Touch and tactile neuropathic pain sensitivity are set by corticospinal projections.

Current models of somatosensory perception emphasize transmission from primary sensory neurons to the spinal cord and on to the brain1-4. Mental influence on perception is largely assumed to occur locally within the brain. Here we investigate whether sensory inflow through the spinal cord undergoes direct top-down control by the cortex. Although the corticospinal tract (CST) is traditionally viewed as a primary motor pathway5, a subset of corticospinal neurons (CSNs) originating in the primary and secondary somatosensory cortex directly innervate the spinal dorsal horn via CST axons. Either reduction in somatosensory CSN activity or transection of the CST in mice selectively impairs behavioural responses to light touch without altering responses to noxious stimuli. Moreover, such CSN manipulation greatly attenuates tactile allodynia in a model of peripheral neuropathic pain. Tactile stimulation activates somatosensory CSNs, and their corticospinal projections facilitate light-touch-evoked activity of cholecystokinin interneurons in the deep dorsal horn. This touch-driven feed-forward spinal-cortical-spinal sensitization loop is important for the recruitment of spinal nociceptive neurons under tactile allodynia. These results reveal direct cortical modulation of normal and pathological tactile sensory processing in the spinal cord and open up opportunities for new treatments for neuropathic pain.

DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors.

Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1ß (NRXN1ß) interaction. DSCAM extracellular domain was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors, such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs.SIGNIFICANCE STATEMENTDSCAM is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1ß interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism.

Reversing behavioural abnormalities in mice exposed to maternal inflammation.

Viral infection during pregnancy is correlated with increased frequency of neurodevelopmental disorders, and this is studied in mice prenatally subjected to maternal immune activation (MIA). We previously showed that maternal T helper 17 cells promote the development of cortical and behavioural abnormalities in MIA-affected offspring. Here we show that cortical abnormalities are preferentially localized to a region encompassing the dysgranular zone of the primary somatosensory cortex (S1DZ). Moreover, activation of pyramidal neurons in this cortical region was sufficient to induce MIA-associated behavioural phenotypes in wild-type animals, whereas reduction in neural activity rescued the behavioural abnormalities in MIA-affected offspring. Sociability and repetitive behavioural phenotypes could be selectively modulated according to the efferent targets of S1DZ. Our work identifies a cortical region primarily, if not exclusively, centred on the S1DZ as the major node of a neural network that mediates behavioural abnormalities observed in offspring exposed to maternal inflammation.

Activity in grafted human iPS cell-derived cortical neurons integrated in stroke-injured rat brain regulates motor behavior.

Stem cell transplantation can improve behavioral recovery after stroke in animal models but whether stem cell-derived neurons become functionally integrated into stroke-injured brain circuitry is poorly understood. Here we show that intracortically grafted human induced pluripotent stem (iPS) cell-derived cortical neurons send widespread axonal projections to both hemispheres of rats with ischemic lesions in the cerebral cortex. Using rabies virus-based transsynaptic tracing, we find that at 6 mo after transplantation, host neurons in the contralateral somatosensory cortex receive monosynaptic inputs from grafted neurons. Immunoelectron microscopy demonstrates myelination of the graft-derived axons in the corpus callosum and that their terminals form excitatory, glutamatergic synapses on host cortical neurons. We show that the stroke-induced asymmetry in a sensorimotor (cylinder) test is reversed by transplantation. Light-induced inhibition of halorhodopsin-expressing, grafted neurons does not recreate the impairment, indicating that its reversal is not due to neuronal activity in the graft. However, we find bilateral decrease of motor performance in the cylinder test after light-induced inhibition of either grafted or endogenous halorhodopsin-expressing cortical neurons, located in the same area, and after inhibition of endogenous halorhodopsin-expressing cortical neurons by exposure of their axons to light on the contralateral side. Our data indicate that activity in the grafted neurons, probably mediated through transcallosal connections to the contralateral hemisphere, is involved in maintaining normal motor function. This is an example of functional integration of efferent projections from grafted neurons into the stroke-affected brain's neural circuitry, which raises the possibility that such repair might be achievable also in humans affected by stroke.

