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Funder: Tampereen Yliopisto (University of Tampere); doi: https://doi.org/10.13039/501100004371, Funder: Tekes (Finnish Funding Agency for Innovation); doi: https://doi.org/10.13039/501100003406, Human pluripotent stem cell (hPSC)-derived neurons provide exciting opportunities for in vitro modeling of neurological diseases and for advancing drug development and neurotoxicological studies. However, generating electrophysiologically mature neuronal networks from hPSCs has been challenging. Here, we report the differentiation of functionally active hPSC-derived cortical networks on defined laminin-521 substrate. We apply microelectrode array (MEA) measurements to assess network events and compare the activity development of hPSC-derived networks to that of widely used rat embryonic cortical cultures. In both of these networks, activity developed through a similar sequence of stages and time frames; however, the hPSC-derived networks showed unique patterns of bursting activity. The hPSC-derived networks developed synchronous activity, which involved glutamatergic and GABAergic inputs, recapitulating the classical cortical activity also observed in rodent counterparts. Principal component analysis (PCA) based on spike rates, network synchronization and burst features revealed the segregation of hPSC-derived and rat network recordings into different clusters, reflecting the species-specific and maturation state differences between the two networks. Overall, hPSC-derived neural cultures produced with a defined protocol generate cortical type network activity, which validates their applicability as a human-specific model for pharmacological studies and modeling network dysfunctions.

Recently, an increasing interest in investigating interactions between brain regions using functional connectivity (FC) methods has shifted the initial focus of cognitive neuroimaging research from localizing functional circuits based on task activation to mapping brain networks based on intrinsic FC dynamics. Leveraging the advantages of the latter approach, it has been shown that despite primarily invariant intrinsic organization of the large-scale functional networks, interactions between and within these networks significantly differ between various behavioral and cognitive states. These differences presumably indicate transient reconfiguration of functional connections-an instantaneous process that flexibly mediates and calibrates human behavior according to momentary demands of the environment. Nevertheless, the specificity of these reconfigured FC patterns to the task at hand and their relevance to adaptive processes during learning remain elusive. To address this knowledge gap, we investigated (1) to what extent FC within the somatomotor network is reconfigured during motor skill practice, and (2) how these changes are related to learning. We applied a seed-driven FC approach to data collected during a continuous task-free condition, so-called resting state, and during a motor sequence learning task using functional magnetic resonance imaging. During the task, participants repeatedly performed a short five-element sequence with their non-dominant (left) hand. As predicted, such unimanual sequence production was associated with lateralized activation of the right somatomotor cortex (SMC). Using this "active" region as a seed, here we show that unimanual performance of the motor sequence relies on functional segregation between the two SMC and selective integration between the "active" SMC and supplementary motor area. Whereas, greater segregation between the two SMC was associated with gains in performance rate, greater segregation within the "active" SMC itself was associated with more consistent performance by the end of training. Nether the resting-state FC patterns within the somatomotor network nor their relative modulation by the task state predicted these behavioral benefits of learning. Our results suggest that task-induced FC changes reflect reconfiguration of the connectivity patterns within the somatomotor network rather than a simple amplification or silencing of its intrinsic dynamics. Such reconfiguration not only supports motor behavior but may also predict learning. ispartof: FRONTIERS IN NEUROLOGY vol:10 ispartof: location:Switzerland status: published

Aging and central vision loss are associated with cortical atrophies, but little is known about the relationship between cortical thinning and the underlying cellular structure. We compared the macro- and micro-structure of the cortical gray and superficial white matter of 38 patients with juvenile (JMD) or age-related (AMD) macular degeneration and 38 healthy humans (19-84 years) by multimodal MRI including diffusion-tensor imaging (DTI). A factor analysis showed that cortical thickness, tissue-dependent measures, and DTI-based measures were sensitive to distinct components of brain structure. Age-related cortical thinning and increased diffusion were observed across most of the cortex, but increased T1-weighted intensities (frontal), reduced T2-weighted intensities (occipital), and reduced anisotropy (medial) were limited to confined cortical regions. Vision loss was associated with cortical thinning and enhanced diffusion in the gray matter (less in the white matter) of the occipital central visual field representation. Moreover, AMD (but not JMD) patients showed enhanced diffusion in lateral occipito-temporal cortex and cortical thinning in the posterior cingulum. These findings demonstrate that changes in brain structure are best quantified by multimodal imaging. They further suggest that age-related brain atrophies (cortical thinning) reflect diverse micro-structural etiologies. Moreover, juvenile and age-related macular degeneration are associated with distinct patterns of micro-structural alterations.

Neuromodulators such as monoamines are often expressed in neurons that also release at least one fast-acting neurotransmitter. The release of a combination of transmitters provides both “classical” and “modulatory” signals that could produce diverse and/or complementary effects in associated circuits. Here, we establish that the majority of Drosophila octopamine (OA) neurons are also glutamatergic and identify the individual contributions of each neurotransmitter on sex-specific behaviors. Males without OA display low levels of aggression and high levels of inter-male courtship. Males deficient for dVGLUT solely in OA-glutamate neurons (OGNs) also exhibit a reduction in aggression, but without a concurrent increase in inter-male courtship. Within OGNs, a portion of VMAT and dVGLUT puncta differ in localization suggesting spatial differences in OA signaling. Our findings establish a previously undetermined role for dVGLUT in OA neurons and suggests that glutamate uncouples aggression from OA-dependent courtship-related behavior. These results indicate that dual neurotransmission can increase the efficacy of individual neurotransmitters while maintaining unique functions within a multi-functional social behavior neuronal network., Author summary Neurons communicate with each other via electrical events and the release of chemical signals. An emerging challenge in understanding neuron communication is the realization that many neurons release more than one type of chemical signal or neurotransmitter. Here we ask how does the release of more than one neurotransmitter from a single neuron impact circuits that control behavior? We determined the monoamine octopamine and the classical transmitter glutamate are co-expressed in the Drosophila adult CNS. By manipulating the release of glutamate in OA-glutamate neurons, we demonstrated glutamate has both separable actions and complementary actions with OA on aggression and reproductive behaviors respectively. Aggression is a behavior that is highly conserved between organisms and present in many human disease states, including depression and Alzheimer’s disease. Our results show that aggressive behavior requires the release of both neurotransmitters in dual-transmitting neurons and suggests within this set of neurons, glutamate may provide a new therapeutic target to modulate aggression in pathological conditions.

