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1.
Nat Neurosci ; 24(11): 1586-1600, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34663958

RESUMO

The basolateral amygdala (BLA) plays essential roles in behaviors motivated by stimuli with either positive or negative valence, but how it processes motivationally opposing information and participates in establishing valence-specific behaviors remains unclear. Here, by targeting Fezf2-expressing neurons in the BLA, we identify and characterize two functionally distinct classes in behaving mice, the negative-valence neurons and positive-valence neurons, which innately represent aversive and rewarding stimuli, respectively, and through learning acquire predictive responses that are essential for punishment avoidance or reward seeking. Notably, these two classes of neurons receive inputs from separate sets of sensory and limbic areas, and convey punishment and reward information through projections to the nucleus accumbens and olfactory tubercle, respectively, to drive negative and positive reinforcement. Thus, valence-specific BLA neurons are wired with distinctive input-output structures, forming a circuit framework that supports the roles of the BLA in encoding, learning and executing valence-specific motivated behaviors.


Assuntos
Tonsila do Cerebelo/metabolismo , Atenção/fisiologia , Aprendizagem da Esquiva/fisiologia , Corpo Estriado/metabolismo , Proteínas de Ligação a DNA/genética , Rede Nervosa/metabolismo , Proteínas do Tecido Nervoso/genética , Animais , Proteínas de Ligação a DNA/biossíntese , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Motivação/fisiologia , Proteínas do Tecido Nervoso/biossíntese
2.
Int J Mol Sci ; 22(17)2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34502519

RESUMO

Optogenetics approach is used widely in neurobiology as it allows control of cellular activity with high spatial and temporal resolution. In most studies, optogenetics is used to control neuronal activity. In the present study optogenetics was used to stimulate astrocytes with the aim to modulate neuronal activity. To achieve this goal, light stimulation was applied to astrocytes expressing a version of ChR2 (ionotropic opsin) or Opto-α1AR (metabotropic opsin). Optimal optogenetic stimulation parameters were determined using patch-clamp recordings of hippocampal pyramidal neurons' spontaneous activity in brain slices as a readout. It was determined that the greatest increase in the number of spontaneous synaptic currents was observed when astrocytes expressing ChR2(H134R) were activated by 5 s of continuous light. For the astrocytes expressing Opto-α1AR, the greatest response was observed in the pulse stimulation mode (T = 1 s, t = 100 ms). It was also observed that activation of the astrocytic Opto-a1AR but not ChR2 results in an increase of the fEPSP slope in hippocampal neurons. Based on these results, we concluded that Opto-a1AR expressed in hippocampal astrocytes provides an opportunity to modulate the long-term synaptic plasticity optogenetically, and may potentially be used to normalize the synaptic transmission and plasticity defects in a variety of neuropathological conditions, including models of Alzheimer's disease and other neurodegenerative disorders.


Assuntos
Astrócitos/metabolismo , Rede Nervosa/fisiologia , Optogenética/métodos , Animais , Astrócitos/fisiologia , Encéfalo/metabolismo , Região CA1 Hipocampal/metabolismo , Channelrhodopsins/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Opsinas/genética , Opsinas/metabolismo , Técnicas de Patch-Clamp , Células Piramidais/metabolismo , Transmissão Sináptica
3.
J Neurosci ; 41(42): 8839-8847, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34531286

RESUMO

The mechanisms underlying accumulation of Alzheimer's disease (AD)-related tau pathology outside of the medial temporal lobe (MTL) in older adults are unknown but crucial to understanding cognitive decline. A growing body of evidence from human and animal studies strongly implicates neural connectivity in the propagation of tau in humans, but the pathways of neocortical tau spread and its consequences for cognitive function are not well understood. Using resting state functional magnetic resonance imaging (fMRI) and tau PET imaging from a sample of 97 male and female cognitively normal older adults, we examined MTL structures involved in medial parietal tau accumulation and associations with memory function. Functional connectivity between hippocampus (HC) and retrosplenial cortex (RsC), a key region of the medial parietal lobe, was associated with tau in medial parietal lobe. By contrast, connectivity between entorhinal cortex (EC) and RsC did not correlate with medial parietal lobe tau. Further, greater hippocampal-retrosplenial (HC-RsC) connectivity was associated with a stronger correlation between MTL and medial parietal lobe tau. Finally, an interaction between connectivity strength and medial parietal tau was associated with episodic memory performance, particularly in the visuospatial domain. This pattern of tau accumulation thus appears to reflect pathways of neural connectivity, and propagation of tau from EC to medial parietal lobe via the HC may represent a critical process in the evolution of cognitive dysfunction in aging and AD.SIGNIFICANCE STATEMENT The accumulation of tau pathology in the neocortex is a fundamental process underlying Alzheimer's disease (AD). Here, we use functional connectivity in cognitively normal older adults to track the accumulation of tau in the medial parietal lobe, a key region for memory processing that is affected early in the progression of AD. We show that the strength of connectivity between the hippocampus (HC) and retrosplenial cortex (RsC) is related to medial parietal tau burden, and that these tau and connectivity measures interact to associate with episodic memory performance. These findings establish the HC as the origin of medial parietal tau and implicate tau pathology in this region as a crucial marker of the beginnings of AD.


