RESUMO
"What makes us human?" is a central question of many research fields, notably anthropology. In this review, we focus on the development of the human neocortex, the part of the brain with a key role in cognition, to gain neurobiological insight toward answering this question. We first discuss cortical stem and progenitor cells and human-specific genes that affect their behavior. We thus aim to understand the molecular foundation of the expansion of the neocortex that occurred in the course of human evolution, as this expansion is generally thought to provide a basis for our unique cognitive abilities. We then review the emerging evidence pointing to differences in the development of the neocortex between present-day humans and Neanderthals, our closest relatives. Finally, we discuss human-specific genes that have been implicated in neuronal circuitry and offer a perspective for future studies addressing the question of what makes us human.
Assuntos
Evolução Biológica , Neocórtex , Humanos , Neocórtex/embriologia , Neocórtex/crescimento & desenvolvimento , Neocórtex/metabolismo , Animais , Homem de Neandertal/genética , Cognição , Neurônios/metabolismoRESUMO
The neocortex varies in size and complexity among mammals due to the tremendous variability in the number and diversity of neuronal subtypes across species. The increased cellular diversity is paralleled by the expansion of the pool of neocortical progenitors and the emergence of indirect neurogenesis during brain evolution. The molecular pathways that control these biological processes and are disrupted in neurological disorders remain largely unknown. Here we show that the transcription factors BRN1 and BRN2 have an evolutionary conserved function in neocortical progenitors to control their proliferative capacity and the switch from direct to indirect neurogenesis. Functional studies in mice and ferrets show that BRN1/2 act in concert with NOTCH and primary microcephaly genes to regulate progenitor behavior. Analysis of transcriptomics data from genetically modified macaques provides evidence that these molecular pathways are conserved in non-human primates. Our findings thus demonstrate that BRN1/2 are central regulators of gene expression programs in neocortical progenitors critical to determine brain size during evolution.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Neocórtex , Células-Tronco Neurais , Neurogênese , Fatores do Domínio POU , Animais , Feminino , Masculino , Camundongos , Proliferação de Células , Furões , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Macaca , Neocórtex/metabolismo , Neocórtex/embriologia , Neocórtex/citologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Neurogênese/genética , Fatores do Domínio POU/metabolismo , Fatores do Domínio POU/genética , Receptores Notch/metabolismo , Receptores Notch/genéticaRESUMO
Large-scale analysis of single-cell gene expression has revealed transcriptomically defined cell subclasses present throughout the primate neocortex with gene expression profiles that differ depending upon neocortical region. Here, we test whether the interareal differences in gene expression translate to regional specializations in the physiology and morphology of infragranular glutamatergic neurons by performing Patch-seq experiments in brain slices from the temporal cortex (TCx) and motor cortex (MCx) of the macaque. We confirm that transcriptomically defined extratelencephalically projecting neurons of layer 5 (L5 ET neurons) include retrogradely labeled corticospinal neurons in the MCx and find multiple physiological properties and ion channel genes that distinguish L5 ET from non-ET neurons in both areas. Additionally, while infragranular ET and non-ET neurons retain distinct neuronal properties across multiple regions, there are regional morpho-electric and gene expression specializations in the L5 ET subclass, providing mechanistic insights into the specialized functional architecture of the primate neocortex.
