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Preview: Cerebral Cortex - Advance Access

Cerebral Cortex Advance Access





Published: Fri, 17 Nov 2017 00:00:00 GMT

Last Build Date: Fri, 17 Nov 2017 00:43:56 GMT

 



Neural Mechanisms of Episodic Retrieval Support Divergent Creative Thinking

2017-11-17

Abstract
Prior research has indicated that brain regions and networks that support semantic memory, top-down and bottom-up attention, and cognitive control are all involved in divergent creative thinking. Kernels of evidence suggest that neural processes supporting episodic memory—the retrieval of particular elements of prior experiences—may also be involved in divergent thinking, but such processes have typically been characterized as not very relevant for, or even a hindrance to, creative output. In the present study, we combine functional magnetic resonance imaging with an experimental manipulation to test formally, for the first time, episodic memory’s involvement in divergent thinking. Following a manipulation that facilitates detailed episodic retrieval, we observed greater neural activity in the hippocampus and stronger connectivity between a core brain network linked to episodic processing and a frontoparietal brain network linked to cognitive control during divergent thinking relative to an object association control task that requires little divergent thinking. Stronger coupling following the retrieval manipulation extended to a subsequent resting-state scan. Neural effects of the episodic manipulation were consistent with behavioral effects of enhanced idea production on divergent thinking but not object association. The results indicate that conceptual frameworks should accommodate the idea that episodic retrieval can function as a component process of creative idea generation, and highlight how the brain flexibly utilizes the retrieval of episodic details for tasks beyond simple remembering.



Contextual Fear Extinction Induces Hippocampal Metaplasticity Mediated by Metabotropic Glutamate Receptor 5

2017-11-09

Abstract
Dysregulated fear memory can lead to a broad spectrum of anxiety disorders. The brain systems underlying fear memory are manifold, with the hippocampus being prominently involved by housing fear-related spatial memories as engrams, which are created and stored through neural changes such as synaptic plasticity. Although metabotropic glutamate (mGlu) receptors contribute significantly to both fear behavior and hippocampal synaptic plasticity, the relationship between these two phenomena has not been fully elucidated. Here, we report that contextual fear extinction induces a novel form of metaplasticity mediated by mGlu5 at the hippocampal SC-CA1 synapse. Further, blockade of mGlu5 prevents both contextual fear extinction and expression of this metaplasticity. This form of metaplasticity was absent in a mouse model of MECP2-duplication syndrome, corresponding to a complete deficit in extinction learning. These findings suggest that mGlu5-dependent metaplasticity within the hippocampus may play a critical role in extinction of contextual fear.



Focal Suppression of Distractor Sounds by Selective Attention in Auditory Cortex

2017-11-09

Abstract
Auditory selective attention is required for parsing crowded acoustic environments, but cortical systems mediating the influence of behavioral state on auditory perception are not well characterized. Previous neurophysiological studies suggest that attention produces a general enhancement of neural responses to important target sounds versus irrelevant distractors. However, behavioral studies suggest that in the presence of masking noise, attention provides a focal suppression of distractors that compete with targets. Here, we compared effects of attention on cortical responses to masking versus non-masking distractors, controlling for effects of listening effort and general task engagement. We recorded single-unit activity from primary auditory cortex (A1) of ferrets during behavior and found that selective attention decreased responses to distractors masking targets in the same spectral band, compared with spectrally distinct distractors. This suppression enhanced neural target detection thresholds, suggesting that limited attention resources serve to focally suppress responses to distractors that interfere with target detection. Changing effort by manipulating target salience consistently modulated spontaneous but not evoked activity. Task engagement and changing effort tended to affect the same neurons, while attention affected an independent population, suggesting that distinct feedback circuits mediate effects of attention and effort in A1.