Assuntos
Giro do Cíngulo/metabolismo , Hipocampo/metabolismo , Memória/fisiologia , Neocórtex/metabolismo , Rede Nervosa/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Estudos Transversais , Feminino , Giro do Cíngulo/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neocórtex/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos
4.
Elife ; 102021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34505577

RESUMO

Cortical inactivation represents a key causal manipulation allowing the study of cortical circuits and their impact on behavior. A key assumption in inactivation studies is that the neurons in the target area become silent while the surrounding cortical tissue is only negligibly impacted. However, individual neurons are embedded in complex local circuits composed of excitatory and inhibitory cells with connections extending hundreds of microns. This raises the possibility that silencing one part of the network could induce complex, unpredictable activity changes in neurons outside the targeted inactivation zone. These off-target side effects can potentially complicate interpretations of inactivation manipulations, especially when they are related to changes in behavior. Here, we demonstrate that optogenetic inactivation of glutamatergic neurons in the superficial layers of monkey primary visual cortex (V1) induces robust suppression at the light-targeted site, but destabilizes stimulus responses in the neighboring, untargeted network. We identified four types of stimulus-evoked neuronal responses within a cortical column, ranging from full suppression to facilitation, and a mixture of both. Mixed responses were most prominent in middle and deep cortical layers. These results demonstrate that response modulation driven by lateral network connectivity is diversely implemented throughout a cortical column. Importantly, consistent behavioral changes induced by optogenetic inactivation were only achieved when cumulative network activity was homogeneously suppressed. Therefore, careful consideration of the full range of network changes outside the inactivated cortical region is required, as heterogeneous side effects can confound interpretation of inactivation experiments.


Assuntos
Comportamento Animal , Rede Nervosa/fisiologia , Plasticidade Neuronal , Optogenética/efeitos adversos , Córtex Visual/fisiologia , Percepção Visual , Animais , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Ácido Glutâmico/metabolismo , Macaca mulatta , Masculino , Rede Nervosa/citologia , Rede Nervosa/metabolismo , Estimulação Luminosa , Transmissão Sináptica , Córtex Visual/citologia , Córtex Visual/metabolismo
5.
J Neurosci ; 41(39): 8134-8149, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34417327