Assuntos
Neurônios , Transcriptoma , Animais , Neurônios/metabolismo , Neurônios/citologia , Transcriptoma/genética , Neocórtex/citologia , Neocórtex/metabolismo , Córtex Motor/citologia , Córtex Motor/metabolismo , Masculino , Lobo Temporal/citologia , Lobo Temporal/metabolismo , Macaca mulattaRESUMO
Cerebrospinal fluid (CSF) is a fluid critical to brain development, function, and health. It is actively secreted by the choroid plexus, and it emanates from brain tissue due to osmolar exchange and the constant contribution of brain metabolism and astroglial fluid output to interstitial fluid into the ventricles of the brain. CSF acts as a growth medium for the developing cerebral cortex and a source of nutrients and signalling throughout life. Together with perivascular glymphatic and interstitial fluid movement through the brain and into CSF, it also acts to remove toxins and maintain metabolic balance. In this study, we focused on cerebral folate status, measuring CSF concentrations of folate receptor alpha (FOLR1); aldehyde dehydrogenase 1L1, also known as 10-formyl tetrahydrofolate dehydrogenase (ALDH1L1 and FDH); and total folate. These demonstrate the transport of folate from blood across the blood-CSF barrier and into CSF (FOLR1 + folate), and the transport of folate through the primary FDH pathway from CSF into brain FDH + ve astrocytes. Based on our hypothesis that CSF flow, drainage issues, or osmotic forces, resulting in fluid accumulation, would have an associated cerebral folate imbalance, we investigated folate status in CSF from neurological conditions that have a severity association with enlarged ventricles. We found that all the conditions we examined had a folate imbalance, but these folate imbalances were not all the same. Given that folate is essential for key cellular processes, including DNA/RNA synthesis, methylation, nitric oxide, and neurotransmitter synthesis, we conclude that ageing or some form of trauma in life can lead to CSF accumulation and ventricular enlargement and result in a specific folate imbalance/deficiency associated with the specific neurological condition. We believe that addressing cerebral folate imbalance may therefore alleviate many of the underlying deficits and symptoms in these conditions.
Assuntos
Ácido Fólico , Ácido Fólico/líquido cefalorraquidiano , Ácido Fólico/metabolismo , Humanos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Neocórtex/metabolismo , Ventrículos Cerebrais/metabolismo , Receptor 1 de Folato/metabolismo , Receptor 1 de Folato/genética , Idoso , Líquido Cefalorraquidiano/metabolismo , Astrócitos/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NHRESUMO
Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aß plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aß deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Animais Recém-Nascidos , Neurônios Colinérgicos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neocórtex , Animais , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Camundongos , Neocórtex/metabolismo , Neocórtex/patologia , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Neurônios Colinérgicos/patologia , Neurônios Colinérgicos/metabolismo , Presenilina-1/genética , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/genética , Lesões Encefálicas/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/genética , Colina O-Acetiltransferase/metabolismo , Colina O-Acetiltransferase/genética , Humanos , Masculino , Modelos Animais de DoençasRESUMO
Murine organotypic brain slice cultures have been widely used in neuroscientific research and are offering the opportunity to study neuronal function under normal and disease conditions. Despite the broad application, the mechanisms governing the maturation of immature cortical circuits in vitro are not well understood. In this study, we present a detailed investigation into the development of the neocortex in vitro. Using a holistic approach, we studied organotypic whole hemisphere brain slice cultures from postnatal mice and tracked the development of the somatosensory area over a 5-wk period. Our analysis revealed the maturation of passive and active intrinsic properties of pyramidal cells together with their morphology, closely resembling in vivo development. Detailed multielectrode array (MEA) electrophysiological assessments and RNA expression profiling demonstrated stable network properties by 2 wk in culture, followed by the transition of spontaneous activity toward more complex patterns including high-frequency oscillations. However, culturing weeks 4 and 5 exhibited increased variability and initial signs of neuronal loss, highlighting the importance of considering developmental stages in experimental design. This comprehensive characterization is vital for understanding the temporal dynamics of the neocortical development in vitro, with implications for neuroscientific research methodologies, particularly in the investigation of diseases such as epilepsy and other neurodevelopmental disorders.NEW & NOTEWORTHY The development of the mouse neocortex in vitro mimics the in vivo development. Mouse brain cultures can serve as a model system for cortical development for the first 2 wk in vitro and as a model system for the adult cortex from 2 to 4 wk in vitro. Mouse organotypic brain slice cultures develop high-frequency network oscillations at γ frequency after 2 wk in vitro. Mouse brain cultures exhibit increased heterogeneity and variability after 4 wk in culture.