Cell-Type Specific Burst Firing Interacts with Theta and Beta Activity in Prefrontal Cortex During Attention States

2017-11-09

Abstract
Population-level theta and beta band activity in anterior cingulate and prefrontal cortices (ACC/PFC) are prominent signatures of self-controlled, adaptive behaviors. But how these rhythmic activities are linked to cell-type specific activity has remained unclear. Here, we suggest such a cell-to-systems level linkage. We found that the rate of burst spiking events is enhanced particularly during attention states and that attention-specific burst spikes have a unique temporal relationship to local theta and beta band population-level activities. For the 5–10 Hz theta frequency range, bursts coincided with transient increases of local theta power relative to nonbursts, particularly for bursts of putative interneurons. For the 16–30 Hz beta frequency, bursts of putative interneurons phase synchronized stronger than nonbursts, and were associated with larger beta power modulation. In contrast, burst of putative pyramidal cells showed similar beta power modulation as nonbursts, but were accompanied by stronger beta power only when they occurred early in the beta cycle. These findings suggest that in the ACC/PFC during attention states, mechanisms underlying burst firing are intimately linked to narrow band population-level activities, providing a cell-type specific window into rhythmic inhibitory gating and the emergence of rhythmically coherent network states during goal directed behavior.



Meta-Connectomic Analysis Reveals Commonly Disrupted Functional Architectures in Network Modules and Connectors across Brain Disorders

2017-11-09

Abstract
Neuropsychiatric disorders are increasingly conceptualized as disconnection syndromes that are associated with abnormal network integrity in the brain. However, whether different neuropsychiatric disorders show commonly dysfunctional connectivity architectures in large-scale brain networks remains largely unknown. Here, we performed a meta-connectomic study to identify disorder-related functional modules and brain regions by combining meta-analyses of 182 published resting-state functional MRI studies in 11 neuropsychiatric disorders and graph-theoretical analyses of 3 independent resting-state functional MRI datasets with healthy and diseased populations (Alzheimer’s disease and major depressive disorder [MDD]). Three major functional modules, the default mode, frontoparietal, and sensorimotor networks were commonly abnormal across disorders. Moreover, most of the disorders preferred to target the network connector nodes that were primarily involved in intermodule communications and multiple cognitive components. Apart from these common dysfunctions, different brain disorders were associated with specific alterations in network modules and connector regions. Finally, these meta-connectomic findings were confirmed by two empirical example cases of Alzheimer’s disease and MDD. Collectively, our findings shed light on the shared biological mechanisms of network dysfunctions of diverse disorders and have implications for clinical diagnosis and treatment from a network perspective.



Same Genes, Different Brains: Neuroanatomical Differences Between Monozygotic Twins Discordant for Musical Training

2017-11-09

Abstract
Numerous cross-sectional and observational longitudinal studies show associations between expertise and regional brain anatomy. However, since these designs confound training with genetic predisposition, the causal role of training remains unclear. Here, we use a discordant monozygotic (identical) twin design to study expertise-dependent effects on neuroanatomy using musical training as model behavior, while essentially controlling for genetic factors and shared environment of upbringing. From a larger cohort of monozygotic twins, we were able to recruit 18 individuals (9 pairs) that were highly discordant for piano practice. We used structural and diffusion magnetic resonance imaging to analyze the auditory-motor network and within-pair differences in cortical thickness, cerebellar regional volumes and white-matter microstructure/fractional anisotropy. The analyses revealed that the musically active twins had greater cortical thickness in the auditory-motor network of the left hemisphere and more developed white matter microstructure in relevant tracts in both hemispheres and the corpus callosum. Furthermore, the volume of gray matter in the left cerebellar region of interest comprising lobules I–IV + V, was greater in the playing group. These findings provide the first clear support for that a significant portion of the differences in brain anatomy between experts and nonexperts depend on causal effects of training.



