RESUMO
Overexpression of the Ube3a gene and the resulting increase in Ube3a protein are linked to autism spectrum disorder (ASD). However, the cellular and molecular processes underlying Ube3a-dependent ASD remain unclear. Using both male and female mice, we find that neurons in the somatosensory cortex of the Ube3a 2× Tg ASD mouse model display reduced dendritic spine density and increased immature filopodia density. Importantly, the increased gene dosage of Ube3a in astrocytes alone is sufficient to confer alterations in neurons as immature dendritic protrusions, as observed in primary hippocampal neuron cultures. We show that Ube3a overexpression in astrocytes leads to a loss of astrocyte-derived spinogenic protein, thrombospondin-2 (TSP2), due to a suppression of TSP2 gene transcription. By neonatal intraventricular injection of astrocyte-specific virus, we demonstrate that Ube3a overexpression in astrocytes in vivo results in a reduction in dendritic spine maturation in prelimbic cortical neurons, accompanied with autistic-like behaviors in mice. These findings reveal an astrocytic dominance in initiating ASD pathobiology at the neuronal and behavior levels. SIGNIFICANCE STATEMENT: Increased gene dosage of Ube3a is tied to autism spectrum disorders (ASDs), yet cellular and molecular alterations underlying autistic phenotypes remain unclear. We show that Ube3a overexpression leads to impaired dendritic spine maturation, resulting in reduced spine density and increased filopodia density. We find that dysregulation of spine development is not neuron autonomous, rather, it is mediated by an astrocytic mechanism. Increased gene dosage of Ube3a in astrocytes leads to reduced production of the spinogenic glycoprotein thrombospondin-2 (TSP2), leading to abnormalities in spines. Astrocyte-specific Ube3a overexpression in the brain in vivo confers dysregulated spine maturation concomitant with autistic-like behaviors in mice. These findings indicate the importance of astrocytes in aberrant neurodevelopment and brain function in Ube3a-depdendent ASD.
Assuntos
Transtorno do Espectro Autista , Espinhas Dendríticas , Neuroglia , Ubiquitina-Proteína Ligases , Animais , Camundongos , Astrócitos/metabolismo , Astrócitos/patologia , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Células Cultivadas , Espinhas Dendríticas/patologia , Espinhas Dendríticas/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/fisiologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Córtex Somatossensorial/metabolismo , Córtex Somatossensorial/patologia , Trombospondinas/metabolismo , Trombospondinas/genética , Trombospondinas/biossíntese , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Microglia are subject to change in tandem with the endogenously generated biological oscillations known as our circadian rhythm. Studies have shown microglia harbor an intrinsic molecular clock which regulates diurnal changes in morphology and influences inflammatory responses. In the adult brain, microglia play an important role in the regulation of condensed extracellular matrix structures called perineuronal nets (PNNs), and it has been suggested that PNNs are also regulated in a circadian and diurnal manner. We sought to determine whether microglia mediate the diurnal regulation of PNNs via CSF1R inhibitor dependent microglial depletion in C57BL/6J mice, and how the absence of microglia might affect cortical diurnal gene expression rhythms. While we observe diurnal differences in microglial morphology, where microglia are most ramified at the onset of the dark phase, we do not find diurnal differences in PNN intensity. However, PNN intensity increases across many brain regions in the absence of microglia, supporting a role for microglia in the regulation of PNNs. Here, we also show that cortical diurnal gene expression rhythms are intact, with no cycling gene changes without microglia. These findings demonstrate a role for microglia in the maintenance of PNNs, but not in the maintenance of diurnal rhythms.
Assuntos
Ondas Encefálicas , Ritmo Circadiano , Microglia/patologia , Rede Nervosa/patologia , Córtex Somatossensorial/patologia , Animais , Ondas Encefálicas/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Rede Nervosa/fisiopatologia , Compostos Orgânicos/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Córtex Somatossensorial/efeitos dos fármacos , Córtex Somatossensorial/metabolismo , Córtex Somatossensorial/fisiopatologia , Fatores de TempoRESUMO
Behavioral experience and flexibility are crucial for survival in a constantly changing environment. Despite evolutionary pressures to develop adaptive behavioral strategies in a dynamically changing sensory landscape, the underlying neural correlates have not been well explored. Here, we use genetically encoded voltage imaging to measure signals in primary somatosensory cortex (S1) during sensory learning and behavioral adaptation in the mouse. In response to changing stimulus statistics, mice adopt a strategy that modifies their detection behavior in a context dependent manner as to maintain reward expectation. Surprisingly, neuronal activity in S1 shifts from simply representing stimulus properties to transducing signals necessary for adaptive behavior in an experience dependent manner. Our results suggest that neuronal signals in S1 are part of an adaptive framework that facilitates flexible behavior as individuals gain experience, which could be part of a general scheme that dynamically distributes the neural correlates of behavior during learning.