Assuntos
Neocórtex , Técnicas de Cultura de Órgãos , Animais , Neocórtex/crescimento & desenvolvimento , Neocórtex/citologia , Neocórtex/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Células Piramidais/fisiologiaRESUMO
Thrombospondins (TSPs) are astrocyte-secreted extracellular matrix proteins that play key roles as regulators of synaptogenesis in the central nervous system. We previously showed that TSP1/2 are upregulated in the partial neocortical isolation model ("undercut" or "UC" below) of posttraumatic epileptogenesis and may contribute to abnormal axonal sprouting, aberrant synaptogenesis and epileptiform discharges in the UC cortex. These results led to the hypothesis that posttraumatic epileptogeneis would be reduced in TSP1/2 knockout (TSP1/2 KO) mice. To test the hypothesis, we made UC lesions at P21, and subsequent experiments were conducted 14d later at P35. Ex vivo extracellular single or multi-electrode field potential recordings were obtained from layer V in cortical slices at P35 and in vivo video-EEGs of spontaneous epileptiform bursts were recorded to examine the effect of TSP1/2 deletion on epileptogenesis following cortical injury. Immunohistochemical experiments were performed to assess the effect of TSP1/2 KO + UC on the number of putative excitatory synapses and the expression of TSP4 and HEVIN, other astrocytic proteins known to up-regulate excitatory synapse formation. Unexpectedly, our results showed that, compared with WT + UC mice, TSP1/2 KO + UC mice displayed increased epileptiform activity, as indicated by 1) increased incidence and more rapid propagation of evoked and spontaneous epileptiform discharges in UC neocortical slices; 2) increased occurrence of spontaneous epileptiform discharges in vivo. There was an associated increase in the density of VLUT1/PSD95-IR colocalizations (putative excitatory synapses) and significantly upregulated TSP4- and HEVIN-IR in TSP1/2 KO + UC versus WT + UC mice. Results suggest that TSP1/2 deletion plays a potential epileptogenic role following neocortical injury, associated with compensatory upregulation of TSP4 and HEVIN, which may contribute to the increase in the density of excitatory synapses and resulting neural network hyperexcitability.
Assuntos
Camundongos Knockout , Trombospondina 1 , Trombospondinas , Animais , Trombospondinas/genética , Trombospondinas/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Epilepsia/genética , Epilepsia/fisiopatologia , Epilepsia/metabolismo , Sinapses/metabolismo , Eletroencefalografia , Neocórtex/metabolismo , Neocórtex/fisiopatologiaRESUMO
Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving epilepsy, intellectual disability, speech delay, and craniofacial defects. Here we show that Satb2 controls neuronal migration and callosal axonal outgrowth during murine neocortical development by inducing the expression of the GPI-anchored protein, Semaphorin 7A (Sema7A). We find that Sema7A exerts this biological activity by heterodimerizing in cis with the transmembrane semaphorin, Sema4D. We could also observe that heterodimerization with Sema7A promotes targeting of Sema4D to the plasma membrane in vitro. Finally, we report an epilepsy-associated de novo mutation in Sema4D (Q497P) that inhibits normal glycosylation and plasma membrane localization of Sema4D-associated complexes. These results suggest that neuronal use of semaphorins during neocortical development is heteromeric, and a greater signaling complexity exists than was previously thought.
