n = 497). Diagnoses of MDD and subtypes were based on DSM-IV symptoms. Additional symptoms were measured with the Inventory of Depressive Symptomatology. Blood levels of leptin and adiposity indexes (body mass index and waist circumference) were assessed. RESULTS: As compared to control subjects, higher leptin was associated with the atypical MDD subtype both for remitted (n = 144, odds ratio = 1.53, 95% confidence interval = 1.16-2.03, p = .003) and current (n = 270, odds ratio = 1.90, 95% confidence interval = 1.51-2.93, p = 5.3e-8) cases. This association was stronger for increasing adiposity levels (leptin by body mass index interaction, p < .02), strengthening the hypothesis of the involvement of leptin resistance. No association with leptin was found for overall MDD or the typical subtype. Among currently depressed patients, higher leptin was associated with key symptoms identifying the atypical subtype, such as hyperphagia, increased weight, and leaden paralysis. CONCLUS[...]



Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study.
Related Articles Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biol Psychiatry. 2016 Sep 15;80(6):424-31 Authors: Singh JB, Fedgchin M, Daly E, Xi L, Melman C, De Bruecker G, Tadic A, Sienaert P, Wiegand F, Manji H, Drevets WC, Van Nueten L Abstract BACKGROUND: The purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous (IV) infusion in patients with treatment-resistant depression (TRD). METHODS: This multicenter, randomized, placebo-controlled trial was conducted in 30 patients with TRD. Patients were randomly assigned 1:1:1 to receive an IV infusion of .20 mg/kg or .40 mg/kg esketamine or placebo over 40 minutes on day 1. The primary end point was change in Montgomery-Åsberg Depression Rating Scale total score from day 1 (baseline) to day 2. Nonresponders who received placebo on day 1 were randomly assigned again 1:1 to IV esketamine .20 mg/kg or .40 mg/kg on day 4. Secondary efficacy and safety measures were also evaluated. RESULTS: Of the enrolled patients, 97% (29 of 30) completed the study. The least squares mean changes (SE) from baseline to day 2 in Montgomery-Åsberg Depression Rating Scale total score for the esketamine .20 mg/kg and .40 mg/kg dose groups were -16.8 (3.00) and -16.9 (2.61), respectively, and showed significant improvement (one-sided p = .001 for both groups) compared with placebo (-3.8 [2.97]). Esketamine showed a rapid (within 2 hours) and robust antidepressant effect. Treatment-emergent adverse events were dose dependent. The most common treatment-emergent adverse events were headache, nausea, and dissociation; the last-mentioned was transient and did not persist beyond 4 hours from the start of the esketamine infusion. CONCLUSIONS: A rapid onset of robust antidepressant effects was observed in patients with T[...]



Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice.
Related Articles Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice. Biol Psychiatry. 2017 Jan 15;81(2):101-110 Authors: Mandyam CD, Schilling JM, Cui W, Egawa J, Niesman IR, Kellerhals SE, Staples MC, Busija AR, Risbrough VB, Posadas E, Grogman GC, Chang JW, Roth DM, Patel PM, Patel HH, Head BP Abstract BACKGROUND: Studies in vitro demonstrate that neuronal membrane/lipid rafts (MLRs) establish cell polarity by clustering progrowth receptors and tethering cytoskeletal machinery necessary for neuronal sprouting. However, the effect of MLR and MLR-associated proteins on neuronal aging is unknown. METHODS: Here, we assessed the impact of neuron-targeted overexpression of an MLR scaffold protein, caveolin-1 (Cav-1) (via a synapsin promoter, SynCav1), in the hippocampus in vivo in adult (6-month-old) and aged (20-month-old) mice on biochemical, morphologic, and behavioral changes. RESULTS: SynCav1 resulted in increased expression of Cav-1, MLRs, and MLR-localization of Cav-1 and tropomyosin-related kinase B receptor independent of age and time post gene transfer. Cav-1 overexpression in adult mice enhanced dendritic arborization within the apical dendrites of hippocampal cornu ammonis 1 and granule cell neurons, effects that were also observed in aged mice, albeit to a lesser extent, indicating preserved impact of Cav-1 on structural plasticity of hippocampal neurons with age. Cav-1 overexpression enhanced contextual fear memory in adult and aged mice demonstrating improved hippocampal function. CONCLUSIONS: Neuron-targeted overexpression of Cav-1 in the adult and aged hippocampus enhances functional MLRs with corresponding roles in cell signaling and protein trafficking. The resultant structural alterations in hippocampal neurons in vivo are associated with improvements in hippo[...]



Hippocampus Contributions to Food Intake Control: Mnemonic, Neuroanatomical, and Endocrine Mechanisms.
Related Articles Hippocampus Contributions to Food Intake Control: Mnemonic, Neuroanatomical, and Endocrine Mechanisms. Biol Psychiatry. 2017 May 01;81(9):748-756 Authors: Kanoski SE, Grill HJ Abstract Food intake is a complex behavior that can occur or cease to occur for a multitude of reasons. Decisions about where, when, what, and how much to eat are not merely reflexive responses to food-relevant stimuli or to changes in energy status. Rather, feeding behavior is modulated by various contextual factors and by previous experiences. The data reviewed here support the perspective that neurons in multiple hippocampal subregions constitute an important neural substrate linking the external context, the internal context, and mnemonic and cognitive information to control both appetitive and ingestive behavior. Feeding behavior is heavily influenced by hippocampal-dependent mnemonic functions, including episodic meal-related memories and conditional learned associations between food-related stimuli and postingestive consequences. These mnemonic processes are undoubtedly influenced by both external and internal factors relating to food availability, location, and physiological energy status. The afferent and efferent neuroanatomical connectivity of the subregions of the hippocampus is reviewed with regard to the integration of visuospatial and olfactory sensory information (the external context) with endocrine and gastrointestinal interoceptive stimuli (the internal context). Also discussed are recent findings demonstrating that peripherally derived endocrine signals act on receptors in hippocampal neurons to reduce (leptin, glucagon-like peptide-1) or increase (ghrelin) food intake and learned food reward-driven responding, thereby highlighting endocrine and neuropeptidergic signaling in hippocampal neurons as a novel substrate of importance in the higher-[...]