BackgroundReward associations during auditory learning induce cortical plasticity in the primary auditory cortex. A prominent source of such influence is the ventral tegmental area (VTA), which conveys a dopaminergic teaching signal to the primary auditory cortex. It is currently unknown, however, how the VTA circuitry thereby influences cortical frequency information processing and spectral integration. In this study, we therefore investigated the temporal effects of direct optogenetic stimulation of the VTA onto spectral integration in the auditory cortex on a synaptic circuit level by current-source-density analysis in anesthetized Mongolian gerbils.ResultsWhile auditory lemniscal input predominantly terminates in the granular input layers III/IV, we found that VTA-mediated modulation of spectral processing is relayed by a different circuit, namely enhanced thalamic inputs to the infragranular layers Vb/VIa. Activation of this circuit yields a frequency-specific gain amplification of local sensory input and enhances corticocortical information transfer, especially in supragranular layers I/II. This effects further persisted over more than 30 minutes after VTA stimulation.ConclusionsAltogether, we demonstrate that the VTA exhibits a long-lasting influence on sensory cortical processing via infragranular layers transcending the signaling of a mere reward-prediction error. Our findings thereby demonstrate a cellular and circuit substrate for the influence of reinforcement-evaluating brain systems on sensory processing in the auditory cortex.

The layers of the neocortex each have a unique anatomical connectivity and functional role. Their exploration in the human brain, however, has been severely restricted by the limited spatial resolution of non-invasive measurement techniques. Here, we exploit the sensitivity and specificity of ultra-high field fMRI at 7 Tesla to investigate responses to natural sounds at deep, middle, and superficial cortical depths of the human auditory cortex. Specifically, we compare the performance of computational models that represent different hypotheses on sound processing inside and outside the primary auditory cortex (PAC). We observe that while BOLD responses in deep and middle PAC layers are equally well represented by a simple frequency model and a more complex spectrotemporal modulation model, responses in superficial PAC are better represented by the more complex model. This indicates an increase in processing complexity in superficial PAC, which remains present throughout cortical depths in the non-primary auditory cortex. These results suggest that a relevant transformation in sound processing takes place between the thalamo-recipient middle PAC layers and superficial PAC. This transformation may be a first computational step towards sound abstraction and perception, serving to form an increasingly more complex representation of the physical input.

The neocortex is densely innervated by basal forebrain (BF) cholinergic neurons. Long-range axons of cholinergic neurons regulate higher-order cognitive function and dysfunction in the neocortex by releasing acetylcholine (ACh). ACh release dynamically reconfigures neocortical microcircuitry through differential spatiotemporal actions on cell-types and their synaptic connections. At the cellular level, ACh release controls neuronal excitability and firing rate, by hyperpolarizing or depolarizing target neurons. At the synaptic level, ACh impacts transmission dynamics not only by altering the presynaptic probability of release, but also the magnitude of the postsynaptic response. Despite the crucial role of ACh release in physiology and pathophysiology, a comprehensive understanding of the way it regulates the activity of diverse neocortical cell-types and synaptic connections has remained elusive. This review aims to summarize the state-of-the-art anatomical and physiological data to develop a functional map of the cellular, synaptic and microcircuit effects of ACh in the neocortex of rodents and non-human primates, and to serve as a quantitative reference for those intending to build data-driven computational models on the role of ACh in governing brain states.

The human prefrontal cortex (PFC) has been shown to be important for metacognition, the capacity to monitor and control one's own cognitive processes. Here we dissected the neural architecture of somatosensory metacognition using navigated single-pulse transcranial magnetic stimulation (TMS) to modulate tactile working memory (WM) processing. We asked subjects to perform tactile WM tasks and to give a confidence rating for their performance after each trial. We circumvented the challenge of interindividual variability in functional brain anatomy by applying TMS to two PFC areas that, according to tractography, were neurally connected with the primary somatosensory cortex (S1): one area in the superior frontal gyrus (SFG), another in the middle frontal gyrus (MFG). These two PFC locations and a control cortical area were stimulated during both spatial and temporal tactile WM tasks. We found that tractography-guided TMS of the SFG area selectively enhanced metacognitive accuracy of tactile temporal, but not spatial WM. Stimulation of the MFG area that was also neurally connected with the S1 had no such effect on metacognitive accuracy of either the temporal or spatial tactile WM. Our findings provide causal evidence that the PFC contains distinct neuroanatomical substrates for introspective accuracy of tactile WM.

Huntington's disease (HD) is an autosomal dominantly inherited, and currently untreatable, neuropsychiatric disorder. This progressive and ultimately fatal disease is named after the American physician George Huntington and according to the underlying molecular biological mechanisms is assigned to the human polyglutamine or CAG-repeat diseases. In the present article we give an overview of the currently known neurodegenerative hallmarks of the brains of HD patients. Subsequent to recent pathoanatomical studies the prevailing reductionistic concept of HD as a human neurodegenerative disease, which is primarily and more or less exclusively confined to the striatum (ie, caudate nucleus and putamen) has been abandoned. Many recent studies have improved our neuropathological knowledge of HD; many of the early groundbreaking findings of neuropathological HD research have been rediscovered and confirmed. The results of this investigation have led to the stepwise revision of the simplified pathoanatomical and pathophysiological HD concept and culminated in the implementation of the current concept of HD as a multisystem degenerative disease of the human brain. The multisystem character of the neuropathology of HD is emphasized by a brain distribution pattern of neurodegeneration (i) which apart from the striatum includes the cerebral neo-and allocortex, thalamus, pallidum, brainstem and cerebellum, and which (ii) therefore, shares more similarities with polyglutamine spinocerebellar ataxias than previously thought.

Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning. © 2015 Wiley Periodicals, Inc. Dev Psychobiol 58: 315-327, 2016.

We conducted a comparative analysis of primate cerebral size and neocortical folding using magnetic resonance imaging data from 65 individuals belonging to 34 different species. We measured several neocortical folding parameters and studied their evolution using phylogenetic comparative methods. Our results suggest that the most likely model for neuroanatomical evolution is one where differences appear randomly (the Brownian Motion model), however, alternative models cannot be completely ruled out. We present estimations of the ancestral primate phenotypes as well as estimations of the rates of phenotypic change. Based on the Brownian Motion model, the common ancestor of primates may have had a folded cerebrum similar to that of a small lemur such as the aye-aye. Finally, we observed a non-linear relationship between fold wavelength and fold depth with cerebral volume. In particular, gyrencephalic primate neocortices across different groups exhibited a strikingly stable fold wavelength of about 12 mm (± 20%), despite a 20-fold variation in cerebral volume. We discuss our results in the context of current theories of neocortical folding.