Perturbation of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Induces Trans-regional Metaplasticity at the Medial Prefrontal Cortex

2017-11-09

Abstract
GABAergic synapses in the basolateral amygdala (BLA) play an important role in fear memory generation. We have previously reported that reduction in GABAergic synapses innervating specifically at the axon initial segment (AIS) of principal neurons of BLA, by neurofascin (NF) knockdown, impairs fear extinction. BLA is bidirectionally connected with the medial prefrontal cortex (mPFC), which is a key region involved in extinction of acquired fear memory. Here, we showed that reducing AIS GABAergic synapses within the BLA leads to impairment of synaptic plasticity in the BLA-mPFC pathway, as well as in the ventral subiculum (vSub)-mPFC pathway, which is independent of BLA involvement. The results suggest that the alteration within the BLA subsequently resulted in a form of trans-regional metaplasticity in the mPFC. In support of that notion, we observed that NF knockdown induced a severe deficit in behavioral flexibility as measured by reversal learning. Interestingly, reversal learning similar to extinction learning is an mPFC-dependent behavior. In agreement with that, measurement of the immediate-early gene, c-Fos immunoreactivity after reversal learning was reduced in the mPFC and BLA, supporting further the notion that the BLA GABAergic manipulation resulted in trans-regional metaplastic alterations within the mPFC.



Reverse NCX Attenuates Cellular Sodium Loading in Metabolically Compromised Cortex

2017-11-09

Abstract
In core regions of ischemic stroke, disruption of blood flow causes breakdown of ionic gradients and, ultimately, calcium overload and cell death. In the surrounding penumbra, cells may recover upon reperfusion, but recovery is hampered by additional metabolic demands imposed by peri-infarct depolarizations (PIDs). There is evidence that sodium influx drives PIDs, but no data exist on PID-related sodium accumulations in vivo. Here, we found that PIDs in mouse neocortex are associated with propagating sodium elevations in neurons and astrocytes. Similar transient sodium elevations were induced in acute tissue slices by brief chemical ischemia. Blocking NMDA-receptors dampened sodium and accompanying calcium loads of neurons in tissue slices, while inhibiting glutamate transport diminished sodium influx into astrocytes, but amplified neuronal sodium loads. In both cell types, inhibition of sodium/calcium exchange (NCX) increased sodium transients. Blocking NCX also significantly reduced calcium transients, a result confirmed in vivo. Our study provides the first quantitative data on sodium elevations in peri-infarct regions in vivo. They suggest that sodium influx drives reversal of NCX, triggering a massive secondary calcium elevation while promoting export of sodium. Reported neuroprotective effects of NCX activity in stroke models might thus be related to its dampening of ischemia-induced sodium loading.



Representations of Fine Digit Movements in Posterior and Anterior Parietal Cortex Revealed Using Long-Train Intracortical Microstimulation in Macaque Monkeys

2017-11-09

Abstract
The current investigation in macaque monkeys utilized long-train intracortical microstimulation to determine the extent of cortex from which movements could be evoked. Not only were movements evoked from motor areas (PMC and M1), but they were also evoked from posterior parietal (5, 7a, 7b) and anterior parietal areas (3b, 1, 2). Large representations of digit movements involving only the index finger (D2) and thumb (D1), were elicited from areas 1, 2, 7b, and M1. Other movements evoked from these regions were similar to ethologically relevant movements that have been described in other primates. These include combined forelimb and mouth movements and full hand grasps. However, many other movements were much more complex and could not be categorized into any of the previously described ethological categories. Movements involving specific digits, which mimic precision grips, are unique to macaques and have not been described in New World or prosimian primates. We propose that these multiple and expanded motor representations of the digits co-evolved with the emergence of the opposable thumb and alterations in grip type in some anthropoid lineages.



The Bat as a New Model of Cortical Development

2017-11-09

Abstract
The organization of the mammalian cerebral cortex shares fundamental features across species. However, while the radial thickness of grey matter varies within one order of magnitude, the tangential spread of the cortical sheet varies by orders of magnitude across species. A broader sample of model species may provide additional clues for understanding mechanisms that drive cortical expansion. Here, we introduce the bat Carollia perspicillata as a new model species. The brain of C. perspicillata is similar in size to that of mouse but has a cortical neurogenic period at least 5 times longer than mouse, and nearly as long as that of the rhesus macaque, whose brain is 100 times larger. We describe the development of laminar and regional structures, neural precursor cell identity and distribution, immune cell distribution, and a novel population of Tbr2+ cells in the caudal ganglionic eminence of the developing neocortex of C. perspicillata. Our data indicate that unique mechanisms guide bat cortical development, particularly concerning cell cycle length. The bat model provides new perspective on the evolution of developmental programs that regulate neurogenesis in mammalian cerebral cortex, and offers insight into mechanisms that contribute to tangential expansion and gyri formation in the cerebral cortex.