Unique Subtype of Microglia in Degenerative Thalamus After Cortical Stroke.

BACKGROUND AND PURPOSE: Stroke disrupts neuronal functions in both local and remotely connected regions, leading to network-wide deficits that can hinder recovery. The thalamus is particularly affected, with progressive development of neurodegeneration accompanied by inflammatory responses. However, the complexity of the involved inflammatory responses is poorly understood. Herein we investigated the spatiotemporal changes in the secondary degenerative thalamus after cortical stroke, using targeted transcriptome approach in conjunction with histology and flow cytometry. METHODS: Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery in male C57BL6J mice. Neurodegeneration, neuroinflammatory responses, and microglial activation were examined in naive and stroke mice at from poststroke days (PD) 1 to 84, in both ipsilesional somatosensory cortex and ipsilesional thalamus. NanoString neuropathology panel (780 genes) was used to examine transcriptome changes at PD7 and PD28. Fluorescence activated cell sorting was used to collect CD11c+ microglia from ipsilesional thalamus, and gene expressions were validated by quantitative real-time polymerase chain reaction. RESULTS: Neurodegeneration in the thalamus was detected at PD7 and progressively worsened by PD28. This was accompanied by rapid microglial activation detected as early as PD1, which preceded the neurodegenerative changes. Transcriptome analysis showed higher number of differentially expressed genes in ipsilesional thalamus at PD28. Notably, neuroinflammation was the top activated pathway, and microglia was the most enriched cell type. Itgax (CD11c) was the most significantly increased gene, and its expression was highly detected in microglia. Flow-sorted CD11c+ microglia from degenerative thalamus indicated molecular signatures similar to neurodegenerative disease-associated microglia; these included downregulated Tmem119 and CX3CR1 and upregulated ApoE, Axl, LpL, CSF1, and Cst7. CONCLUSIONS: Our findings demonstrate the dynamic changes of microglia after stroke and highlight the importance of investigating stroke network-wide deficits. Importantly, we report the existence of a unique subtype of microglia (CD11c+) with neurodegenerative disease-associated microglia features in the degenerative thalamus after stroke.

Midlife aerobic exercise and brain structural integrity: Associations with age and cardiorespiratory fitness.

Lower midlife physical activity is associated with higher risk of neurodegenerative disease in late life. However, it remains unknown whether physical exercise and fitness are associated with brain structural integrity during midlife. The purpose of this study was to compare brain structures between middle-aged aerobically trained adults (MA), middle-aged sedentary (MS), and young sedentary (YS) adults. Thirty MA (54±4 years), 30 MS (54±4 years), and 30 YS (32±6 years) participants (50% women) underwent measurements of brain volume, cortical thickness, and white matter (WM) fiber integrity using MRI. MA participants had aerobic training for 24.8±9.6 years and the highest cardiorespiratory fitness level (i.e., peak oxygen uptake: VO2peak) among all groups. Global WM integrity, as assessed with fractional anisotropy (FA) from diffusion tensor imaging, was lower in the MS compared with the YS group. However, global FA in the MA group was significantly higher than that in the MS group (P<0.05) and at a similar level to the YS group. Furthermore, tract-based spatial statistical analysis demonstrated that FA in the anterior, superior, and limbic WM tracts (e.g., the genu of the corpus callosum, superior longitudinal fasciculus, uncinate fasciculus) was higher in the MA compared with MS groups, and positively associated with VO2peak, independently from age and sex. From cortical thickness analysis, MS and MA participants showed thinner prefrontal and parieto-temporal areas than the YS group. On the other hand, the MA group exhibited thicker precentral, postcentral, pericalcarine, and lateral occipital cortices than the MS and YS groups. But, the insula and right superior frontal gyrus showed thinner cortical thickness in the MA compared with the MS groups. Collectively, these findings suggest that midlife aerobic exercise is associated with higher WM integrity and greater primary motor and somatosensory cortical thickness.