Assuntos
Antígenos CD , Membrana Celular , Proteínas de Ligação à Região de Interação com a Matriz , Neocórtex , Neurônios , Multimerização Proteica , Semaforinas , Fatores de Transcrição , Semaforinas/metabolismo , Semaforinas/genética , Animais , Neocórtex/metabolismo , Membrana Celular/metabolismo , Humanos , Camundongos , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Antígenos CD/metabolismo , Antígenos CD/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Neurônios/metabolismo , Mutação , Movimento Celular , Axônios/metabolismo , Epilepsia/metabolismo , Epilepsia/genética , Corpo Caloso/metabolismo , Células HEK293 , Glicosilação , Masculino , Feminino , Camundongos Endogâmicos C57BLRESUMO
Adolescent development of human brain structural and functional networks is increasingly recognized as fundamental to emergence of typical and atypical adult cognitive and emotional proodal magnetic resonance imaging (MRI) data collected from N [Formula: see text] 300 healthy adolescents (51%; female; 14 to 26 y) each scanned repeatedly in an accelerated longitudinal design, to provide an analyzable dataset of 469 structural scans and 448 functional MRI scans. We estimated the morphometric similarity between each possible pair of 358 cortical areas on a feature vector comprising six macro- and microstructural MRI metrics, resulting in a morphometric similarity network (MSN) for each scan. Over the course of adolescence, we found that morphometric similarity increased in paralimbic cortical areas, e.g., insula and cingulate cortex, but generally decreased in neocortical areas, and these results were replicated in an independent developmental MRI cohort (N [Formula: see text] 304). Increasing hubness of paralimbic nodes in MSNs was associated with increased strength of coupling between their morphometric similarity and functional connectivity. Decreasing hubness of neocortical nodes in MSNs was associated with reduced strength of structure-function coupling and increasingly diverse functional connections in the corresponding fMRI networks. Neocortical areas became more structurally differentiated and more functionally integrative in a metabolically expensive process linked to cortical thinning and myelination, whereas paralimbic areas specialized for affective and interoceptive functions became less differentiated, as hypothetically predicted by a developmental transition from periallocortical to proisocortical organization of the cortex. Cytoarchitectonically distinct zones of the human cortex undergo distinct neurodevelopmental programs during typical adolescence.
Assuntos
Imageamento por Ressonância Magnética , Neocórtex , Humanos , Adolescente , Feminino , Masculino , Neocórtex/diagnóstico por imagem , Neocórtex/crescimento & desenvolvimento , Neocórtex/fisiologia , Adulto , Adulto Jovem , Mapeamento Encefálico/métodos , Desenvolvimento do Adolescente/fisiologia , Rede Nervosa/fisiologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/crescimento & desenvolvimento , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologiaRESUMO
The language network of the human brain has core components in the inferior frontal cortex and superior/middle temporal cortex, with left-hemisphere dominance in most people. Functional specialization and interconnectivity of these neocortical regions is likely to be reflected in their molecular and cellular profiles. Excitatory connections between cortical regions arise and innervate according to layer-specific patterns. Here, we generated a gene expression dataset from human postmortem cortical tissue samples from core language network regions, using spatial transcriptomics to discriminate gene expression across cortical layers. Integration of these data with existing single-cell expression data identified 56 genes that showed differences in laminar expression profiles between the frontal and temporal language cortex together with upregulation in layer II/III and/or layer V/VI excitatory neurons. Based on data from large-scale genome-wide screening in the population, DNA variants within these 56 genes showed set-level associations with interindividual variation in structural connectivity between the left-hemisphere frontal and temporal language cortex, and with the brain-related disorders dyslexia and schizophrenia which often involve affected language. These findings identify region-specific patterns of laminar gene expression as a feature of the brain's language network.
Assuntos
Idioma , Neocórtex , Humanos , Neocórtex/metabolismo , Lobo Temporal/metabolismo , Masculino , Feminino , Esquizofrenia/genética , Esquizofrenia/metabolismo , Neurônios/metabolismo , Lobo Frontal/metabolismo , Transcriptoma , AdultoRESUMO
The astrocyte-to-neuron lactate shuttle model entails that, upon glutamatergic neurotransmission, glycolytically derived pyruvate in astrocytes is mainly converted to lactate instead of being entirely catabolized in mitochondria. The mechanism of this metabolic rewiring and its occurrence in human brain are unclear. Here by using immunohistochemistry (4 brains) and imaging mass cytometry (8 brains) we show that astrocytes of the adult human neocortex and hippocampal formation express barely detectable amounts of mitochondrial proteins critical for performing oxidative phosphorylation (OXPHOS). These data are corroborated by queries of transcriptomes (107 brains) of neuronal versus non-neuronal cells fetched from the Allen Institute for Brain Science for genes coding for a much larger repertoire of entities contributing to OXPHOS, showing that human non-neuronal elements barely expressed mRNAs coding for such proteins. With less OXPHOS, human brain astrocytes are thus bound to produce more lactate to avoid interruption of glycolysis.