Immune Endophenotypes in Children With Autism Spectrum Disorder.
Related Articles Immune Endophenotypes in Children With Autism Spectrum Disorder. Biol Psychiatry. 2017 Mar 01;81(5):434-441 Authors: Careaga M, Rogers S, Hansen RL, Amaral DG, Van de Water J, Ashwood P Abstract BACKGROUND: Autism spectrum disorder (ASD) is characterized by social communication deficits and restricted, repetitive patterns of behavior. Varied immunological findings have been reported in children with ASD. To address the question of heterogeneity in immune responses, we sought to examine the diversity of immune profiles within a representative cohort of boys with ASD. METHODS: Peripheral blood mononuclear cells from male children with ASD (n = 50) and from typically developing age-matched male control subjects (n = 16) were stimulated with either lipopolysaccharide or phytohemagglutinin. Cytokine production was assessed after stimulation. The ASD study population was clustered into subgroups based on immune responses and assessed for behavioral outcomes. RESULTS: Children with ASD who had a proinflammatory profile based on lipopolysaccharide stimulation were more developmentally impaired as assessed by the Mullen Scales of Early Learning. They also had greater impairments in social affect as measured by the Autism Diagnostic Observation Schedule. These children also displayed more frequent sleep disturbances and episodes of aggression. Similarly, children with ASD and a more activated T cell cytokine profile after phytohemagglutinin stimulation were more developmentally impaired as measured by the Mullen Scales of Early Learning. CONCLUSIONS: Children with ASD may be phenotypically characterized based upon their immune profile. Those showing either an innate proinflammatory response or increased T cell activation/skewing display a more impaired behavioral profile than children with nonin[...]



Prenatal Caffeine Exposure and Child IQ at Age 5.5 Years: The EDEN Mother-Child Cohort.
Related Articles Prenatal Caffeine Exposure and Child IQ at Age 5.5 Years: The EDEN Mother-Child Cohort. Biol Psychiatry. 2016 Nov 01;80(9):720-726 Authors: Galéra C, Bernard JY, van der Waerden J, Bouvard MP, Lioret S, Forhan A, De Agostini M, Melchior M, Heude B, EDEN Mother-Child Cohort Study Group Abstract BACKGROUND: Evidence from animal studies suggests maternal caffeine intake during pregnancy has detrimental effects on subsequent brain development in offspring. However, human data in this area are limited. The aim of this study was to assess whether caffeine intake by women during pregnancy is associated with impaired cognitive development in offspring at age 5.5 years. METHODS: Multivariate modeling was conducted using data of 1083 mother-child pairs from a population-based birth cohort in France followed from pregnancy to age 5.5 years of the children. Measures included an estimate of maternal caffeine intake during pregnancy, children's IQ at age 5.5, and individual and family characteristics. RESULTS: Prenatal caffeine exposure was common in the sample (91%) with 12% displaying an intake ≥200 mg/day (high). Multivariable modeling showed a significant negative relationship between caffeine intake and children's IQ at 5.5 years (-.94 [95% confidence interval = -1.70, -.17] full IQ unit per 100 mg daily caffeine intake). In particular, children of mothers consuming ≥200 mg/day were more likely to have borderline or lower IQ compared with children of mothers consuming <100 mg/day (13.5% vs. 7.3%; odds ratio = 2.30, 95% confidence interval = 1.13, 4.69). CONCLUSIONS: We found an association between caffeine intake during pregnancy and impaired cognitive development in offspring, a result in line with animal data. More epidemiologic and biologically grounded res[...]



Neonatal Cytokine Profiles Associated With Autism Spectrum Disorder.
Related Articles Neonatal Cytokine Profiles Associated With Autism Spectrum Disorder. Biol Psychiatry. 2017 Mar 01;81(5):442-451 Authors: Krakowiak P, Goines PE, Tancredi DJ, Ashwood P, Hansen RL, Hertz-Picciotto I, Van de Water J Abstract BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that can be reliably diagnosed at age 24 months. Immunological phenomena, including skewed cytokine production, have been observed among children with ASD. Little is known about whether immune dysregulation is present before diagnosis of ASD. METHODS: We examined neonatal blood spots from 214 children with ASD (141 severe, 73 mild/moderate), 62 children with typical development, and 27 children with developmental delay as control subjects who participated in the Childhood Autism Risks from Genetics and the Environment study, a population-based case-control study. Levels of 17 cytokines and chemokines were compared across groups and in relation to developmental and behavioral domains. RESULTS: Interleukin (IL)-1β and IL-4 were independently associated with ASD compared with typical development, although these relationships varied by ASD symptom intensity. Elevated IL-4 was associated with increased odds of severe ASD (odds ratio [OR] = 1.40, 95% confidence interval [CI], 1.03, 1.91), whereas IL-1β was associated with increased odds of mild/moderate ASD (OR = 3.02, 95% CI, 1.43, 6.38). Additionally, IL-4 was associated with a higher likelihood of severe ASD versus mild/moderate ASD (OR = 1.35, 95% CI, 1.04, 1.75). In male subjects with ASD, IL-4 was negatively associated with nonverbal cognitive ability (β = -3.63, SE = 1.33, p = .04). CONCLUSIONS: This study is part of a growing effort to identify early biological markers for AS[...]