Targeting the mitochondrial permeability transition pore for neuroprotection in a piglet model of neonatal hypoxic-ischemic encephalopathy.

Neonatal hypoxic-ischemic encephalopathy (HIE) causes significant morbidity despite treatment with therapeutic hypothermia. Mitochondrial dysfunction may drive the mechanisms underlying neuronal cell death, thereby making mitochondria prime targets for neuroprotection. The mitochondrial permeability transition pore (mPTP) is one such target within mitochondria. In adult animal models, mPTP inhibition is neuroprotective. However, evidence for mPTP inhibition in neonatal models of neurologic disease is less certain. We tested the therapeutic efficacy of the mPTP small molecule inhibitor GNX-4728 and examined the developmental presence of brain mPTP proteins for drug targeting in a neonatal piglet model of hypoxic-ischemic brain injury. Male neonatal piglets were randomized to hypoxia-ischemia (HI) or sham procedure with GNX-4728 (15 mg/kg, IV) or vehicle (saline/cyclodextrin/DMSO, IV). GNX-4728 was administered as a single dose within 5 min after resuscitation from bradycardic arrest. Normal, ischemic, and injured neurons were counted in putamen and somatosensory cortex using hematoxylin and eosin staining. In separate neonatal and juvenile pigs, western blots of putamen mitochondrial-enriched fractions were used to evaluate mitochondrial integrity and the presence of mPTP proteins. We found that a single dose of GNX-4728 did not protect putamen and cortical neurons from cell death after HI. However, loss of mitochondrial matrix integrity occurred within 6h after HI, and while mPTP components are present in the neonatal brain their levels were significantly different compared to that of a mature juvenile brain. Thus, the neonatal brain mPTP may not be a good target for current neurotherapeutic drugs that are developed based on adult mitochondria.

Mapping the physiological and molecular markers of stress and SSRI antidepressant treatment in S100a10 corticostriatal neurons.

In mood disorders, psychomotor and sensory abnormalities are prevalent, disabling, and intertwined with emotional and cognitive symptoms. Corticostriatal neurons in motor and somatosensory cortex are implicated in these symptoms, yet mechanisms of their vulnerability are unknown. Here, we demonstrate that S100a10 corticostriatal neurons exhibit distinct serotonin responses and have increased excitability, compared with S100a10-negative neurons. We reveal that prolonged social isolation disrupts the specific serotonin response which gets restored by chronic antidepressant treatment. We identify cell-type-specific transcriptional signatures in S100a10 neurons that contribute to serotonin responses and strongly associate with psychomotor and somatosensory function. Our studies provide a strong framework to understand the pathogenesis and create new avenues for the treatment of mood disorders.

Reorganization of Thalamic Inputs to Lesioned Cortex Following Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) disrupts thalamic and cortical integrity. The effect of post-injury reorganization and plasticity in thalamocortical pathways on the functional outcome remains unclear. We evaluated whether TBI causes structural changes in the thalamocortical axonal projection terminals in the primary somatosensory cortex (S1) that lead to hyperexcitability. TBI was induced in adult male Sprague Dawley rats with lateral fluid-percussion injury. A virus carrying the fluorescent-tagged opsin channel rhodopsin 2 transgene was injected into the ventroposterior thalamus. We then traced the thalamocortical pathways and analyzed the reorganization of their axonal terminals in S1. Next, we optogenetically stimulated the thalamocortical relays from the ventral posterior lateral and medial nuclei to assess the post-TBI functionality of the pathway. Immunohistochemical analysis revealed that TBI did not alter the spatial distribution or lamina-specific targeting of projection terminals in S1. TBI reduced the axon terminal density in the motor cortex by 44% and in S1 by 30%. A nematic tensor-based analysis revealed that in control rats, the axon terminals in layer V were orientated perpendicular to the pial surface (60.3°). In TBI rats their orientation was more parallel to the pial surface (5.43°, difference between the groups p < 0.05). Moreover, the level of anisotropy of the axon terminals was high in controls (0.063) compared with TBI rats (0.045, p < 0.05). Optical stimulation of the sensory thalamus increased alpha activity in electroencephalography by 312% in controls (p > 0.05) and 237% (p > 0.05) in TBI rats compared with the baseline. However, only TBI rats showed increased beta activity (33%) with harmonics at 5 Hz. Our findings indicate that TBI induces reorganization of thalamocortical axonal terminals in the perilesional cortex, which alters responses to thalamic stimulation.