Assuntos
Astrócitos , Hipocampo , Mitocôndrias , Neocórtex , Fosforilação Oxidativa , Humanos , Astrócitos/metabolismo , Hipocampo/metabolismo , Hipocampo/citologia , Neocórtex/metabolismo , Neocórtex/citologia , Mitocôndrias/metabolismo , Adulto , Masculino , Feminino , Neurônios/metabolismoRESUMO
BACKGROUND: Mainly known as a transcription factor patterning the rostral brain and governing its histogenesis, FOXG1 has been also detected outside the nucleus; however, biological meaning of that has been only partially clarified. RESULTS: Prompted by FOXG1 expression in cytoplasm of pallial neurons, we investigated its implication in translational control. We documented the impact of FOXG1 on ribosomal recruitment of Grin1-mRNA, encoding for the main subunit of NMDA receptor. Next, we showed that FOXG1 increases GRIN1 protein level by enhancing the translation of its mRNA, while not increasing its stability. Molecular mechanisms underlying this activity included FOXG1 interaction with EIF4E and, possibly, Grin1-mRNA. Besides, we found that, within murine neocortical cultures, de novo synthesis of GRIN1 undergoes a prominent and reversible, homeostatic regulation and FOXG1 is instrumental to that. Finally, by integrated analysis of multiple omic data, we inferred that FOXG1 is implicated in translational control of hundreds of neuronal genes, modulating ribosome engagement and progression. In a few selected cases, we experimentally verified such inference. CONCLUSIONS: These findings point to FOXG1 as a key effector, potentially crucial to multi-scale temporal tuning of neocortical pyramid activity, an issue with profound physiological and neuropathological implications.
Assuntos
Fatores de Transcrição Forkhead , Neocórtex , Proteínas do Tecido Nervoso , Neurônios , Receptores de N-Metil-D-Aspartato , Animais , Feminino , Masculino , Camundongos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Neocórtex/metabolismo , Neocórtex/embriologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Biossíntese de Proteínas/genética , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
New tasks are often learned in stages with each stage reflecting a different learning challenge. Accordingly, each learning stage is likely mediated by distinct neuronal processes. And yet, most rodent studies of the neuronal correlates of goal-directed learning focus on individual outcome measures and individual brain regions. Here, we longitudinally studied mice from naïve to expert performance in a head-fixed, operant conditioning whisker discrimination task. In addition to tracking the primary behavioral outcome of stimulus discrimination, we tracked and compared an array of object-based and temporal-based behavioral measures. These behavioral analyses identify multiple, partially overlapping learning stages in this task, consistent with initial response implementation, early stimulus-response generalization, and late response inhibition. To begin to understand the neuronal foundations of these learning processes, we performed widefield Ca2+ imaging of dorsal neocortex throughout learning and correlated behavioral measures with neuronal activity. We found distinct and widespread correlations between neocortical activation patterns and various behavioral measures. For example, improvements in sensory discrimination correlated with target stimulus evoked activations of response-related cortices along with distractor stimulus evoked global cortical suppression. Our study reveals multidimensional learning for a simple goal-directed learning task and generates hypotheses for the neuronal modulations underlying these various learning processes.