Assuntos
Adaptação Psicológica/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Encéfalo , Aprendizagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Percepção , Recompensa , Córtex Somatossensorial/patologiaRESUMO
Intraaxial tumors of the central lobe are challenging lesions to deal with because of the high eloquence of this anatomic area.1,2 Diffusion tensor imaging magnetic resonance imaging and fluorescein (F) have proven to be useful in the planning and execution, respectively of glioma surgery.3-9 Nevertheless, the advantages of intraoperative use of augmented reality (AR) with diffusion tensor imaging-based high-definition fiber tractography (HDFT) are still underestimated. In the AR HDFT-F technique reported by our group, the integration of AR into the microscope comes through the BrainLAB Curve navigation platform (BrainLAB AG, Munich Germany), Smartbrush software (BrainLAB AG), KINEVO 900 surgical microscope (Carl Zeiss, Oberkochen, Germany), and YELLOW 560 filter (Carl Zeiss).9 The microscope establishes a wired autodetection of the navigation platform, and the eyepiece functions as a "see-through display" of the AR images, which are overlapped onto the surgical field. Video 1 shows the technical key aspects of the intraoperative use of the AR HDFT-F technique in the maximal safe anatomic resection of a postcentral gyrus high-grade glioma.
Assuntos
Realidade Aumentada , Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Imagem de Tensor de Difusão/métodos , Fluoresceína , Glioma/diagnóstico por imagem , Glioma/cirurgia , Humanos , Neuronavegação/métodos , Córtex Somatossensorial/patologiaRESUMO
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.
Assuntos
Transtorno do Espectro Autista/metabolismo , Moléculas de Adesão Celular/deficiência , Espinhas Dendríticas/metabolismo , Neurogênese/fisiologia , Córtex Somatossensorial/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Células COS , Moléculas de Adesão Celular/genética , Células Cultivadas , Chlorocebus aethiops , Espinhas Dendríticas/patologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Córtex Somatossensorial/patologiaRESUMO
The aim of this study was to investigate central pain representations during loading of the periodontium induced by orthodontic and occlusal stress. Nineteen healthy male volunteers (25.7 ± 2.8 years) were tested on two consecutive days: after phenotyping (questionnaires) and determination of warmth (WPT) and heat (HPT) pain thresholds, functional magnetic resonance imaging was performed as event-related paradigm including 36 tooth clenchings of 3 s duration, alternating with rest periods varying between 20-30 s. The task was performed in absence (T1) and 24 h after placement of an elastic separator between the second bicuspid and the first molar on the right side of the lower jaw (T2). No significant changes in WPT and HPT were observed but pain ratings were significantly elevated at T2. Significantly elevated activation at T2, as compared to T1, was found in bilateral sensorimotor cortex, bilateral secondary sensory cortex, supplementary motor area, right rolandic operculum, and bilateral insula. Our data show for the first time in humans that periodontal stimulation, as tested by tooth clenching in the presence of an elastic separator, goes along with specific expressions of pain at behavioral and neuronal network levels. Findings supplement the existing neuroimaging literature on odontogenic pain.
Assuntos
Imageamento por Ressonância Magnética/métodos , Dor Pós-Operatória/patologia , Bolsa Periodontal/cirurgia , Córtex Somatossensorial/patologia , Adulto , Voluntários Saudáveis , Humanos , Masculino , Adulto JovemRESUMO
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.