Dendritic Spines in Early Postnatal Fragile X Mice Are Insensitive to Novel Sensory Experience.

Autism spectrum disorders are often associated with atypical sensory processing and sensory hypersensitivity, which can lead to maladaptive behaviors, such as tactile defensiveness. Such altered sensory perception in autism spectrum disorders could arise from disruptions in experience-dependent maturation of circuits during early brain development. Here, we tested the hypothesis that synaptic structures of primary somatosensory cortex (S1) neurons in Fragile X syndrome (FXS), which is a common inherited cause of autism, are not modulated by novel sensory information during development. We used chronic in vivo two-photon microscopy to image dendritic spines and axon "en passant" boutons of layer 2/3 pyramidal neurons in S1 of male and female WT and Fmr1 KO mice, a model of FXS. We found that a brief (overnight) exposure to dramatically enhance sensory inputs in the second postnatal week led to a significant increase in spine density in WT mice, but not in Fmr1 KO mice. In contrast, axon "en passant" boutons dynamics were impervious to this novel sensory experience in mice of both genotypes. We surmise that the inability of Fmr1 KO mice to modulate postsynaptic dynamics in response to increased sensory input, at a time when sensory information processing first comes online in S1 cortex, could play a role in altered sensory processing in FXS.SIGNIFICANCE STATEMENT Very few longitudinal in vivo imaging studies have investigated synaptic structure and dynamics in early postnatal mice. Moreover, those studies tend to focus on the effects of sensory input deprivation, a process that rarely occurs during normal brain development. Early postnatal imaging experiments are critical because a variety of neurodevelopmental disorders, including those characterized by autism, could result from alterations in how circuits are shaped by incoming sensory inputs during critical periods of development. In this study, we focused on a mouse model of Fragile X syndrome and demonstrate how dendritic spines are insensitive to a brief period of novel sensory experience.

Aberrant Somatosensory Processing and Connectivity in Mice Lacking Engrailed-2.

Overreactivity and defensive behaviors in response to tactile stimuli are common symptoms in autism spectrum disorder (ASD) patients. Similarly, somatosensory hypersensitivity has also been described in mice lacking ASD-associated genes such as Fmr1 (fragile X mental retardation protein 1). Fmr1 knock-out mice also show reduced functional connectivity between sensory cortical areas, which may represent an endogenous biomarker for their hypersensitivity. Here, we measured whole-brain functional connectivity in Engrailed-2 knock-out (En2-/-) adult mice, which show a lower expression of Fmr1 and anatomical defects common to Fmr1 knock-outs. MRI-based resting-state functional connectivity in adult En2-/- mice revealed significantly reduced synchronization in somatosensory-auditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test, En2-/- but not WT mice of both sexes showed fear behavior in response to repeated whisker stimulation. En2-/- mice undergoing this test exhibited decreased c-Fos-positive neurons (a marker of neuronal activity) in layer IV of the primary somatosensory cortex and increased immunoreactive cells in the basolateral amygdala compared with WT littermates. Conversely, when tested in a sensory maze, En2-/- and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved in En2 mutants. Therefore, fearful responses to somatosensory stimuli in En2-/- mice are accompanied by reduced basal connectivity of sensory regions, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala, suggesting that impaired somatosensory processing is a common feature in mice lacking ASD-related genes.SIGNIFICANCE STATEMENT Overreactivity to tactile stimuli is a common symptom in autism spectrum disorder (ASD) patients. Recent studies performed in mice bearing ASD-related mutations confirmed these findings. Here, we evaluated the behavioral response to whisker stimulation in mice lacking the ASD-related gene Engrailed-2 (En2-/- mice). Compared with WT controls, En2-/- mice showed reduced functional connectivity in the somatosensory cortex, which was paralleled by fear behavior, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala in response to repeated whisker stimulation. These results suggest that impaired somatosensory signal processing is a common feature in mice harboring ASD-related mutations.