Effective Connectivity Measured Using Optogenetically Evoked Hemodynamic Signals Exhibits Topography Distinct from Resting State Functional Connectivity in the Mouse

2017-11-09

Abstract
Brain connectomics has expanded from histological assessment of axonal projection connectivity (APC) to encompass resting state functional connectivity (RS-FC). RS-FC analyses are efficient for whole-brain mapping, but attempts to explain aspects of RS-FC (e.g., interhemispheric RS-FC) based on APC have been only partially successful. Neuroimaging with hemoglobin alone lacks specificity for determining how activity in a population of cells contributes to RS-FC. Wide-field mapping of optogenetically defined connectivity could provide insights into the brain’s structure–function relationship. We combined optogenetics with optical intrinsic signal imaging to create an efficient, optogenetic effective connectivity (Opto-EC) mapping assay. We examined EC patterns of excitatory neurons in awake, Thy1-ChR2 transgenic mice. These Thy1-based EC (Thy1-EC) patterns were evaluated against RS-FC over the cortex. Compared to RS-FC, Thy1-EC exhibited increased spatial specificity, reduced interhemispheric connectivity in regions with strong RS-FC, and appreciable connection strength asymmetry. Comparing the topography of Thy1-EC and RS-FC patterns to maps of APC revealed that Thy1-EC more closely resembled APC than did RS-FC. The more general method of Opto-EC mapping with hemoglobin can be determined for 100 sites in single animals in under an hour, and is amenable to other neuroimaging modalities. Opto-EC mapping represents a powerful strategy for examining evolving connectivity-related circuit plasticity.



Characteristic Increases in EEG Connectivity Correlate With Changes of Structural MRI in Amyotrophic Lateral Sclerosis

2017-11-09

Abstract
Amyotrophic lateral sclerosis (ALS) is a terminal progressive adult-onset neurodegeneration of the motor system. Although originally considered a pure motor degeneration, there is increasing evidence of disease heterogeneity with varying degrees of extra-motor involvement. How the combined motor and nonmotor degeneration occurs in the context of broader disruption in neural communication across brain networks has not been well characterized. Here, we have performed high-density crossectional and longitudinal resting-state electroencephalography (EEG) recordings on 100 ALS patients and 34 matched controls, and have identified characteristic patterns of altered EEG connectivity that have persisted in longitudinal analyses. These include strongly increased EEG coherence between parietal–frontal scalp regions (in γ-band) and between bilateral regions over motor areas (in θ-band). Correlation with structural MRI from the same patients shows that disease-specific structural degeneration in motor areas and corticospinal tracts parallels a decrease in neural activity over scalp motor areas, while the EEG over the scalp regions associated with less extensively involved extra-motor regions on MRI exhibit significantly increased neural communication. Our findings demonstrate that EEG-based connectivity mapping can provide novel insights into progressive network decline in ALS. These data pave the way for development of validated cost-effective spectral EEG-based biomarkers that parallel changes in structural imaging.



Amyloid Network Topology Characterizes the Progression of Alzheimer’s Disease During the Predementia Stages

2017-11-09

Abstract
There is increasing evidence showing that the accumulation of the amyloid-β (Aβ) peptide into extracellular plaques is a central event in Alzheimer's disease (AD). These abnormalities can be detected as lowered levels of Aβ42 in the cerebrospinal fluid (CSF) and are followed by increased amyloid burden on positron emission tomography (PET) several years before the onset of dementia. The aim of this study was to assess amyloid network topology in nondemented individuals with early stage Aβ accumulation, defined as abnormal CSF Aβ42 levels and normal Florbetapir PET (CSF+/PET−), and more advanced Aβ accumulation, defined as both abnormal CSF Aβ42 and Florbetapir PET (CSF+/PET+). The amyloid networks were built using correlations in the mean 18F-florbetapir PET values between 72 brain regions and analyzed using graph theory analyses. Our findings showed an association between early amyloid stages and increased covariance as well as shorter paths between several brain areas that overlapped with the default-mode network (DMN). Moreover, we found that individuals with more advanced amyloid accumulation showed more widespread changes in brain regions both within and outside the DMN. These findings suggest that amyloid network topology could potentially be used to assess disease progression in the predementia stages of AD.