Cortical involvement in postural control is well recognized, however the role of non-visual afferents remains unclear. Parietal cortical areas are strongly implicated in vestibulo-spatial functions, but topographical localization during balance tasks remains limited. Here, we use electroencephalography (EEG) during continuous balance tasks of increasing difficulty at single electrode positions. Twenty-four healthy, right-handed individuals performed four balance tasks of increasing difficulty (bipedal and unipedal) and a seated control condition with eyes closed. Subjective ratings of task difficulty were obtained. EEG was recorded from 32 electrodes; 5 overlying sensory and motor regions of interest (ROIs) were chosen for further investigation: C3, Cz, C4, P3, P4. Spectral power and coherence during balance tasks were analyzed in theta (4–8 Hz) and alpha (8–12 Hz) bands. Alpha power reduced as task difficulty increased and this reduction correlated with subjective difficulty ratings. Alpha coherence increased with task difficulty between C3–Cz–C4 electrode pairs. Differential changes in power were observed in Cz, suggestive of a distinct role at this electrode location, which captures lower limb cortical representation. Hemispheric asymmetry was observed, as reflected by greater reductions in theta and alpha power in right-sided areas. Our results demonstrate the functional importance of bilateral central and parietal cortices in continuous balance control. The hemispheric asymmetry observed implies that the non-dominant hemisphere is involved with online monitoring of postural control. Although the posterior parietal asymmetry found may relate to vestibular, somatosensory or multisensory feedback processing, we argue that the finding relates to active balance control rather than simple sensory-intake or reflex circuit activation.

The mouse brain is the most extensively studied brain of all species. We performed an exhaustive review of the literature to establish our current state of knowledge on cell numbers in mouse brain regions, arguably the most fundamental property to measure when attempting to understand a brain. The synthesized information, collected in one place, can be used by both theorists and experimentalists. Although for commonly-studied regions cell densities could be obtained for principal cell types, overall we know very little about how many cells are present in most brain regions and even less about cell-type specific densities. There is also substantial variation in cell density values obtained from different sources. This suggests that we need a new approach to obtain cell density datasets for the mouse brain.

Understanding the underlying mechanisms of the human brain in health and disease will require models with necessary and sufficient details to explain how function emerges from the underlying anatomy and is shaped by neuromodulation. Here, we provide such a detailed causal explanation using a whole-brain model integrating multimodal imaging in healthy human participants undergoing manipulation of the serotonin system. Specifically, we combined anatomical data from diffusion magnetic resonance imaging (dMRI) and functional magnetic resonance imaging (fMRI) with neurotransmitter data obtained with positron emission tomography (PET) of the detailed serotonin 2A receptor (5-HT2AR) density map. This allowed us to model the resting state (with and without concurrent music listening) and mechanistically explain the functional effects of 5-HT2AR stimulation with lysergic acid diethylamide (LSD) on healthy participants. The whole-brain model used a dynamical mean-field quantitative description of populations of excitatory and inhibitory neurons as well as the associated synaptic dynamics, where the neuronal gain function of the model is modulated by the 5-HT2AR density. The model identified the causative mechanisms for the non-linear interactions between the neuronal and neurotransmitter system, which are uniquely linked to (1) the underlying anatomical connectivity, (2) the modulation by the specific brainwide distribution of neurotransmitter receptor density, and (3) the non-linear interactions between the two. Taking neuromodulatory activity into account when modeling global brain dynamics will lead to novel insights into human brain function in health and disease and opens exciting possibilities for drug discovery and design in neuropsychiatric disorders., ERC Advanced Grant DYSTRUCTURE (295129), the Spanish Research ProjectPSI2016-75688-P, and the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 785907 (Human Brain Project SGA2). ERC Consolidator Grant: CAREGIVING (615539) and Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117). Alex Mosley Charitable Trust, and the study that yielded the empirical LSD data was carried out as part of a Beckley-Imperial research collaboration. J. Cabral is supported under the project NORTE-01-0145-FEDER-000023 from the Northern Portugal Regional Operational Program (NORTE 2020) under the Portugal 2020 Partnership Agreement through the European Regional Development Fund (FEDER). Cimbi database were supported by a centre grant from the Lundbeck Foundation (2010-5364)

Glycine receptors (GlyRs) containing the α2 subunit are highly expressed in the developing brain, where they regulate neuronal migration and maturation, promote spontaneous network activity and subsequent development of synaptic connections. Mutations in GLRA2 are associated with autism spectrum disorder, but the underlying pathophysiology is not described yet. Here, using Glra2-knockout mice, we found a GlyR-dependent effect on neonatal spontaneous activity of dorsal striatum medium spiny neurons (MSNs) and maturation of the incoming glutamatergic innervation. Our data demonstrate that functional GlyRs are highly expressed in MSNs of one-week-old mice, but they do not generate endogenous chloride-mediated tonic or phasic current. Despite of that, knocking out the Glra2 severely affects the shape of action potentials and impairs spontaneous activity and the frequency of miniature AMPA receptor-mediated currents in MSNs. This reduction in spontaneous activity and glutamatergic signaling can attribute to the observed changes in neonatal behavioral phenotypes as seen in ultrasonic vocalizations and righting reflex. In adult Glra2-knockout animals, the glutamatergic synapses in MSNs remain functionally underdeveloped. The number of glutamatergic synapses and release probability at presynaptic site remain unaffected, but the amount of postsynaptic AMPA receptors is decreased. This deficit is a consequence of impaired development of the neuronal circuitry since acute inhibition of GlyRs by strychnine in adult MSNs does not affect the properties of glutamatergic synapses. Altogether, these results demonstrate that GlyR-mediated signaling supports neonatal spontaneous MSN activity and, in consequence, promotes the functional maturation of glutamatergic synapses on MSNs. The described mechanism might shed light on the pathophysiological mechanisms in GLRA2-linked autism spectrum disorder cases., SCOPUS: ar.j, info:eu-repo/semantics/published

Repetitive excessive alcohol intoxication leads to neuronal damage and brain shrinkage. We examined cytoskeletal protein expression in human post-mortem tissue from Brodmann&rsquo, s area 9 of the prefrontal cortex (PFC). Brain samples from 44 individuals were divided into equal groups of 11 control, 11 alcoholic, 11 non-alcoholic suicides, and 11 suicide alcoholics matched for age, sex, and post-mortem delay. Tissue from alcoholic cohorts displayed significantly reduced expression of &alpha, and &beta, tubulins, and increased levels of acetylated &alpha, tubulin. Protein levels of histone deacetylase-6 (HDAC6), and the microtubule-associated proteins MAP-2 and MAP-tau were reduced in alcoholic cohorts, although for MAPs this was not significant. Tubulin gene expressions increased in alcoholic cohorts but not significantly. Brains from rats administered alcohol for 4 weeks also displayed significantly reduced tubulin protein levels and increased &alpha, tubulin acetylation. PFC tissue from control subjects had reduced tubulin protein expression that was most notable from the sixth to the eighth decade of life. Collectively, loss of neuronal tubulin proteins are a hallmark of both chronic alcohol consumption and natural brain ageing. The reduction of cytosolic tubulin proteins could contribute to the brain volumetric losses reported for alcoholic patients and the elderly.