RESUMO

Tuberous sclerosis complex (TSC) is a multisystem developmental disorder characterized by hamartomas in various organs, such as the brain, lungs, and kidneys. Epilepsy, along with autism and intellectual disability, is one of the neurologic impairments associated with TSC that has an intimate relationship with developmental outcomes and quality of life. Sustained activation of the mammalian target of rapamycin (mTOR) via TSC1 or TSC2 mutations is known to be involved in the onset of epilepsy in TSC. However, the mechanism by which mTOR causes seizures remains unknown. In this study, we showed that, human induced pluripotent stem cell-derived TSC2-deficient (TSC2 -/-) neurons exhibited elevated neuronal activity with highly synchronized Ca2+ spikes. Notably, TSC2 -/- neurons presented enhanced Ca2+ influx via L-type Ca2+ channels (LTCCs), which contributed to the abnormal neurite extension and sustained activation of cAMP response element binding protein (CREB), a critical mediator of synaptic plasticity. Expression of Cav1.3, a subtype of LTCCs, was increased in TSC2 -/- neurons, but long-term rapamycin treatment suppressed this increase and reversed the altered neuronal activity and neurite extensions. Thus, we identified Cav1.3 LTCC as a critical downstream component of TSC-mTOR signaling that would trigger enhanced neuronal network activity of TSC2 -/- neurons. We suggest that LTCCs could be potential novel targets for the treatment of epilepsy in TSC.SIGNIFICANCE STATEMENT There is a close relationship between elevated mammalian target of rapamycin (mTOR) activity and epilepsy in tuberous sclerosis complex (TSC). However, the underlying mechanism by which mTOR causes epilepsy remains unknown. In this study, using human TSC2 -/- neurons, we identified elevated Ca2+ influx via L-type Ca2+ channels as a critical downstream component of TSC-mTOR signaling and a potential cause of both elevated neuronal activity and neurite extension in TSC2 -/- neurons. Our findings demonstrate a previously unrecognized connection between sustained mTOR activation and elevated Ca2+ signaling via L-type Ca2+ channels in human TSC neurons, which could cause epilepsy in TSC.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Rede Nervosa/metabolismo , Neurônios/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Diferenciação Celular/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação , Crescimento Neuronal/fisiologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética
6.
Sci Rep ; 11(1): 17189, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433854

RESUMO

Neuronal nitric oxide synthase (nNOS) neurons play a fundamental role in inhibitory neurotransmission, within the enteric nervous system (ENS), and in the establishment of gut motility patterns. Clinically, loss or disruption of nNOS neurons has been shown in a range of enteric neuropathies. However, the effects of nNOS loss on the composition and structure of the ENS remain poorly understood. The aim of this study was to assess the structural and transcriptional consequences of loss of nNOS neurons within the murine ENS. Expression analysis demonstrated compensatory transcriptional upregulation of pan neuronal and inhibitory neuronal subtype targets within the Nos1-/- colon, compared to control C57BL/6J mice. Conventional confocal imaging; combined with novel machine learning approaches, and automated computational analysis, revealed increased interconnectivity within the Nos1-/- ENS, compared to age-matched control mice, with increases in network density, neural projections and neuronal branching. These findings provide the first direct evidence of structural and molecular remodelling of the ENS, upon loss of nNOS signalling. Further, we demonstrate the utility of machine learning approaches, and automated computational image analysis, in revealing previously undetected; yet potentially clinically relevant, changes in ENS structure which could provide improved understanding of pathological mechanisms across a host of enteric neuropathies.


Assuntos
Sistema Nervoso Entérico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Animais , Sistema Nervoso Entérico/citologia , Aprendizado de Máquina , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/citologia , Rede Nervosa/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Óxido Nítrico Sintase Tipo I/deficiência
7.
Cells ; 10(8)2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34440631

RESUMO

The extracellular matrix (ECM) plays a key role in synaptogenesis and the regulation of synaptic functions in the central nervous system. Recent studies revealed that in addition to dopaminergic and serotoninergic neuromodulatory systems, microglia also contribute to the regulation of ECM remodeling. In the present work, we investigated the physiological role of microglia in the remodeling of perineuronal nets (PNNs), predominantly associated with parvalbumin-immunopositive (PV+) interneurons, and the perisynaptic ECM around pyramidal neurons in the hippocampus. Adult mice were treated with PLX3397 (pexidartinib), as the inhibitor of colony-stimulating factor 1 receptor (CSF1-R), to deplete microglia. Then, confocal analysis of the ECM and synapses was performed. Although the elimination of microglia did not alter the overall number or intensity of PNNs in the CA1 region of the hippocampus, it decreased the size of PNN holes and elevated the expression of the surrounding ECM. In the neuropil area in the CA1 str. radiatum, the depletion of microglia increased the expression of perisynaptic ECM proteoglycan brevican, which was accompanied by the elevated expression of presynaptic marker vGluT1 and the increased density of dendritic spines. Thus, microglia regulate the homeostasis of pre- and postsynaptic excitatory terminals and the surrounding perisynaptic ECM as well as the fine structure of PNNs enveloping perisomatic-predominantly GABAergic-synapses.