Building a schizophrenia genetic network: transcription factor 4 regulates genes involved in neuronal development and schizophrenia risk.

The transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SCZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SCZ association findings. We identified 11 322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having ≥1 Ebox) and implicate a gene set enriched for genes downregulated in TCF4 small-interfering RNA (siRNA) knockdown experiments, indicating the validity of our findings. The TCF4 gene set was also enriched among (1) gene ontology categories such as axon/neuronal development, (2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex and (3) genes downregulated in postmortem brain tissue from SCZ patients (odds ratio, OR = 2.8, permutation P < 4x10-5). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA-binding proteins such as FOXP2 and the SCZ-associated EP300. TCF4 binding sites were modestly enriched among SCZ risk loci from the Psychiatric Genomic Consortium (OR = 1.56, P = 0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site ±10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. These findings confirm TCF4 as an important regulator of neural genes and point toward functional interactions with potential relevance for SCZ.

Neurobiological commonalities and distinctions among 3 major psychiatric disorders: a graph theoretical analysis of the structural connectome

Background: White matter network alterations have increasingly been implicated in major depressive disorder, bipolar disorder and schizophrenia. The aim of this study was to identify shared and distinct white matter network alterations among the 3 disorders. Methods: We used analysis of covariance, with age and gender as covariates, to investigate white matter network alterations in 123 patients with schizophrenia, 123 with bipolar disorder, 124 with major depressive disorder and 209 healthy controls. Results: We found significant group differences in global network efficiency (F = 3.386, p = 0.018), nodal efficiency (F = 8.015, p < 0.001 corrected for false discovery rate [FDR]) and nodal degree (F = 5.971, pFDR < 0.001) in the left middle occipital gyrus, as well as nodal efficiency (F = 6.930, pFDR < 0.001) and nodal degree (F = 5.884, pFDR < 0.001) in the left postcentral gyrus. We found no significant alterations in patients with major depressive disorder. Post hoc analyses revealed that compared with healthy controls, patients in the schizophrenia and bipolar disorder groups showed decreased global network efficiency, nodal efficiency and nodal degree in the left middle occipital gyrus. Furthermore, patients in the schizophrenia group showed decreased nodal efficiency and nodal degree in the left postcentral gyrus compared with healthy controls. Limitations: Our findings could have been confounded in part by treatment differences. Conclusion: Our findings implicate graded white matter network alterations across the 3 disorders, enhancing our understanding of shared and distinct pathophysiological mechanisms across diagnoses and providing vital insights into neuroimaging-based methods for diagnosis and research.

Structural brain changes in young males addicted to video-gaming.

Excessive video gaming has a number of psychological and social consequences. In this study, we looked at possible changes in gray and white matter and asked whether these changes are correlated to psychological measures. Twentynine players of violent videogames (mean daily playing time 4.7 h) and age matched controls were subjected to a battery of questionnaires assessing aggression, empathy, hostility, internet addiction and psychological well-being. Diffusion tensor and 3D T1-weighted MR images were obtained to examine gray (via voxel-based morphometry) and white (via tract-based spatial statistics) matter changes. Widespread regions of decreased gray matter in the players were found but no region showed increased intensity of gray matter. Density of gray matter showed a negative correlation with the total length of playing in years in the right posterior cingulate gyrus, left pre- and postcentral gyrus, right thalamus, among others. Furthermore, fractional anisotropy, a marker for white matter structure, was decreased in the left and right cingulum in the players. Both, gray and white matter changes correlated with measures of aggression, hostility, self esteem, and the degree of internet addiction. This study thus shows profound changes of brain structure as a function of excessive playing of violent video games.