OBJECTIVE: Electrical impedance tomography (EIT) can be used to image impedance changes associated with epileptiform activity and so holds therapeutic potential for improving presurgical localisation of the ictal onset zone in patients with treatment-resistant epilepsy. There are two principal impedance changes which occur during seizures that may be imaged with EIT: (a) a fast, transient impedance decrease over milliseconds due to hypersynchronous neuronal depolarisation in individual ictal discharges; and (b) a larger, slow impedance increase caused by cell swelling over the course of the seizure. The magnitude of these signals is highly dependent on the carrier frequency of applied current used for obtaining impedance measurements. The purpose of this work was to characterise the frequency response of the fast and slow impedance changes during epileptiform activity. APPROACH: Seizures were induced in anaesthetised rats by electrically stimulating the cerebral cortex. During each seizure, impedance measurements were obtained by delivering 50 µA, through two electrodes on an epicortical array, at one of 20 frequencies in the 1-10 kHz range. Recordings were demodulated to determine the magnitude of fast and slow impedance responses at each frequency. MAIN RESULTS: The fast impedance change during averaged ictal discharges reached a maximal amplitude and signal-to-noise ratio (SNR) of -0.36% ± 0.05% and 50.2 ± 11.3, respectively, at 1355 Hz. At this frequency, the slow impedance change had an amplitude of 4.61% ± 1.32% and an SNR of 545 ± 125, which did not significantly change across frequency (p > 0.01). SIGNIFICANCE: We conclude that the optimal frequency for imaging epileptiform activity is 1355 Hz, which maximises the SNR of fast neural changes whilst enabling simultaneous measurement of slow changes. These findings will inform future investigations aimed at imaging epilepsy in subcortical brain structures, where SNR is considerably reduced, and those using parallel, multi-frequency EIT.

Architecture of phase relationships among neural oscillations is central for their functional significance but has remained theoretically poorly understood. We use phenomenological model of delay-coupled oscillators with increasing degree of topological complexity to identify underlying principles by which the spatio-temporal structure of the brain governs the phase lags between oscillatory activity at distant regions. Phase relations and their regions of stability are derived and numerically confirmed for two oscillators and for networks with randomly distributed or clustered bimodal delays, as a first approximation for the brain structural connectivity. Besides in-phase, clustered delays can induce anti-phase synchronization for certain frequencies, while the sign of the lags is determined by the natural frequencies and by the inhomogeneous network interactions. For in-phase synchronization faster oscillators always phase lead, while stronger connected nodes lag behind the weaker during frequency depression, which consistently arises for in-silico results. If nodes are in anti-phase regime, then a distance π is added to the in-phase trends. The statistics of the phases is calculated from the phase locking values (PLV), as in many empirical studies, and we scrutinize the method's impact. The choice of surrogates do not affects the mean of the observed phase lags, but higher significance levels that are generated by some surrogates, cause decreased variance and might fail to detect the generally weaker coherence of the interhemispheric links. These links are also affected by the non-stationary and intermittent synchronization, which causes multimodal phase lags that can be misleading if averaged. Taken together, the results describe quantitatively the impact of the spatio-temporal connectivity of the brain to the synchronization patterns between brain regions, and to uncover mechanisms through which the spatio-temporal structure of the brain renders phases to be distributed around 0 and π.Trial registrationSouth African Clinical Trials Register: http://www.sanctr.gov.za/SAClinicalbrnbspTrials/tabid/169/Default.aspx, then link to respiratory tract then link to tuberculosis, pulmonary; and TASK Applied Sciences Clinical Trials, AP-TB-201-16 (ALOPEXX): https://task.org.za/clinical-trials/.

The building of the brain is a multistep process that requires the coordinate expression of thousands of genes and an intense nucleocytoplasmic transport of RNA and proteins. This transport is mediated by karyopherins that comprise importins and exportins. Here, we investigated the role of the beta-importin, importin-8 (IPO8) during mouse cerebral corticogenesis as several of its cargoes have been shown to be essential during this process. First, we showed that Ipo8 mRNA is expressed in mouse brain at various embryonic ages with a clear signal in the sub-ventricular/ventricular zone (SVZ/VZ), the cerebral cortical plate (CP) and the ganglionic eminences. We found that acute knockdown of IPO8 in cortical progenitors reduced both their proliferation and cell cycle exit leading to the increase in apical progenitor pool without influencing the number of basal progenitors (BPs). Projection neurons ultimately reached their appropriate cerebral cortical layer, but their dendritogenesis was specifically affected, resulting in neurons with reduced dendrite complexity. IPO8 knockdown also slowed the migration of cortical interneurons. Together, our data demonstrate that IPO8 contribute to the coordination of several critical steps of cerebral cortex development. These results suggest that the impairment of IPO8 function might be associated with some diseases of neuronal migration defects.

The cerebral cortex underwent rapid expansion and increased complexity during recent hominid evolution. Gene duplications constitute a major evolutionary force, but their impact on human brain development remains unclear. Using tailored RNA sequencing (RNA-seq), we profiled the spatial and temporal expression of hominid-specific duplicated (HS) genes in the human fetal cortex and identified a repertoire of 35 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among them NOTCH2NL, human-specific paralogs of the NOTCH2 receptor, stood out for their ability to promote cortical progenitor maintenance. NOTCH2NL promote the clonal expansion of human cortical progenitors, ultimately leading to higher neuronal output. At the molecular level, NOTCH2NL function by activating the Notch pathway through inhibition of cis Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes active during human corticogenesis and reveals how human-specific NOTCH paralogs may have contributed to the expansion of the human cortex. Human-specific NOTCH2NL expands cortical progenitors and neuronal output and thus may have contributed to the expansion of the human cortex., SCOPUS: ar.j, info:eu-repo/semantics/published

Summary The transplantation of pluripotent stem-cell-derived neurons constitutes a promising avenue for the treatment of several brain diseases. However, their potential for the repair of the cerebral cortex remains unclear, given its complexity and neuronal diversity. Here, we show that human visual cortical cells differentiated from embryonic stem cells can be transplanted and can integrate successfully into the lesioned mouse adult visual cortex. The transplanted human neurons expressed the appropriate repertoire of markers of six cortical layers, projected axons to specific visual cortical targets, and were synaptically active within the adult brain. Moreover, transplant maturation and integration were much less efficient following transplantation into the lesioned motor cortex, as previously observed for transplanted mouse cortical neurons. These data constitute an important milestone for the potential use of human PSC-derived cortical cells for the reassembly of cortical circuits and emphasize the importance of cortical areal identity for successful transplantation., Graphical Abstract, Highlights • Human PSC-derived cortical neurons efficiently integrate into the adult mouse brain • PSC-derived human neurons reestablish axonal pathways in the lesioned adult cortex • Restoration of cortical pathways requires a donor and recipient area-identity match, Espuny-Camacho et al. show that transplanted ESC-derived human cortical neurons integrate functionally into the lesioned adult mouse brain. Transplanted neurons display visual cortical identity and show specific restoration of damaged cortical pathways following transplantation into the visual but not the motor cortex, suggesting the importance of areal-identity match for successful cortical repair.