Assuntos
Região CA1 Hipocampal/patologia , Sinapses Elétricas/patologia , Potenciais Pós-Sinápticos Excitadores , Matriz Extracelular/patologia , Microglia/patologia , Aminopiridinas/toxicidade , Animais , Brevicam/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Sinapses Elétricas/metabolismo , Matriz Extracelular/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Pirróis/toxicidade , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Ácido gama-Aminobutírico/metabolismo
8.
J Neurochem ; 159(1): 12-14, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252196

RESUMO

Various neuroimaging approaches have reported alterations in brain connectivity in patients with autism spectrum disorder (ASD). Nevertheless, specific cellular and molecular mechanisms underlying these alterations remain to be elucidated. In the present Editorial, we highlight an article in the current issue of the Journal of Neurochemistry that provides first evidence for the structural and cellular basis of an atypical corpus callosum long-distance connectivity impairments observed in ASD patients. The authors used a juvenile valproic acid (VPA) rat model of ASD that presents with reduced myelin level, specifically in the corpus callosum, and with an altered myelin sheet structure that is closely associated with the behavioral alteration found in these rats. This hypomyelination occurs primarily during infancy prior to oligodendroglial alterations, implicating that axonal-oligodendroglial connections are compromised in this model. Concomitant with the hypomyelination, the ASD rat model showed an atypical brain metabolic pattern, with hypometabolic activity across the whole brain, and hypermetabolism in brain areas related to autistic-like behavior. These findings contribute to unravel the neurobiological basis underlying white matter alteration and altered long-distance brain connectivity as described in ASD, paving the way to the development of new early diagnostic markers and toward developing future specific therapies for ASD.


Assuntos
Transtorno Autístico/induzido quimicamente , Transtorno Autístico/metabolismo , Corpo Caloso/metabolismo , Rede Nervosa/metabolismo , Ácido Valproico/toxicidade , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Transtorno Autístico/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Corpo Caloso/efeitos dos fármacos , Humanos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/patologia , Ratos
9.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281244

RESUMO

Olfaction is an important neural system for survival and fundamental behaviors such as predator avoidance, food finding, memory formation, reproduction, and social communication. However, the neural circuits and pathways associated with the olfactory system in various behaviors are not fully understood. Recent advances in optogenetics, high-resolution in vivo imaging, and reconstructions of neuronal circuits have created new opportunities to understand such neural circuits. Here, we generated a transgenic zebrafish to manipulate olfactory signal optically, expressing the Channelrhodopsin (ChR2) under the control of the olfactory specific promoter, omp. We observed light-induced neuronal activity of olfactory system in the transgenic fish by examining c-fos expression, and a calcium indicator suggesting that blue light stimulation caused activation of olfactory neurons in a non-invasive manner. To examine whether the photo-activation of olfactory sensory neurons affect behavior of zebrafish larvae, we devised a behavioral choice paradigm and tested how zebrafish larvae choose between two conflicting sensory cues, an aversive odor or the naturally preferred phototaxis. We found that when the conflicting cues (the preferred light and aversive odor) were presented together simultaneously, zebrafish larvae swam away from the aversive odor. However, the transgenic fish with photo-activation were insensitive to the aversive odor and exhibited olfactory desensitization upon optical stimulation of ChR2. These results show that an aversive olfactory stimulus can override phototaxis, and that olfaction is important in decision making in zebrafish. This new transgenic model will be useful for the analysis of olfaction related behaviors and for the dissection of underlying neural circuits.


Assuntos
Channelrhodopsins/metabolismo , Percepção Olfatória/genética , Olfato/genética , Animais , Animais Geneticamente Modificados/genética , Channelrhodopsins/genética , Sinais (Psicologia) , Larva/fisiologia , Luz , Rede Nervosa/metabolismo , Neurônios/metabolismo , Odorantes , Optogenética/métodos , Estimulação Luminosa , Regiões Promotoras Genéticas/genética , Natação , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
11.
Ann Neurol ; 90(3): 391-406, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34279043