Local and Global Spatial Organization of Interaural Level Difference and Frequency Preferences in Auditory Cortex

2017-11-09

Abstract
Despite decades of microelectrode recordings, fundamental questions remain about how auditory cortex represents sound-source location. Here, we used in vivo 2-photon calcium imaging to measure the sensitivity of layer II/III neurons in mouse primary auditory cortex (A1) to interaural level differences (ILDs), the principal spatial cue in this species. Although most ILD-sensitive neurons preferred ILDs favoring the contralateral ear, neurons with either midline or ipsilateral preferences were also present. An opponent-channel decoder accurately classified ILDs using the difference in responses between populations of neurons that preferred contralateral-ear-greater and ipsilateral-ear-greater stimuli. We also examined the spatial organization of binaural tuning properties across the imaged neurons with unprecedented resolution. Neurons driven exclusively by contralateral ear stimuli or by binaural stimulation occasionally formed local clusters, but their binaural categories and ILD preferences were not spatially organized on a more global scale. In contrast, the sound frequency preferences of most neurons within local cortical regions fell within a restricted frequency range, and a tonotopic gradient was observed across the cortical surface of individual mice. These results indicate that the representation of ILDs in mouse A1 is comparable to that of most other mammalian species, and appears to lack systematic or consistent spatial order.



Age-Related Declines in Motor Performance are Associated With Decreased Segregation of Large-Scale Resting State Brain Networks

2017-11-09

Abstract
Aging is typically associated with substantial declines in motor functioning as well as robust changes in the functional organization of brain networks. Previous research has investigated the link between these 2 age-varying factors but examinations were predominantly limited to the functional organization within motor-related brain networks. Little is known about the relationship between age-related behavioral impairments and changes in functional organization at the whole brain (i.e., multiple network) level. This knowledge gap is surprising given that the decreased segregation of brain networks (i.e., increased internetwork connectivity) can be considered a hallmark of the aging process. Accordingly, we investigated the association between declines in motor performance across the adult lifespan (20–75 years) and age-related modulations of functional connectivity within and between resting state networks. Results indicated that stronger internetwork resting state connectivity observed as a function of age was significantly related to worse motor performance. Moreover, performance had a significantly stronger association with the strength of internetwork as compared with intranetwork connectivity, including connectivity within motor networks. These findings suggest that age-related declines in motor performance may be attributed to a breakdown in the functional organization of large-scale brain networks rather than simply age-related connectivity changes within motor-related networks.



The Laminar Organization of Piriform Cortex Follows a Selective Developmental and Migratory Program Established by Cell Lineage

2017-11-09

Abstract
Piriform cortex (PC) is a 3-layer paleocortex receiving primary afferent input from the olfactory bulb. The past decade has seen significant progress in understanding the synaptic, cellular and functional organization of PC, but PC embryogenesis continues to be enigmatic. Here, using birthdating strategies and clonal analyses, we probed the early development and laminar specificity of neurogenesis/gliogenesis as it relates to the organization of the PC. Our data demonstrate a temporal sequence of laminar-specific neurogenesis following the canonical “inside-out” pattern, with the notable exception of PC Layer II which exhibited an inverse “outside-in” temporal neurogenic pattern. Of interest, we found no evidence of a neurogenic gradient along the anterior to posterior axis, although the timing of neuronal migration and laminar development was delayed rostrally by approximately 24 h. To begin probing if lineage affected cell fate in the PC, we labeled PC neuroblasts using a multicolor technique and analyzed their laminar organization. Our results suggested that PC progenitors were phenotypically committed to reach specific layers early in the development. Collectively, these studies shed new light on the determinants of the laminar specificity of neuronal/glial organization in PC and the likely role of subpopulations of committed progenitors in regulating PC embryogenesis.