INTRODUCTION Scientists are building detailed maps of the cellular composition in the human brain to learn about its development. In the human cortex, the largest area of the mammalian brain, neural circuits are formed through anatomical refinement, including axon and synaptic pruning, and the emergence of complex patterns of network activity during early fetal development. Cellular analyses in the human brain are restricted to postmortem material, which cannot reveal the process of development. Model organisms are, therefore, commonly used for studies of brain physiology, development, and pathogenesis, but the results from model organisms do not always translate to humans. RATIONALE Systems to model human neuron dynamics and their dysfunction in vivo are needed. While biopsy specimens and the generation of neurons from induced pluripotent stem cells (iPSCs) could provide the necessary human genetic background, two- and three-dimensional cultures lack factors that normally support neuronal development, including blood vessels, immune cells, and interaction with innervating neurons from other brain areas. On the basis of previous stem cell transplantation studies in mice, we reasoned that the physiological microenvironment of the adult mouse brain could support the growth of human cortical tissue grafts that had been generated from iPSC-derived neuronal progenitors. With human neurons implanted into the mouse brain, high-resolution, real-time in vivo monitoring of human neuron dynamics for periods of time spanning the range from subseconds to several months becomes feasible. RESULTS We found that transplanted human iPSC–derived neuronal progenitors consistently assembled into vascularized territories with complex cytoarchitecture, mimicking key features of the human fetal cortex, such as its large size and cell diversification. Single-cell-resolution intravital microscopy showed that human neuronal arbors were refined via branch-specific retraction, rather than degeneration. Human synaptic networks restructured over the course of 4 months, while maintaining balanced rates of synapse formation and elimination. Human functional neurons rapidly and consistently acquired oscillatory population activity, which persisted over the 5-month observation period. Lastly, we used cortical tissue grafts derived from the fibroblasts of two individuals with Down syndrome, caused by supernumerary chromosome 21. We found that neuronal synapses in cells derived from these individuals were overly stable and that oscillatory neural activity was reduced in these grafts, revealing in vivo cellular phenotypes not otherwise apparent. CONCLUSION By combining live imaging in a multistructured tissue environment in mice with a human-specific genetic background, we provide insights into the earliest stages of human axon, synaptic, and network activity development and uncover cellular phenotypes in Down syndrome. Our work provides an alternative experimental system that can be used to study other disorders affecting the developing human cortex.

Background: There are indications that transcranial electrical stimulation (TES) assesses the motor function of the spinal cord in horses in a more sensitive and reproducible fashion than transcranial magnetic stimulation (TMS). However, no normative data of TES evoked motor potentials (MEP) is available.In this prospective study normative data of TES induced MEP wave characteristics (motor latency times (MLT); amplitude and waveform) was obtained from the extensor carpi radialis (ECR) and tibial cranialis (TC) muscles in a group of healthy horses to create a reference frame for functional diagnostic purposes. For the 12 horses involved in the study 95% confidence intervals for MLTs were 16.1-22.6 ms and 31.9-41.1 ms for ECR and TC muscles respectively. Intraindividual coefficients of variation (CV) and mean of MLTs were: ECR: 2.2-8,2% and 4.5% and TC: 1.4-6.3% and 3.5% respectively. Inter-individual CVs for MLTs were higher, though below 10% on all occasions. The mean +/- sd of MEP amplitudes was respectively 3.61 +/- 2.55 mV (ECR muscle left) and 4.53 +/- 3.1 mV (right) and 2.66 +/- 2.22 mV (TC muscle left) and 2.55 +/- 1.85 mV (right). MLTs showed no significant left versus right differences. All MLTs showed significant (p Conclusions: TES is a novel and sensitive technique to assess spinal motor function in horses. It is easy applicable and highly reproducible. This study provides normative data in healthy horses on TES induced MEPs in the extensor carpi radialis and tibialis cranialis muscles bilaterally. No significant differences between MLTs of the left and right side could be demonstrated. A significant effect of stimulation voltage on MLTs was found. No significant effect of height at the withers could be found based upon the results of the current study. A study in which both TMS and TES are applied on the same group of horses is needed.

for the INSIGHT-preAD study group; International audience; The accumulation of amyloid plaques is one of the earliest pathological changes in Alzheimer's disease (AD) and may occur 20 years before the onset of symptoms. Examining associations between amyloid pathology and other early brain changes is critical for understanding the pathophysiological underpinnings of AD. Alterations in gray matter networks might already start at early preclinical stages of AD. In this study, we examined the regional relationship between amyloid aggregation measured with positron emission tomography (PET) and gray matter network measures in elderly subjects with subjective memory complaints. Single-subject gray matter networks were extracted from T1-weigthed structural MRI in cognitively normal subjects (n = 318, mean age 76.1 ± 3.5, 64% female, 28% amyloid positive). Degree, clustering, path length and small world properties were computed. Global and regional amyloid load was determined using [ 18 F]-Florbetapir PET. Associations between standardized uptake value ratio (SUVr) values and network measures were examined using linear regression models. We found that higher global SUVr was associated with lower clustering (β = −0.12, p < 0.05), and small world values (β = −0.16, p < 0.01). Associations were most prominent in orbito-and dorsolateral frontal and parieto-occipital regions. Local SUVr values showed less anatomical variability and did not convey additional information beyond global amyloid burden. In conclusion, we found that in cognitively normal elderly subjects, increased global amyloid pathology is associated with alterations in gray matter networks that are indicative of incipient network breakdown towards AD dementia.

Neural stem cells (NSCs) often give rise to a mixed population of cells during differentiation. However, the dynamical origin of these mixed states is poorly understood. In this article, our mathematical modeling study demonstrates that the bone morphogenetic protein 2 (BMP2) mediated disparate differentiation dynamics of NSCs in central and peripheral nervous systems essentially function through two distinct bistable switches that are mutually interconnected via a mushroom-like bifurcation. Stochastic simulations of the model reveal that the mixed population originates due to the existence of these bistable switching regulations and that the maintenance of such mixed states depends on the level of stochastic fluctuations of the system. It further demonstrates that due to extrinsic variability, cells in an NSC population can dynamically transit from mushroom to a unique isola kind of bifurcation state, which essentially extends the range of the BMP2-driven mixed population state during differentiation. Importantly, the model predicts that by individually altering the expression level of key regulatory proteins, the NSCs can be converted entirely to a preferred phenotype for BMP2 doses that previously resulted in a mixed population. Our findings show that efficient neuronal regeneration can be achieved by systematically maneuvering the differentiation dynamics.