RESUMO

OBJECTIVE: The hippocampus is connected to 2 distinct cortical brain networks, the posterior-medial and the anterior-temporal networks, involving different medial temporal lobe (MTL) subregions. The aim of this study was to assess the functional alterations of these 2 networks, their changes over time, and links to cognition in Alzheimer's disease. METHODS: We assessed MTL connectivity in 53 amyloid-ß-positive patients with mild cognitive impairment and AD dementia and 68 healthy elderly controls, using resting-state functional magnetic resonance imaging, cross-sectionally and longitudinally. First, we compared the functional connectivity of the posterior-medial and anterior-temporal networks within the control group to highlight their specificities. Second, we compared the connectivity of these networks between groups, and between baseline and 18-month follow-up in patients. Third, we assessed the association in the connectivity changes between the 2 networks, and with cognitive performance. RESULTS: We found decreased connectivity in patients specifically between the hippocampus and the posterior-medial network, together with increased connectivity between several MTL subregions and the anterior-temporal network. Moreover, changes in the posterior-medial and anterior-temporal networks were interrelated such that decreased MTL-posterior-medial connectivity was associated with increased MTL-anterior-temporal connectivity. Finally, both MTL-posterior-medial decrease and MTL-anterior-temporal increase predicted cognitive decline. INTERPRETATION: Our findings demonstrate that longitudinal connectivity changes in the posterior-medial and anterior-temporal hippocampal networks are linked together and that they both contribute to cognitive decline in Alzheimer's disease. These results shed light on the critical role of the posterior-medial and anterior-temporal networks in Alzheimer's disease pathophysiology and clinical symptoms. ANN NEUROL 2021;90:391-406.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/tendências , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/tendências
12.
J Neurochem ; 158(5): 1172-1185, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34287909

RESUMO

Neuropeptide cocaine- and amphetamine-regulated transcript (CART) is known to influence the activity of the canonical mesolimbic dopaminergic pathway and modulate reward seeking behaviour. CART neurons of the lateral hypothalamus (LH) send afferents to the ventral tegmental area (VTA) and paraventricular thalamic nucleus (PVT) and these nuclei, in turn, send secondary projections to nucleus accumbens. We try to dissect the precise sites of CART's action in these circuits in promoting reward. Rats were implanted with bipolar electrode targeted at the lateral hypothalamus-medial forebrain bundle (LH-MFB) and trained to press the lever through intracranial self-stimulation (ICSS) protocol. CART (55-102) administered directly into posterior VTA (pVTA) or PVT of the conditioned rats significantly increased the number of lever presses, indicating reward-promoting activity of the peptide. Concomitant increase in dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) efflux was noted in the microdialysate collected from the nucleus accumbens shell (AcbSh). On the other hand, immunoneutralization of endogenous CART with CART antibodies injected directly in the pVTA or PVT reduced the lever press activity as well as DA and DOPAC efflux in the AcbSh. Injection of CART (1-39) in pVTA or PVT was ineffective. We suggest that CART cells in the LH-MFB area send afferents to (a) pVTA and influence dopaminergic neurons projecting to AcbSh and (b) PVT, from where the secondary neurons may feed into the AcbSh. Excitation of the CARTergic pathway to the pVTA as well as the PVT seems to promote DA release in the AcbSh and contribute to the generation of reward.


Assuntos
Dopamina/metabolismo , Rede Nervosa/metabolismo , Proteínas do Tecido Nervoso/administração & dosagem , Proteínas do Tecido Nervoso/metabolismo , Núcleo Accumbens/metabolismo , Recompensa , Animais , Eletrodos Implantados , Masculino , Microdiálise/métodos , Rede Nervosa/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar
13.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070424

RESUMO

BACKGROUND: The extracellular matrix of the PNS/CNS is unusual in that it is dominated by glycosaminoglycans, especially hyaluronan, whose space filling and hydrating properties make essential contributions to the functional properties of this tissue. Hyaluronan has a relatively simple structure but its space-filling properties ensure micro-compartments are maintained in the brain ultrastructure, ensuring ionic niches and gradients are maintained for optimal cellular function. Hyaluronan has cell-instructive, anti-inflammatory properties and forms macro-molecular aggregates with the lectican CS-proteoglycans, forming dense protective perineuronal net structures that provide neural and synaptic plasticity and support cognitive learning. AIMS: To highlight the central nervous system/peripheral nervous system (CNS/PNS) and its diverse extracellular and cell-associated proteoglycans that have cell-instructive properties regulating neural repair processes and functional recovery through interactions with cell adhesive molecules, receptors and neuroregulatory proteins. Despite a general lack of stabilising fibrillar collagenous and elastic structures in the CNS/PNS, a sophisticated dynamic extracellular matrix is nevertheless important in tissue form and function. CONCLUSIONS: This review provides examples of the sophistication of the CNS/PNS extracellular matrix, showing how it maintains homeostasis and regulates neural repair and regeneration.