Terminal Arbors of Callosal Axons Undergo Plastic Changes in Early-Amputated Rats.

Sensory information is processed in specific brain regions, and shared between the cerebral hemispheres by axons that cross the midline through the corpus callosum. However, sensory deprivation usually causes sensory losses and/or functional changes. This is the case of people who suffered limb amputation and show changes of body map organization within the somatosensory cortex (S1) of the deafferented cerebral hemisphere (contralateral to the amputated limb), as well as in the afferented hemisphere (ipsilateral to the amputated limb). Although several studies have approached these functional changes, the possible finer morphological alterations, such as those occurring in callosal axons, still remain unknown. The present work combined histochemistry, single-axon tracing and 3D microscopy to analyze the fine morphological changes that occur in callosal axons of the forepaw representation in early amputated rats. We showed that the forepaw representation in S1 was reduced in the deafferented hemisphere and expanded in the afferented side. Accordingly, after amputation, callosal axons originating from the deafferented cortex undergo an expansion of their terminal arbors with increased number of terminal boutons within the homotopic representation at the afferented cerebral hemisphere. Similar microscale structural changes may underpin the macroscale morphological and functional phenomena that characterize limb amputation in humans.

Direct and Collateral Alterations of Functional Cortical Circuits in a Rat Model of Subcortical Band Heterotopia.

Subcortical band heterotopia (SBH), also known as double-cortex syndrome, is a neuronal migration disorder characterized by an accumulation of neurons in a heterotopic band below the normotopic cortex. The majority of patients with SBH have mild to moderate intellectual disability and intractable epilepsy. However, it is still not clear how cortical networks are organized in SBH patients and how this abnormal organization contributes to improper brain function. In this study, cortical networks were investigated in the barrel cortex in an animal model of SBH induced by in utero knockdown of Dcx, main causative gene of this condition in human patients. When the SBH was localized below the Barrel Field (BF), layer (L) four projection to correctly positioned L2/3 pyramidal cells was weakened due to lower connectivity. Conversely, when the SBH was below an adjacent cortical region, the excitatory L4 to L2/3 projection was stronger due to increased L4 neuron excitability, synaptic strength and excitation/inhibition ratio of L4 to L2/3 connection. We propose that these developmental alterations contribute to the spectrum of clinical dysfunctions reported in patients with SBH.

Ethanol Exposure In Utero Disrupts Radial Migration and Pyramidal Cell Development in the Somatosensory Cortex.

Deficits in sensory processing in Fetal Alcohol Spectrum Disorders (FASD) implicate dysfunction in the somatosensory cortex. However, the effects of prenatal ethanol exposure on the development of this region await elucidation. Here, we used an established mouse model of FASD with binge-type ethanol exposure from embryonic day 13.5-16.5 to investigate the effects of prenatal ethanol exposure on pyramidal neurons in the somatosensory cortex. Specifically, we focused on the radial migration of primordial pyramidal neurons during embryonic corticogenesis and their morphology and function during active synaptogenesis in early postnatal development. We found that prenatal ethanol exposure resulted in aberrant radial migration, particularly affecting the populations of postmitotic pyramidal neurons. In addition, there was an enduring effect of prenatal ethanol exposure on glutamate-mediated synaptic transmission in layer V/VI pyramidal neurons. This persisted beyond a transient decrease in pyramidal neuron dendritic complexity that was evident only during early postnatal development. Adolescent mice exposed prenatally to ethanol also displayed decreased tactile sensitivity, as revealed by a modified adhesive tape removal assay. Our findings demonstrate the persistent effects of binge-type in utero ethanol exposure on pyramidal neuron form and function and ultimately sensory processing, the latter being reminiscent of that seen in individuals with FASD.

Brain circuit-gene expression relationships and neuroplasticity of multisensory cortices in blind children.