Compared to transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES) more specifically assesses the motor function of the spinal cord and excludes reproducibility errors from coil repositioning. Objective: to assess the applicability of multipulse TES in horses and retrieve optimal TES parameters to elicit muscular motor-evoked potentials in the m. extensor carpi radialis (ECR) and the m. tibialis cranialis (TC) in a scouting study. This is a prospective observational study in five healthy horses based on TES as a novel alternative to TMS to assess the motor function of the spinal cord for clinical diagnosis in search for optimal settings of stimulation parameters. After sedation, a subcutaneous anesthetic ring block was placed on the forehead around bilateral TES needle electrodes. In each step of a specific parameter optimizing protocol, one parameter was varied while leaving others at default values: TES motor threshold +30 V, n = 3 pulses/train (ppt), interpulse interval (ipi) = 1.3 ms, and 0.1 ms/phase biphasic pulses. Variable parameters were TES voltage (0–200 V), n (1–5 ppt), and ipi (0.5–4.5 ms). A multipulse facilitation factor (MPFF) quantified the motor neuron recruitment gain by multipulse stimulation. Mean latency times, MPFF, optimal ipi, and n for the ECR muscles were, respectively, 18.6 (1.26) (mean[SD]) ms, 7.1 (3.4), 1.25 (0.21) ms, 3.0 (1.4) ppt (left) and 18.4 (1.10) ms, 4.3 (1.4), 1.9 (0.7) ms, 3.5 (1.3) ppt (right) and for the TC muscles, respectively, 34.5 (0.96) ms, 5.3 (2.4), 1.2 (0.28) ms, 3.3 (1.0) ppt (left) and 33.4 (1.52) ms, 17.5 (21.2), 1.3 (0,17) ms, 3.3 (0.5) ppt (right). Optimal multipulse TES parameters were n = 3 ppt and ipi = 1.2 to 1.3 ms. Multipulse TES is well tolerated and an attractive alternative to TMS. Transcranial electrical stimulation is expected to be a more robust technique than TMS for evaluation of spinal motor function in horses. A better reproducibility of repeated stimulations is expected due to fixed electrodes, and a reduced sensitivity to hyperpolarizing effects of sedatives is expected.

Ionizing radiation is a potent activator of the tumor suppressor gene p53, which itself regulates the transcription of genes involved in canonical pathways such as the cell cycle, DNA repair and apoptosis as well as other biological processes like metabolism, autophagy, differentiation and development. In this study, we performed a meta-analysis on gene expression data from different in vivo and in vitro experiments to identify a signature of early radiation-responsive genes which were predicted to be predominantly regulated by p53. Moreover, we found that several genes expressed different transcript isoforms after irradiation in a p53-dependent manner. Among this gene signature, we identified novel p53 targets, some of which have not yet been functionally characterized. Surprisingly, in contrast to genes from the canonical p53-regulated pathways, our gene signature was found to be highly enriched during embryonic and post-natal brain development and during in vitro neuronal differentiation. Furthermore, we could show that for a number of genes, radiation-responsive transcript variants were upregulated during development and differentiation, while radiation non-responsive variants were not. This suggests that radiation exposure of the developing brain and immature cortical neurons results in the p53-mediated activation of a neuronal differentiation program. Overall, our results further increase the knowledge of the radiation-induced p53 network of the embryonic brain and provide more evidence concerning the importance of p53 and its transcriptional targets during mouse brain development. ispartof: Biology Open vol:4 issue:3 pages:331-44 ispartof: location:England status: published

Frontiers in Neuroinformatics, 12, ISSN:1662-5196

Understanding the mechanisms of neurodegeneration is crucial for development of therapies to treat neurological disorders. S100 proteins are extensively expressed in the injured brain but S100's role and signalling in neural cells remain elusive. We recently demonstrated that the S100A4 protein protects neurons in brain injury and designed S100A4-derived peptides mimicking its beneficial effects. Here we show that neuroprotection by S100A4 involves the growth factor family receptor ErbB4 and its ligand Neuregulin 1 (NRG), key regulators of neuronal plasticity and implicated in multiple brain pathologies. The neuroprotective effect of S100A4 depends on ErbB4 expression and the ErbB4 signalling partners ErbB2/Akt, and is reduced by functional blockade of NRG/ErbB4 in cell models of neurodegeneration. We also detect binding of S100A4 with ErbB1 (EGFR) and ErbB3. S100A4-derived peptides interact with, and signal through ErbB, are neuroprotective in primary and immortalized dopaminergic neurons, and do not affect cell proliferation/motility - features which make them promising as potential neuroprotectants. Our data suggest that the S100- ErbB axis may be an important mechanism regulating neuronal survival and plasticity

BackgroundOur understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.MethodsThis study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).ResultsMeta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (βstd = −0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.ConclusionsUsing an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Background 22q11.2 deletion syndrome (22q11DS) is the third-largest known genetic risk factor for the development of psychosis. Dysconnectivity has consistently been implicated in the physiopathology of psychosis. Structural covariance of cortical morphology is a method of exploring connectivity among brain regions that to date has not been employed in 22q11DS. Methods In the present study we employed structural covariance of cortical thickness to explore connectivity alterations in a group of 108 patients with 22q11DS compared with 96 control subjects. We subsequently divided patients into two subgroups of 31 subjects each according to the presence of attenuated psychotic symptoms. FreeSurfer software was used to obtain the mean cortical thickness in 148 brain regions from T1-weighted 3T images. For each population we reconstructed a brain graph using Pearson correlation between the average thickness of each couple of brain regions, which we characterized in terms of mean correlation strength and in terms of network architecture using graph theory. Results Patients with 22q11DS presented increased mean correlation strength, but there was no difference in global architecture compared with control subjects. However, symptomatic patients presented increased mean correlation strength coupled with increased segregation and decreased integration compared with both control subjects and nonsymptomatic patients. They also presented increased centrality for a cluster of anterior cingulate and dorsomedial prefrontal regions. Conclusions These results confirm the importance of cortical dysconnectivity in the physiopathology of psychosis. Moreover they support the significance of aberrant anterior cingulate connectivity.

We evaluate a fully automatic technique for labeling hippocampal subfields and cortical subregions in the medial temporal lobe in in vivo 3 Tesla MRI. The method performs segmentation on a T2-weighted MRI scan with 0.4 x 0.4 x 2.0 mm(3) resolution, partial brain coverage, and oblique orientation. Hippocampal subfields, entorhinal cortex, and perirhinal cortex are labeled using a pipeline that combines multi-atlas label fusion and learning-based error correction. In contrast to earlier work on automatic subfield segmentation in T2-weighted MRI [Yushkevich et al., 2010], our approach requires no manual initialization, labels hippocampal subfields over a greater anterior-posterior extent, and labels the perirhinal cortex, which is further subdivided into Brodmann areas 35 and 36. The accuracy of the automatic segmentation relative to manual segmentation is measured using cross-validation in 29 subjects from a study of amnestic mild cognitive impairment (aMCI) and is highest for the dentate gyrus (Dice coefficient is 0.823), CA1 (0.803), perirhinal cortex (0.797), and entorhinal cortex (0.786) labels. A larger cohort of 83 subjects is used to examine the effects of aMCI in the hippocampal region using both subfield volume and regional subfield thickness maps. Most significant differences between aMCI and healthy aging are observed bilaterally in the CA1 subfield and in the left Brodmann area 35. Thickness analysis results are consistent with volumetry, but provide additional regional specificity and suggest nonuniformity in the effects of aMCI on hippocampal subfields and MTL cortical subregions. Hum Brain Mapp, 36:258-287, 2015. (c) 2014 Wiley Periodicals, Inc.