Assuntos
Sistema Nervoso Central/metabolismo , Matriz Extracelular/metabolismo , Rede Nervosa/metabolismo , Neurônios/metabolismo , Sistema Nervoso Periférico/metabolismo , Animais , Sistema Nervoso Central/enzimologia , Sistema Nervoso Central/fisiologia , Humanos , Ácido Hialurônico/metabolismo , Rede Nervosa/enzimologia , Rede Nervosa/fisiologia , Neurogênese/genética , Neurogênese/fisiologia , Sistema Nervoso Periférico/enzimologia , Sistema Nervoso Periférico/fisiologia , Proteoglicanas/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
14.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074027

RESUMO

The development of a biomimetic neuronal network from neural cells is a big challenge for researchers. Recent advances in nanotechnology, on the other hand, have enabled unprecedented tools and techniques for guiding and directing neural stem cell proliferation and differentiation in vitro to construct an in vivo-like neuronal network. Nanotechnology allows control over neural stem cells by means of scaffolds that guide neurons to reform synaptic networks in suitable directions in 3D architecture, surface modification/nanopatterning to decide cell fate and stimulate/record signals from neurons to find out the relationships between neuronal circuit connectivity and their pathophysiological functions. Overall, nanotechnology-mediated methods facilitate precise physiochemical controls essential to develop tools appropriate for applications in neuroscience. This review emphasizes the newest applications of nanotechnology for examining central nervous system (CNS) roles and, therefore, provides an insight into how these technologies can be tested in vitro before being used in preclinical and clinical research and their potential role in regenerative medicine and tissue engineering.


Assuntos
Técnicas de Cultura de Células/métodos , Nanotecnologia/métodos , Rede Nervosa/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese , Engenharia Tecidual/métodos , Animais , Técnicas de Cultura de Células/instrumentação , Humanos , Nanotecnologia/instrumentação , Rede Nervosa/ultraestrutura , Células-Tronco Neurais/ultraestrutura , Neurogênese/fisiologia , Medicina Regenerativa , Engenharia Tecidual/instrumentação
15.
Exp Neurol ; 343: 113783, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34119482

RESUMO

DYT1 dystonia is a debilitating movement disorder characterized by repetitive, unintentional movements and postures. The disorder has been linked to mutation of the TOR1A/DYT1 gene encoding torsinA. Convergent evidence from studies in humans and animal models suggest that striatal medium spiny neurons and cholinergic neurons are important in DYT1 dystonia. What is not known is how torsinA dysfunction in these specific cell types contributes to the pathophysiology of DYT1 dystonia. In this study we sought to determine whether torsinA dysfunction in cholinergic neurons alone is sufficient to generate the sensorimotor dysfunction and brain changes associated with dystonia, or if torsinA dysfunction in a broader subset of cell types is needed. We generated two genetically modified mouse models, one with selective Dyt1 knock-out from dopamine-2 receptor expressing neurons (D2KO) and one where only cholinergic neurons are impacted (Ch2KO). We assessed motor deficits and performed in vivo 11.1 T functional MRI to assess sensory-evoked brain activation and connectivity, along with diffusion MRI to assess brain microstructure. We found that D2KO mice showed greater impairment than Ch2KO mice, including reduced sensory-evoked brain activity in key regions of the sensorimotor network, and altered functional connectivity of the striatum that correlated with motor deficits. These findings suggest that (1) the added impact of torsinA dysfunction in medium spiny and dopaminergic neurons of the basal ganglia generate more profound deficits than the dysfunction of cholinergic neurons alone, and (2) that sensory network impairments are linked to motor deficits in DYT1 dystonia.