Assuntos
Condicionamento Operante , Objetivos , Neocórtex , Vibrissas , Animais , Neocórtex/fisiologia , Condicionamento Operante/fisiologia , Vibrissas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Feminino , Aprendizagem por Discriminação/fisiologia , Aprendizagem/fisiologia , Neurônios/fisiologiaRESUMO
According to the synaptic homeostasis hypothesis (SHY), sleep serves to renormalize synaptic connections that have been potentiated during the prior wake phase due to ongoing encoding of information. SHY focuses on glutamatergic synaptic strength and has been supported by numerous studies examining synaptic structure and function in neocortical and hippocampal networks. However, it is unknown whether synaptic down-regulation during sleep occurs in the hypothalamus, i.e., a pivotal center of homeostatic regulation of bodily functions including sleep itself. We show that sleep, in parallel with the synaptic down-regulation in neocortical networks, down-regulates the levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the hypothalamus of rats. Most robust decreases after sleep were observed at both sites for AMPARs containing the GluA1 subunit. Comparing the effects of selective rapid eye movement (REM) sleep and total sleep deprivation, we moreover provide experimental evidence that slow-wave sleep (SWS) is the driving force of the down-regulation of AMPARs in hypothalamus and neocortex, with no additional contributions of REM sleep or the circadian rhythm. SWS-dependent synaptic down-regulation was not linked to EEG slow-wave activity. However, spindle density during SWS predicted relatively increased GluA1 subunit levels in hypothalamic synapses, which is consistent with the role of spindles in the consolidation of memory. Our findings identify SWS as the main driver of the renormalization of synaptic strength during sleep and suggest that SWS-dependent synaptic renormalization is also implicated in homeostatic control processes in the hypothalamus.
Assuntos
Hipotálamo , Receptores de AMPA , Sono de Ondas Lentas , Sinapses , Animais , Receptores de AMPA/metabolismo , Hipotálamo/metabolismo , Masculino , Sinapses/metabolismo , Sinapses/fisiologia , Ratos , Sono de Ondas Lentas/fisiologia , Sono REM/fisiologia , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia , Sono/fisiologia , Neocórtex/metabolismo , Homeostase , Ratos Sprague-Dawley , Regulação para Baixo , Ratos WistarRESUMO
The role of developmental cell death in the formation of brain circuits is not well understood. Cajal-Retzius cells constitute a major transient neuronal population in the mammalian neocortex, which largely disappears at the time of postnatal somatosensory maturation. In this study, we used mouse genetics, anatomical, functional, and behavioral approaches to explore the impact of the early postnatal death of Cajal-Retzius cells in the maturation of the cortical circuit. We find that before their death, Cajal-Retzius cells mainly receive inputs from layer 1 neurons, which can only develop their mature connectivity onto layer 2/3 pyramidal cells after Cajal-Retzius cells disappear. This developmental connectivity progression from layer 1 GABAergic to layer 2/3 pyramidal cells regulates sensory-driven inhibition within, and more so, across cortical columns. Here we show that Cajal-Retzius cell death prevention leads to layer 2/3 hyper-excitability, delayed learning and reduced performance in a multi-whisker-dependent texture discrimination task.
Assuntos
Morte Celular , Células Piramidais , Córtex Somatossensorial , Animais , Córtex Somatossensorial/fisiologia , Córtex Somatossensorial/citologia , Camundongos , Células Piramidais/fisiologia , Células Piramidais/metabolismo , Neocórtex/citologia , Neocórtex/fisiologia , Neurônios GABAérgicos/fisiologia , Neurônios GABAérgicos/metabolismo , Masculino , Vibrissas/fisiologia , Feminino , Camundongos Endogâmicos C57BL , Inibição Neural/fisiologia , Neurônios/fisiologia , Neurônios/metabolismoRESUMO