Alzheimer's disease (AD) is a neurological disorder that creates neurodegenerative changes at several structural and functional levels in human brain tissue. The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of the human brain. In this study, we investigate spherical harmonic-based FD (SHFD), thickness, and local gyrification index (LGI) to assess whether they identify cortical surface abnormalities toward the conversion to AD. We study 33 AD patients, 122 mild cognitive impairment (MCI) patients (50 MCI converters and 29 MCI nonconverters), and 32 healthy controls (HC). SHFD, thickness, and LGI methodology allowed us to perform not only global level but also local level assessments in each cortical surface vertex. First, we found that global SHFD decreased in AD and future MCI converters compared to HC, and in MCI converters compared to MCI nonconverters. Second, we found that local white matter SHFD was reduced in AD compared to HC and MCI mainly in medial temporal lobe. Third, local white-matter SHFD was significantly reduced in MCI converters compared to MCI nonconverters in distributed areas, including the medial frontal lobe. Thickness and LGI metrics presented a reduction in AD compared to HC. Thickness was significantly reduced in MCI converters compared to healthy controls in entorhinal cortex and lateral temporal. In summary, SHFD was the only surface measure showing differences between MCI individuals that will convert or remain stable in the next 4 years. We suggest that SHFD may be an optimal complement to thickness loss analysis in monitoring longitudinal changes in preclinical and clinical stages of AD. (C) 2017 Wiley Periodicals, Inc.

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles., The mTOR pathway is a key regulator of normal brain development. Here, the authors identify de novo mutations in RHEB, an mTOR activator protein, in patients with intellectual disability associated with megalencephaly and find a role for RHEB in regulating neuronal soma size and migration in vitro and in vivo.

Electroencephalographic recordings from the developing human brain are characterized by spontaneous neuronal bursts, the most common of which is the delta brush. Although similar events in animal models are known to occur in areas of immature cortex and drive their development, their origin in humans has not yet been identified. Here, we use simultaneous EEG-fMRI to localise the source of delta brush events in 10 preterm infants aged 32–36 postmenstrual weeks. The most frequent patterns were left and right posterior-temporal delta brushes which were associated in the left hemisphere with ipsilateral BOLD activation in the insula only; and in the right hemisphere in both the insular and temporal cortices. This direct measure of neural and hemodynamic activity shows that the insula, one of the most densely connected hubs in the developing cortex, is a major source of the transient bursting events that are critical for brain maturation.

Huntington's disease is an autosomal dominant inherited neurodegenerative disease with motor symptoms that are variably co-expressed with mood and cognitive symptoms, and in which variable neuronal degeneration is also observed in the basal ganglia and the cerebral cortex. We have recently shown that the variable symptomatology in Huntington's disease correlates with the variable compartmental pattern of GABA(A) receptor and cell loss in the striatum. To determine whether the phenotypic variability in Huntington's disease is also related to variable neuronal degeneration in the cerebral cortex, we undertook a double-blind study using unbiased stereological cell counting methods to determine the pattern of cell loss in the primary motor and anterior cingulate cortices in the brains of 12 cases of Huntington's disease and 15 controls, and collected detailed data on the clinical symptomatology of the patients with Huntington's disease from family members and clinical records. The results showed a significant association between: (i) pronounced motor dysfunction and cell loss in the primary motor cortex; and (ii) major mood symptomatology and cell loss in the anterior cingulate cortex. This association held for both total neuronal loss (neuronal N staining) and pyramidal cell loss (SMI32 staining), and also correlated with marked dystrophic changes in the remaining cortical neurons. There was also an association between cortical cell loss and striatal neuropathological grade, but no significant association with CAG repeat length in the Huntington's disease gene. These findings suggest that the heterogeneity in clinical symptomatology that characterizes Huntington's disease is associated with variation in the extent of cell loss in the corresponding functional regions of the cerebral cortex whereby motor dysfunction correlates with primary motor cortex cell loss and mood symptomatology is associated with cell loss in the cingulate cortex.

Gap junctions form electrical synapses that modulate neuronal activity by synchronizing action potential (AP) firing of cortical interneurons (INs). Gap junctions are thought to form predominantly within cortical INs of the same functional class and are therefore considered to act within discrete neuronal populations. Here, we challenge that view and show that the probability of electrical coupling is the same within and between regularspiking (RS) and fast-spiking (FS) cortical INs in 16-21 days old mice. Firing properties of these two populations were distinct from other INs types including neurogliaform and low-threshold spiking (LTS) cells. We also demonstrate that pre-junctional APs can depolarize post-junctional neurons and increase the probability of firing. Our findings of frequent gap junction coupling between functionally distinct IN subtypes suggest that cortical IN networks are much more extensive and heterogeneous than previously thought. This may have implications on mechanisms ranging from cognitive functions to modulation of pathological states in epilepsy and other neurological disorders.

Brain dynamics are thought to unfold on a network determined by the pattern of axonal connections linking pairs of neuronal populations; the so-called connectome. Prior work has indicated that structural brain connectivity constrains pairwise correlations in brain dynamics (also called functional connectivity), but it is not known whether inter-regional axonal connectivity is related to the intrinsic dynamics of individual brain areas. Here we investigate this relationship using a weighted, directed mesoscale mouse connectome from the Allen Mouse Brain Connectivity Atlas and resting state functional MRI (rs-fMRI) time-series data measured in 184 brain regions in eighteen anesthetized mice. For each brain region, we measured degree, betweenness, and clustering coefficient from weighted and unweighted, and directed and undirected versions of the connectome. We then characterized the univariate rs-fMRI dynamics at each brain region by computing 6 930 time-series properties using the time-series analysis toolbox, hctsa. After correcting for regional volume variations, strong and robust correlations between structural connectivity properties and rs-fMRI dynamics were found only when edge weights were accounted for, and were associated with variations in the autocorrelation properties of the rs-fMRI signal. The strongest relationships were found for weighted in-degree, which was positively correlated to the autocorrelation of fMRI time series at time lag τ = 34s (partial Spearman correlation ρ = 0.58), as well as a range of related measures such as relative high frequency power (f > 0.4 Hz: ρ= −0.43). Our results indicate that the topology of inter-regional axonal connections of the mouse brain is closely related to intrinsic, spontaneous dynamics such that regions with a greater aggregate strength of incoming projections display longer timescales of activity fluctuations.