Assuntos
Lesões Encefálicas Traumáticas/patologia , Córtex Motor/patologia , Córtex Somatossensorial/patologia , Tálamo/patologia , Animais , Anisotropia , Ritmo beta/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Masculino , Optogenética , Estimulação Luminosa , Ratos Sprague-DawleyRESUMO
CONTEXT: Although diabetic peripheral neuropathy (DPN) is predominantly considered a disorder of the peripheral nerves, some evidence for central nervous system involvement has recently emerged. However, whether or to what extent the microstructure of central somatosensory tracts may be injured remains unknown. OBJECTIVE: This work aimed to detect the microstructure of central somatosensory tracts in type 2 diabetic patients and to correlate it with the severity of DPN. METHODS: A case-control study at a tertiary referral hospital took place with 57 individuals with type 2 diabetes (25 with DPN, 32 without DPN) and 33 nondiabetic controls. The fractional anisotropy (FA) values of 2 major somatosensory tracts (the spinothalamic tract and its thalamocortical [spino-thalamo-cortical, STC] pathway, the medial lemniscus and its thalamocortical [medial lemnisco-thalamo-cortical, MLTC] pathway) were assessed based on diffusion tensor tractography. Regression models were further applied to detect the association of FA values with the severity of DPN in diabetic patients. RESULTS: The mean FA values of left STC and left MLTC pathways were significantly lower in patients with DPN than those without DPN and controls. Moreover, FA values of left STC and left MLTC pathways were significantly associated with the severity of DPN (expressed as Toronto Clinical Scoring System values) in patients after adjusting for multiple confounders. CONCLUSION: Our findings demonstrated the axonal degeneration of central somatosensory tracts in type 2 diabetic patients with DPN. The parallel disease progression of the intracranial and extracranial somatosensory system merits further attention to the central nerves in diabetic patients with DPN.
Assuntos
Neuropatias Diabéticas/patologia , Substância Cinzenta/ultraestrutura , Córtex Somatossensorial/ultraestrutura , Adulto , Estudos de Casos e Controles , China , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/psicologia , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/psicologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Prognóstico , Índice de Gravidade de Doença , Córtex Somatossensorial/diagnóstico por imagem , Córtex Somatossensorial/patologiaRESUMO
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.
Assuntos
Asfixia Neonatal/prevenção & controle , Hipóxia-Isquemia Encefálica/prevenção & controle , Poro de Transição de Permeabilidade Mitocondrial , Fármacos Neuroprotetores/uso terapêutico , Animais , Animais Recém-Nascidos , Morte Celular , Parada Cardíaca , Masculino , Putamen/patologia , Córtex Somatossensorial/patologia , SuínosRESUMO
Traumatic brain injury (TBI) often induces structural damage, disruption of the blood-brain barrier (BBB), neurodegeneration, and dysfunctions of surviving neuronal networks. Nitric oxide (NO) signaling has been suggested to affect brain functions after TBI. The NO exhibits most of its biological effects by activation of the primary targets-guanylyl cyclases (NO-GCs), which exists in two isoforms (NO-GC1 and NO-GC2), and the subsequently produced cyclic guanosine monophosphate (cGMP). However, the specific function of the NO-NO-GCs-cGMP pathway in the context of brain injury is not fully understood. To investigate the specific role of the isoform NO-GC1 early after brain injuries, we performed an in vivo unilateral controlled cortical impact (CCI) in the somatosensory cortex of knockout mice lacking NO-GC1 and their wild-type (WT) littermates. Morphological and electrophysiological changes of cortical neurons located 500 µm distant from the lesion border were studied early (24 h) after TBI. The CCI-operated WT mice exhibited significant BBB disruption, an impairment of dendritic spine morphology, a reduced pre-synaptic glutamate release, and less neuronal activity in the ipsilateral cortical network. The impaired ipsilateral neuronal excitability was associated with increased A-type K+ currents (IA) in the WT mice early after TBI. Interestingly, NO-GC1 KO mice revealed relatively less BBB rupture and a weaker brain edema formation early after TBI. Further, lack of NO-GC1 also prevented the impaired synaptic transmission and network function that were observed in TBI-treated WT mice. These data suggest that NO-GC1 signaling mediates early brain damage and the strength of ipsilateral cortical network in the early phase after TBI.
Assuntos
Edema Encefálico/patologia , Lesões Encefálicas Traumáticas/patologia , Guanilato Ciclase/metabolismo , Óxido Nítrico/metabolismo , Receptores de Superfície Celular/metabolismo , Transmissão Sináptica/fisiologia , Animais , Edema Encefálico/etiologia , Lesões Encefálicas Traumáticas/complicações , GMP Cíclico/metabolismo , Isoenzimas/metabolismo , Camundongos , Camundongos Knockout , Transdução de Sinais/fisiologia , Córtex Somatossensorial/lesões , Córtex Somatossensorial/patologiaRESUMO
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.
Assuntos
Córtex Cerebral/patologia , Microglia/patologia , Doenças Neurodegenerativas/patologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia , Doenças Talâmicas/etiologia , Doenças Talâmicas/patologia , Animais , Antígenos CD11/química , Circulação Cerebrovascular , Encefalite/patologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Somatossensorial/patologia , Tálamo/patologia , TranscriptomaRESUMO
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.