Assuntos
Encéfalo/metabolismo , Distonia Muscular Deformante/metabolismo , Locomoção/fisiologia , Chaperonas Moleculares/metabolismo , Rede Nervosa/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Distonia Muscular Deformante/diagnóstico por imagem , Distonia Muscular Deformante/genética , Técnicas de Silenciamento de Genes/métodos , Masculino , Camundongos , Camundongos Knockout , Chaperonas Moleculares/genética , Rede Nervosa/diagnóstico por imagem
16.
J Neurochem ; 159(1): 128-144, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34081798

RESUMO

Atypical connectivity between brain regions and altered structure of the corpus callosum (CC) in imaging studies supports the long-distance hypoconnectivity hypothesis proposed for autism spectrum disorder (ASD). The aim of this study was to unveil the CC ultrastructural and cellular changes employing the valproic acid (VPA) rat model of ASD. Male Wistar rats were exposed to VPA (450 mg/kg i.p.) or saline (control) during gestation (embryonic day 10.5), and maturation, exploration, and social behavior were subsequently tested. Myelin content, ultrastructure, and oligodendroglial lineage were studied in the CC at post-natal days 15 (infant) and 36 (juvenile). As a functional outcome, brain metabolic activity was determined by positron emission tomography. Concomitantly with behavioral deficits in juvenile VPA rats, the CC showed reduced myelin basic protein, conserved total number of axons, reduced percentage of myelinated axons, and aberrant and less compact arrangements of myelin sheath ultrastructure. Mature oligodendrocytes decreased and oligodendrocyte precursors increased in the absence of astrogliosis or microgliosis. In medial prefrontal and somatosensory cortices of juvenile VPA rats, myelin ultrastructure and oligodendroglial lineage were preserved. VPA animals exhibited global brain hypometabolism and local hypermetabolism in brain regions relevant for ASD. In turn, the CC of infant VPA rats showed reduced myelin content but preserved oligodendroglial lineage. Our findings indicate that CC hypomyelination is established during infancy and prior to oligodendroglial pattern alterations, which suggests that axon-oligodendroglia communication could be compromised in VPA animals. Thus, CC hypomyelination may underlie white matter alterations and contribute to atypical patterns of connectivity and metabolism found in ASD.


Assuntos
Transtorno do Espectro Autista/metabolismo , Corpo Caloso/metabolismo , Rede Nervosa/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Social , Ácido Valproico/toxicidade , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Masculino , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar , Tomografia Computadorizada de Emissão de Fóton Único/métodos
17.
Neuroimage ; 237: 118126, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-33957234

RESUMO

Tau neurofibrillary tangles, a pathophysiological hallmark of Alzheimer's disease (AD), exhibit a stereotypical spatiotemporal trajectory that is strongly correlated with disease progression and cognitive decline. Personalized prediction of tau progression is, therefore, vital for the early diagnosis and prognosis of AD. Evidence from both animal and human studies is suggestive of tau transmission along the brains preexisting neural connectivity conduits. We present here an analytic graph diffusion framework for individualized predictive modeling of tau progression along the structural connectome. To account for physiological processes that lead to active generation and clearance of tau alongside passive diffusion, our model uses an inhomogenous graph diffusion equation with a source term and provides closed-form solutions to this equation for linear and exponential source functionals. Longitudinal imaging data from two cohorts, the Harvard Aging Brain Study (HABS) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), were used to validate the model. The clinical data used for developing and validating the model include regional tau measures extracted from longitudinal positron emission tomography (PET) scans based on the 18F-Flortaucipir radiotracer and individual structural connectivity maps computed from diffusion tensor imaging (DTI) by means of tractography and streamline counting. Two-timepoint tau PET scans were used to assess the goodness of model fit. Three-timepoint tau PET scans were used to assess predictive accuracy via comparison of predicted and observed tau measures at the third timepoint. Our results show high consistency between predicted and observed tau and differential tau from region-based analysis. While the prognostic value of this approach needs to be validated in a larger cohort, our preliminary results suggest that our longitudinal predictive model, which offers an in vivo macroscopic perspective on tau progression in the brain, is potentially promising as a personalizable predictive framework for AD.


Assuntos
Doença de Alzheimer , Imagem de Tensor de Difusão , Progressão da Doença , Modelos Neurológicos , Rede Nervosa , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Conjuntos de Dados como Assunto , Feminino , Humanos , Estudos Longitudinais , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Prognóstico
18.
Neuroimage ; 237: 118167, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34000404