Sensory deprivation reorganizes neurocircuits in the human brain. The biological basis of such neuroplastic adaptations remains elusive. In this study, we applied two complementary graph theory-based functional connectivity analyses, one to evaluate whole-brain functional connectivity relationships and the second to specifically delineate distributed network connectivity profiles downstream of primary sensory cortices, to investigate neural reorganization in blind children compared with sighted controls. We also examined the relationship between connectivity changes and neuroplasticity-related gene expression profiles in the cerebral cortex. We observed that multisensory integration areas exhibited enhanced functional connectivity in blind children and that this reorganization was spatially associated with the transcription levels of specific members of the cAMP Response Element Binding protein gene family. Using systems-level analyses, this study advances our understanding of human neuroplasticity and its genetic underpinnings following sensory deprivation.

Focal neocortical lesions impair distant neuronal information processing.

KEY POINTS: Parts of the fields of neuroscience and neurology consider the neocortex to be a functionally parcelled structure. Viewed through such a conceptual filter, there are multiple clinical observations after localized stroke lesions that seem paradoxical. We tested the effect that localized stroke-like lesions have on neuronal information processing in a part of the neocortex that is distant to the lesion using animal experiments. We find that the distant lesion degrades the quality of neuronal information processing of tactile input patterns in primary somatosensory cortex. The findings suggest that even the processing of primary sensory information depends on an intact neocortical network, with the implication that all neocortical processing may rely on widespread interactions across large parts of the cortex. ABSTRACT: Recent clinical studies report a surprisingly weak relationship between the location of cortical brain lesions and the resulting functional deficits. From a neuroscience point of view, such findings raise questions as to what extent functional localization applies in the neocortex and to what extent the functions of different regions depend on the integrity of others. Here we provide an in-depth analysis of the changes in the function of the neocortical neuronal networks after distant focal stroke-like lesions in the anaesthetized rat. Using a recently introduced high resolution analysis of neuronal information processing, consisting of pre-set spatiotemporal patterns of tactile afferent activation against which the neuronal decoding performance can be quantified, we found that stroke-like lesions in distant parts of the cortex significantly degraded the decoding performance of individual neocortical neurons in the primary somatosensory cortex (decoding performance decreased from 30.9% to 24.2% for n = 22 neurons, Wilcoxon signed rank test, P = 0.028). This degrading effect was not due to changes in the firing frequency of the neuron (Wilcoxon signed rank test, P = 0.499) and was stronger the higher the decoding performance of the neuron, indicating a specific impact on the information processing capacity in the cortex. These findings suggest that even primary sensory processing depends on widely distributed cortical networks and could explain observations of focal stroke lesions affecting a large range of functions.

Shifting brain circuits in pain chronicity.

The evaluation of brain changes to a specific pain condition in pediatric and adult patients allows for insights into potential mechanisms of pain chronicity and possibly long-term brain changes. Here we focused on the primary somatosensory system (SS) involved in pain processing, namely the ventroposterolateral thalamus (VPL) and the primary somatosensory cortex (SI). We evaluated, using MRI, three specific processes: (a) somatotopy of changes in the SS for different pain origins (viz., foot vs. arm); (b) differences in acute (ankle sprain versus complex regional pain syndrome-CRPS); and (c) differences of the effects of CRPS on SS in pediatric versus adult patients. In all cases, age- and sex-matched individuals were used as controls. Our results suggest a shift in concurrent gray matter density (GMD) and resting functional connectivity strengths (rFC) across pediatric and adult CRPS with (a) differential patterns of GMD (VPL) and rFC (SI) on SS in pediatric vs. adult patterns that are consistent with upper and lower limb somatotopical organization; and (b) widespread GMD alterations in pediatric CRPS from sensory, emotional and descending modulatory processes to more confined sensory-emotional changes in adult CRPS and rFC patterns from sensory-sensory alterations in pediatric populations to a sensory-emotional change in adult populations. These results support the idea that pediatric and adult CRPS are differentially represented and may reflect underlying differences in pain chronification across age groups that may contribute to the well-known differences between child and adult pain vulnerability and resilience.