Assuntos
Espessura Cortical do Cérebro , Encéfalo/diagnóstico por imagem , Aptidão Cardiorrespiratória , Exercício Físico , Comportamento Sedentário , Substância Branca/diagnóstico por imagem , Adulto , Fatores Etários , Anisotropia , Encéfalo/patologia , Imagem de Tensor de Difusão , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/diagnóstico por imagem , Córtex Motor/patologia , Doenças Neurodegenerativas , Testes Neuropsicológicos , Tamanho do Órgão , Consumo de Oxigênio , Fatores de Risco , Córtex Somatossensorial/diagnóstico por imagem , Córtex Somatossensorial/patologia , Substância Branca/patologiaRESUMO
We report a patient with reflex tooth-brushing-triggered epilepsy, associated with a post-central lesion within the right somatosensory face area. Contralateral facial sensory and motor phenomena, associated with contralateral upper limb extension, were present at seizure onset after gingival stimulation, but seizures could also be induced by contact with solid food or liquids. Spontaneous seizures also were recorded. Secondary generalization was infrequent. Stereoelectroencephalography implantation was performed, with seizure recording and cortical/subcortical stimulation for mapping, to identify the precise extent of surgical resection. Complete postoperative control of epilepsy was achieved, accompanied by a mild and transient neurological deficit. [Published with video sequence].
Assuntos
Epilepsia Reflexa/diagnóstico , Epilepsia Reflexa/cirurgia , Córtex Somatossensorial , Adulto , Eletrocorticografia , Feminino , Gengiva/fisiopatologia , Humanos , Córtex Somatossensorial/patologia , Córtex Somatossensorial/fisiopatologia , Córtex Somatossensorial/cirurgia , Técnicas EstereotáxicasRESUMO
An increasing number of neuroimaging studies addressing patients with corticobasal syndrome use macroscopic definitions of brain regions. As a closer link to functionally relevant units, we aimed at identifying magnetic resonance-based atrophy patterns in regions defined by probability maps of cortical microstructure. For this purpose, three analyses were conducted: (1) Whole-brain cortical thickness was compared between 36 patients with corticobasal syndrome and 24 controls. A pattern of pericentral atrophy was found, covering primary motor area 4, premotor area 6, and primary somatosensory areas 1, 2, and 3a. Within the central region, only area 3b was without atrophy. (2) In 18 patients, longitudinal measures with follow-ups of up to 59 months (mean 21.3 ± 15.4) were analyzed. Areas 1, 2, and 6 showed significantly faster atrophy rates than primary somatosensory area 3b. (3) In an individual autopsy case, longitudinal in vivo morphometry and postmortem pathohistology were conducted. The rate of magnetic resonance-based atrophy was significantly correlated with tufted-astrocyte load in those cytoarchitectonically defined regions also seen in the group study, with area 3b being selectively unaffected.
Assuntos
Imageamento por Ressonância Magnética , Doenças Neurodegenerativas/patologia , Doença de Parkinson/patologia , Córtex Somatossensorial/diagnóstico por imagem , Córtex Somatossensorial/patologia , Idoso , Astrócitos/patologia , Atrofia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Somatossensorial/citologia , SíndromeRESUMO
Impaired function of GABAergic interneurons, and the subsequent alteration of excitation/inhibition balance, is thought to contribute to autism spectrum disorders (ASD). Altered numbers of GABAergic interneurons and reduced expression of GABA receptors has been detected in the brain of ASD subjects and mouse models of ASD. We previously showed a reduced expression of GABAergic interneuron markers parvalbumin (PV) and somatostatin (SST) in the forebrain of adult mice lacking the Engrailed2 gene (En2-/- mice). Here, we extended this analysis to postnatal day (P) 30 by using in situ hybridization, immunohistochemistry, and quantitative RT-PCR to study the expression of GABAergic interneuron markers in the hippocampus and somatosensory cortex of En2-/- and wild type (WT) mice. In addition, GABA receptor subunit mRNA expression was investigated by quantitative RT-PCR in the same brain regions of P30 and adult En2-/- and WT mice. As observed in adult animals, PV and SST expression was decreased in En2-/- forebrain of P30 mice. The expression of GABA receptor subunits (including the ASD-relevant Gabrb3) was also altered in young and adult En2-/- forebrain. Our results suggest that GABAergic neurotransmission deficits are already evident at P30, confirming that neurodevelopmental defects of GABAergic interneurons occur in the En2 mouse model of ASD.