RESUMO

BACKGROUND: The human brain is inherently organized into distinct networks, as reported widely by resting-state functional magnetic resonance imaging (rs-fMRI), which are based on blood-oxygen-level-dependent (BOLD) signal fluctuations. 11C-UCB-J PET maps synaptic density via synaptic vesicle protein 2A, which is a more direct structural measure underlying brain networks than BOLD rs-fMRI. METHODS: The aim of this study was to identify maximally independent brain source networks, i.e., "spatial patterns with common covariance across subjects", in 11C-UCB-J data using independent component analysis (ICA), a data-driven analysis method. Using a population of 80 healthy controls, we applied ICA to two 40-sample subsets and compared source network replication across samples. We examined the identified source networks at multiple model orders, as the ideal number of maximally independent components (IC) is unknown. In addition, we investigated the relationship between the strength of the loading weights for each source network and age and sex. RESULTS: Thirteen source networks replicated across both samples. We determined that a model order of 18 components provided stable, replicable components, whereas estimations above 18 were not stable. Effects of sex were found in two ICs. Nine ICs showed age-related change, with 4 remaining significant after correction for multiple comparison. CONCLUSION: This study provides the first evidence that human brain synaptic density can be characterized into organized covariance patterns. Furthermore, we demonstrated that multiple synaptic density source networks are associated with age, which supports the potential utility of ICA to identify biologically relevant synaptic density source networks.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Glicoproteínas de Membrana/metabolismo , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Sinapses/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/normas , Piridinas/farmacocinética , Pirrolidinonas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Fatores Sexuais , Processamento de Sinais Assistido por Computador , Adulto Jovem
19.
J Clin Invest ; 131(10)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33998595

RESUMO

The gut microbiota has the capacity to affect host appetite via intestinal satiety pathways, as well as complex feeding behaviors. In this Review, we highlight recent evidence that the gut microbiota can modulate food preference across model organisms. We discuss effects of the gut microbiota on the vagus nerve and brain regions including the hypothalamus, mesolimbic system, and prefrontal cortex, which play key roles in regulating feeding behavior. Crosstalk between commensal bacteria and the central and peripheral nervous systems is associated with alterations in signaling of neurotransmitters and neuropeptides such as dopamine, brain-derived neurotrophic factor (BDNF), and glucagon-like peptide-1 (GLP-1). We further consider areas for future research on mechanisms by which gut microbes may influence feeding behavior involving these neural pathways. Understanding roles for the gut microbiota in feeding regulation will be important for informing therapeutic strategies to treat metabolic and eating disorders.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo , Comportamento Alimentar , Microbioma Gastrointestinal , Trato Gastrointestinal , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Rede Nervosa , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Trato Gastrointestinal/inervação , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/fisiopatologia , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/fisiopatologia , Rede Nervosa/metabolismo , Rede Nervosa/fisiopatologia
20.
Exp Neurol ; 342: 113734, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33945789

RESUMO

Disruptions to either sulfate supply or sulfation enzymes can affect brain development and have long-lasting effects on brain function, yet our understanding of the molecular mechanisms governing this are incomplete. Perineuronal nets (PNNs) are highly sulfated, specialized extracellular matrix structures that regulate the maturation of synaptic connections and neuronal plasticity. We have previously shown that mice heterozygous for the brain sulfate transporter Slc13a4 have abnormal social interactions, memory, exploratory behaviors, stress and anxiety of postnatal origin, pointing to potential deficits in PNN biology, and implicate SLC13A4 as a critical factor required for regulating normal synaptic connectivity and function. Here, we sought to investigate aberrant PNN formation as a potential mechanism contributing to the functional deficits displayed by Slc13a4+/- mice. Following social interactions, we reveal reduced neuronal activation in the somatosensory cortex of Slc13a4+/- mice, and altered inhibitory and excitatory postsynaptic currents. In line with this, we found a reduction in parvalbumin-expressing neurons decorated with PNNs, as well as reduced expression of markers for PNN maturation. Finally, we reveal that postnatal administration of N-acetylcysteine prevented PNN abnormalities from manifesting in Slc13a4+/- adult animals. Collectively, these data highlight a central role for postnatal SLC13A4 in normal PNN formation, circuit function and subsequent animal behavior.


Assuntos
Acetilcisteína/administração & dosagem , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/metabolismo , Transportadores de Sulfato/metabolismo , Simportadores/metabolismo , Animais , Animais Geneticamente Modificados , Animais Recém-Nascidos , Feminino , Sequestradores de Radicais Livres/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Somatossensorial/efeitos dos fármacos , Córtex Somatossensorial/metabolismo , Transportadores de Sulfato/genética , Simportadores/genética
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