BACKGROUND: It is known that the neurodevelopmental disorder associated gene, Satb2, plays important roles in determining the upper layer neuron specification. However, it is not well known how this gene regulates other neocortical regions during the development. It is also lack of comprehensive delineation of its spatially regulatory pathways in neocortical development. RESULTS: In this work, we utilized spatial transcriptomics and immuno-staining to systematically investigate the region-specific gene regulation of Satb2 by comparing the Satb2+/+ and Satb2-/- mice at embryonic stages, including the ventricle zone (VZ) or subventricle zone (SVZ), intermediate zone (IZ) and cortical plate (CP) respectively. The staining result reveals that these three regions become moderately or significantly thinner in the Satb2-/- mice. In the cellular level, the cell number increases in the VZ/SVZ, whereas the cell number decreases in the CP. The spatial transcriptomics data show that many important genes and relevant pathways are dysregulated in Satb2-/- mice in a region-specific manner. In the VZ/SVZ, the key genes involved in neural precursor cell proliferation, including the intermediate progenitor marker Tbr2 and the lactate production related gene Ldha, are up-regulated in Satb2-/- mice. In the IZ, the key genes in regulating neuronal differentiation and migration, such as Rnd2, exhibit ectopic expressions in the Satb2-/- mice. In the CP, the lineage-specific genes, Tbr1 and Bcl11b, are abnormally expressed. The neuropeptide related gene Npy is down-regulated in Satb2-/- mice. Finally, we validated the abnormal expressions of key regulators by using immunofluorescence or qPCR. CONCLUSIONS: In summary, our work provides insights on the region-specific genes and pathways which are regulated by Satb2 in neocortical development.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Ligação à Região de Interação com a Matriz , Neocórtex , Fatores de Transcrição , Transcriptoma , Animais , Neocórtex/metabolismo , Neocórtex/crescimento & desenvolvimento , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Perfilação da Expressão Gênica , Camundongos Knockout , Proteínas Repressoras , Proteínas Supressoras de TumorRESUMO
The human cerebellum is increasingly recognized to be involved in nonmotor and higher-order cognitive functions. Yet, its ties with the entire cerebral cortex have not been holistically studied in a whole brain exploration with a unified analytical framework. Here, we characterized dissociable cortical-cerebellar structural covariation patterns based on regional gray matter volume (GMV) across the brain in n = 38,527 UK Biobank participants. Our results invigorate previous observations in that important shares of cortical-cerebellar structural covariation are described as 1) a dissociation between the higher-level cognitive system and lower-level sensorimotor system and 2) an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel pattern of ipsilateral, rather than contralateral, cerebral-cerebellar associations. Furthermore, phenome-wide association assays revealed key phenotypes, including cognitive phenotypes, lifestyle, physical properties, and blood assays, associated with each decomposed covariation pattern, helping to understand their real-world implications. This systems neuroscience view paves the way for future studies to explore the implications of these structural covariations, potentially illuminating new pathways in our understanding of neurological and cognitive disorders.NEW & NOTEWORTHY Cerebellum's association with the entire cerebral cortex has not been holistically studied in a unified way. Here, we conjointly characterize the population-level cortical-cerebellar structural covariation patterns leveraging â¼40,000 UK Biobank participants whole brain structural scans and â¼1,000 phenotypes. We revitalize the previous hypothesis of an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel ipsilateral cerebral-cerebellar associations. Phenome-wide association (PheWAS) revealed real-world implications of the structural covariation patterns.