Assuntos
Transtorno do Espectro Autista/patologia , Neurônios GABAérgicos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Hipocampo/patologia , Proteínas de Homeodomínio/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Receptores de GABA/metabolismo , Córtex Somatossensorial/patologia , Animais , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/metabolismo , Modelos Animais de Doenças , Feminino , Neurônios GABAérgicos/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Camundongos , Camundongos Knockout , Parvalbuminas/metabolismo , Córtex Somatossensorial/metabolismo , Somatostatina/metabolismoRESUMO
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.
Assuntos
Células-Tronco Pluripotentes Induzidas/fisiologia , Infarto da Artéria Cerebral Média/terapia , Atividade Motora/fisiologia , Neurônios/transplante , Córtex Somatossensorial/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/fisiologia , Diferenciação Celular/fisiologia , Linhagem Celular , Modelos Animais de Doenças , Humanos , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Neurônios/fisiologia , Optogenética , Técnicas de Patch-Clamp , Ratos , Recuperação de Função Fisiológica , Córtex Somatossensorial/citologia , Córtex Somatossensorial/patologiaRESUMO
BACKGROUND: Pain is one of the main symptoms associated with spinal cord injury (SCI) and can be associated with changes to the central nervous system (CNS). PURPOSE: This article provides an overview of the evidence relating to CNS changes (structural and functional) associated with pain in SCIs. DATA SOURCES: A systematic review was performed, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, on PubMed, Embase, and Web of Science in March 2018. STUDY SELECTION: Studies were selected if they concerned changes in the CNS of patients with SCI, regardless of the type of imagery. DATA EXTRACTION: Data were extracted by 2 blinded reviewers. DATA SYNTHESIS: There is moderate evidence for impaired electroencephalographic function and metabolic abnormalities in the anterior cingulate in patients experiencing pain. There is preliminary evidence that patients with pain have morphological and functional changes to the somatosensory cortex and alterations to thalamic metabolism. There are conflicting data regarding the relationships between lesion characteristics and pain. In contrast, patients without pain can display protective neuroplasticity. LIMITATIONS AND CONCLUSION: Further studies are required to elucidate fully the relationships between pain and neuroplasticity in patients with SCIs. However, current evidence might support the use of physical therapist treatments targeting CNS plasticity in patients with SCI pain.
Assuntos
Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Dor Crônica/etiologia , Neuralgia/etiologia , Traumatismos da Medula Espinal/complicações , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/metabolismo , Dor Crônica/fisiopatologia , Eletroencefalografia/métodos , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos , Neuralgia/fisiopatologia , Neuroimagem/métodos , Plasticidade Neuronal/fisiologia , Viés de Seleção , Córtex Somatossensorial/diagnóstico por imagem , Córtex Somatossensorial/patologia , Córtex Somatossensorial/fisiopatologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/metabolismo , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/diagnóstico por imagem , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/metabolismoRESUMO
Primary motor cortex (M1) infarctions sometimes cause sensory impairment. Because sensory signals play a vital role in motor control, sensory impairment compromises the recovery and rehabilitation of motor disability. However, the neural mechanism of the sensory impairment is poorly understood. We show that sensory processing in mouse primary somatosensory cortex (S1) was impaired in the acute phase of M1 infarctions and recovered in a layer-specific manner in the subacute phase. This layer-dependent recovery process and the anatomical connection pattern from M1 to S1 suggested that functional connectivity from M1 to S1 plays a key role in the sensory processing impairment. A simulation study demonstrated that the loss of inhibition from M1 to S1 in the acute phase of M1 infarctions could impair sensory processing in S1, and compensation for the inhibition could recover the temporal coding. Consistently, the optogenetic activation of M1 suppressed the sustained response in S1. Taken together, we revealed how focal stroke in M1 alters the cortical network activity of sensory processing, in which inhibitory input from M1 to S1 may be involved.
Assuntos
Infarto Encefálico/fisiopatologia , Sensação , Córtex Somatossensorial/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Infarto Encefálico/patologia , Masculino , Camundongos , Optogenética , Córtex Somatossensorial/patologia , Acidente Vascular Cerebral/patologiaRESUMO
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.
Assuntos
Comportamento Aditivo/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Internet , Jogos de Vídeo , Adolescente , Adulto , Anisotropia , Comportamento Aditivo/psicologia , Encéfalo/patologia , Estudos de Casos e Controles , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Autoimagem , Córtex Somatossensorial/diagnóstico por imagem , Córtex Somatossensorial/patologia , Tálamo/diagnóstico por imagem , Tálamo/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto JovemRESUMO
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.