OBJECTIVE: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia.METHOD: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness.RESULTS: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: βstd = -0.052; P = 0.021; right: βstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness.CONCLUSION: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

The axon guidance receptor, Robo1, controls the pathfinding of callosal axons in mice. To determine whether the orthologous ROBO1 gene is involved in callosal development also in humans, we studied polymorphisms in the ROBO1 gene and variation in the white matter structure in the corpus callosum using both structural magnetic resonance imaging and diffusion tensor magnetic resonance imaging. We found that five polymorphisms in the regulatory region of ROBO1 were associated with white matter density in the posterior part of the corpus callosum pathways. One of the polymorphisms, rs7631357, was also significantly associated with the probability of connections to the parietal cortical regions. Our results demonstrate that human ROBO1 may be involved in the regulation of the structure and connectivity of posterior part of corpus callosum.

A consensus on the prefrontal cortex (PFC) holds that it is pivotal for flexible behavior and the integration of the cognitive, affective, and motivational domains. Certain models have been put forth and a dominant model postulates a hierarchical anterior-posterior gradient. The structural connectivity principles of this model dictate that increasingly anterior PFC regions exhibit more efferent connections toward posterior ones than vice versa. Such hierarchical asymmetry principles are thought to pertain to the macaque PFC. Additionally, the laminar patterns of the connectivity of PFC regions can be used for defining hierarchies. In the current study, we formally tested the asymmetry-based hierarchical principles of the anterior-posterior model by employing an exhaustive dataset on macaque PFC connectivity and tools from network science. On the one hand, the asymmetry-based principles and predictions of the hierarchical anterior-posterior model were not confirmed. The wiring of the macaque PFC does not fully correspond to the principles of the model, and its asymmetry-based hierarchical layout does not follow a strict anterior-posterior gradient. On the other hand, our results suggest that the laminar-based hierarchy seems a more tenable working hypothesis for models advocating an anterior-posterior gradient. Our results can inform models of the human PFC.

Seizures in the newborn brain represent a major challenge to neonatal medicine. Neonatal seizures are poorly classified, under-diagnosed, difficult to treat and are associated with poor neurodevelopmental outcome. Video-EEG is the current gold-standard approach for seizure detection and monitoring. Interpreting neonatal EEG requires expertise and the impact of seizures on the developing brain remains poorly understood. In this case study we present the first ever images of the haemodynamic impact of seizures on the human infant brain, obtained using simultaneous diffuse optical tomography (DOT) and video-EEG with whole-scalp coverage. Seven discrete periods of ictal electrographic activity were observed during a 60 minute recording of an infant with hypoxic–ischaemic encephalopathy. The resulting DOT images show a remarkably consistent, high-amplitude, biphasic pattern of changes in cortical blood volume and oxygenation in response to each electrographic event. While there is spatial variation across the cortex, the dominant haemodynamic response to seizure activity consists of an initial increase in cortical blood volume prior to a large and extended decrease typically lasting several minutes. This case study demonstrates the wealth of physiologically and clinically relevant information that DOT–EEG techniques can yield. The consistency and scale of the haemodynamic responses observed here also suggest that DOT–EEG has the potential to provide improved detection of neonatal seizures., Highlights • We present the first DOT images of seizures in an infant with whole-scalp coverage. • In this infant, seizures produce consistent, large, biphasic haemodynamic responses. • DOT reveals spatial variation in seizure response despite generalised EEG activity.

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia., Supported by grants from the Spanish Government to B.R. (SAF2010-21723 and CONSOLIDER CSD2007-00023), O.M. (CSD2007-00023), M.D. (SAF2010-16427), and S.C. (CSD2007-00023, BFU2009-09938 and PIM2010ERN-00679, part of the ERANET NEURON TRANSALC project), from Fundación Alicia Koplowitz to B.R., from the Lilly Research Awards Program to B.R. and O.M., and from Fundació la Marató to O.M., B.R., and M.D. B.R. is an EMBO Young Investigator.

The porcine brain closely resembles the human brain in aspects such as development and morphology. Temporal miRNA profiling in the developing embryonic porcine cortex revealed a distinct set of miRNAs, including miR-34c and miR-204, which exhibited a highly specific expression profile across the time of cortical folding. These miRNAs were found to target Doublecortin (DCX), known to be involved in neuron migration during cortical folding of gyrencephalic brains. In vivo modulation of miRNA expression in mouse embryos confirmed that miR-34c and miR-204 can control neuronal migration and cortical morphogenesis, presumably by posttranscriptional regulation of DCX.

Objective: In this study we introduce the use of the current source density (CSD) method as a way to visualize the spatial behavior of evoked responses in the rat subthalamic nucleus (STN) at fixed time stamps resulting from motor cortex stimulation. This method offers opportunities to visualize neuronal input and study the relation between the synaptic input and the neural output of neural populations. Approach: Motor cortex evoked local field potentials and unit activity were measured in the subthalamic region, with a 3D measurement grid consisting of 320 measurement points and high spatial resolution. This allowed us to visualize the evoked synaptic input by estimating the current source density (CSD) from the measured local field potentials, using the inverse CSD method. At the same time, the neuronal output of the cells within the grid is assessed by calculating post stimulus time histograms. Main results: The CSD method resulted in clear and distinguishable sources and sinks of the neuronal input activity in the STN after motor cortex stimulation. We showed that the center of the synaptic input of the STN from the motor cortex is located dorsal to the input from globus pallidus. Furthermore, our results indicate that the long-latency, long-duration inhibitory period following motor cortex stimulation is caused by activation of inhibitory synapses. Significance: For the first time we have performed CSD analysis on motor cortex stimulation evoked LFP responses in the rat STN as a proof of principle. Our results suggest that the CSD method can be used to gain new insights in the spatial extent of synaptic pathways in brain structures and neural circuits.

Astrocytes are a major cell type in the mammalian CNS. Astrocytes are now known to play a number of essential roles in processes including synapse formation and function, as well as blood-brain barrier formation and control of cerebral blood flow. However, our understanding of the molecular mechanisms underlying astrocyte development and function is still rudimentary. This lack of knowledge is at least partly due to the lack of tools currently available for astrocyte biology. ACSA-2 is a commercially available antibody originally developed for the isolation of astrocytes from young postnatal mouse brain, using magnetic cell-sorting methods, but its utility in isolating cells from adult tissue has not yet been published. Using a modified protocol, we now show that this tool can also be used to isolate ultrapure astrocytes from the adult brain. Furthermore, using a variety of techniques (including single-cell sequencing, overexpression and knockdown assays, immunoblotting, and immunohistochemistry), we identify the ACSA-2 epitope for the first time as ATP1B2 and characterize its distribution in the CNS. Finally, we show that ATP1B2 is stably expressed in multiple models of CNS injury and disease. Hence, we show that the ACSA-2 antibody possesses the potential to be an extremely valuable tool for astrocyte research, allowing the purification and characterization of astrocytes (potentially including injury and disease models) without the need for any specialized and expensive equipment. In fact, our results suggest that ACSA-2 should be a first-choice method for astrocyte isolation and characterization. ispartof: Journal of Biological Chemistry vol:292 issue:21 pages:8874-8891 ispartof: location:United States status: published