Assuntos
Cerebelo , Neocórtex , Humanos , Masculino , Feminino , Cerebelo/fisiologia , Cerebelo/anatomia & histologia , Cerebelo/diagnóstico por imagem , Pessoa de Meia-Idade , Neocórtex/fisiologia , Neocórtex/anatomia & histologia , Idoso , Imageamento por Ressonância Magnética , Substância Cinzenta/anatomia & histologia , Substância Cinzenta/fisiologia , Substância Cinzenta/diagnóstico por imagem , Córtex Cerebral/fisiologia , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/diagnóstico por imagem , Vias Neurais/fisiologia , Vias Neurais/anatomia & histologia , AdultoRESUMO
BACKGROUND: Understanding the pathophysiological dynamics that underline Interictal Epileptiform Events (IEEs) such as epileptic spikes, spike-and-waves or High-Frequency Oscillations (HFOs) is of major importance in the context of neocortical refractory epilepsy, as it paves the way for the development of novel therapies. Typically, these events are detected in Local Field Potential (LFP) recordings obtained through depth electrodes during pre-surgical investigations. Although essential, the underlying pathophysiological mechanisms for the generation of these epileptic neuromarkers remain unclear. The aim of this paper is to propose a novel neurophysiologically relevant reconstruction of the neocortical microcircuitry in the context of epilepsy. This reconstruction intends to facilitate the analysis of a comprehensive set of parameters encompassing physiological, morphological, and biophysical aspects that directly impact the generation and recording of different IEEs. METHOD: a novel microscale computational model of an epileptic neocortical column was introduced. This model incorporates the intricate multilayered structure of the cortex and allows for the simulation of realistic interictal epileptic signals. The proposed model was validated through comparisons with real IEEs recorded using intracranial stereo-electroencephalography (SEEG) signals from both humans and animals. Using the model, the user can recreate epileptiform patterns observed in different species (human, rodent, and mouse) and study the intracellular activity associated with these patterns. RESULTS: Our model allowed us to unravel the relationship between glutamatergic and GABAergic synaptic transmission of the epileptic neural network and the type of generated IEE. Moreover, sensitivity analyses allowed for the exploration of the pathophysiological parameters responsible for the transitions between these events. Finally, the presented modeling framework also provides an Electrode Tissue Model (ETI) that adds realism to the simulated signals and offers the possibility of studying their sensitivity to the electrode characteristics. CONCLUSION: The model (NeoCoMM) presented in this work can be of great use in different applications since it offers an in silico framework for sensitivity analysis and hypothesis testing. It can also be used as a starting point for more complex studies.
Assuntos
Epilepsia , Modelos Neurológicos , Neocórtex , Neocórtex/fisiopatologia , Humanos , Epilepsia/fisiopatologia , Animais , Simulação por Computador , EletroencefalografiaRESUMO
Histamine is a modulatory neurotransmitter, which has received relatively less attention in the central nervous system than other neurotransmitters. The functional role of histamine in the neocortex, the brain region that controls higher-order cognitive functions such as attention, learning and memory, remains largely unknown. This article focuses on the emerging roles and mechanisms of histamine release in the neocortex. We describe gaps in current knowledge and propose the application of interdisciplinary tools to dissect the detailed multiscale functional logic of histaminergic action in the neocortex ranging from sub-cellular, cellular, dendritic and synaptic levels to microcircuits and mesoscale effects.
Assuntos
Histamina , Neocórtex , Neocórtex/metabolismo , Neocórtex/fisiologia , Histamina/metabolismo , Animais , Humanos , Neurônios/metabolismoRESUMO
INTRODUCTION: Spatial extent-based measures of how far amyloid beta (Aß) has spread throughout the neocortex may be more sensitive than traditional Aß-positron emission tomography (PET) measures of Aß level for detecting early Aß deposits in preclinical Alzheimer's disease (AD) and improve understanding of Aß's association with tau proliferation and cognitive decline. METHODS: Pittsburgh Compound-B (PIB)-PET scans from 261 cognitively unimpaired older adults from the Harvard Aging Brain Study were used to measure Aß level (LVL; neocortical PIB DVR) and spatial extent (EXT), calculated as the proportion of the neocortex that is PIB+. RESULTS: EXT enabled earlier detection of Aß deposits longitudinally confirmed to reach a traditional LVL-based threshold for Aß+ within 5 years. EXT improved prediction of cognitive decline (Preclinical Alzheimer Cognitive Composite) and tau proliferation (flortaucipir-PET) over LVL. DISCUSSION: These findings indicate EXT may be more sensitive to Aß's role in preclinical AD than level and improve targeting of individuals for AD prevention trials. HIGHLIGHTS: Aß spatial extent (EXT) was measured as the percentage of the neocortex with elevated Pittsburgh Compound-B. Aß EXT improved detection of Aß below traditional PET thresholds. Early regional Aß deposits were spatially heterogeneous. Cognition and tau were more closely tied to Aß EXT than Aß level. Neocortical tau onset aligned with reaching widespread neocortical Aß.