RESUMO
The motor cortex is essential for controlling the flexible movements underlying complex behaviors. Behavioral flexibility involves the ability to integrate and refine new movements, thereby expanding an animal's repertoire. This review discusses recent strides in motor learning mechanisms across spatial and temporal scales, describing how neural networks are remodeled at the level of synapses, cell types, and circuits and across time as animals' learn new skills. It highlights how changes at each scale contribute to the evolving structure and function of neural circuits that accompanies the expansion and refinement of motor skills. We review new findings highlighted by advanced imaging techniques that have opened new vistas in optical physiology and neuroanatomy, revealing the complexity and adaptability of motor cortical circuits, crucial for learning and control. At the structural level, we explore the dynamic regulation of dendritic spines mediating corticocortical and thalamocortical inputs to the motor cortex. We delve into the role of perisynaptic astrocyte processes in maintaining synaptic stability during learning. We also examine the functional diversity among pyramidal neuron subtypes, their dendritic computations and unique contributions to single cell and network function. Further, we highlight how cortical activation is characterized by increased consistency and reduced strength as new movements are learned and how external inputs contribute to these changes. Finally, we consider the motor cortex's necessity as movements unfold over long time scales. These insights will continue to drive new research directions, enhancing our understanding of motor cortical circuit transformations that underpin behavioral changes expressed throughout an animal's life.
Assuntos
Aprendizagem , Córtex Motor , Córtex Motor/fisiologia , Córtex Motor/citologia , Animais , Aprendizagem/fisiologia , Humanos , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Destreza Motora/fisiologia , Espinhas Dendríticas/fisiologiaRESUMO
Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDSCON), imipramine (IMI)-treated versus CSDS (IMICSDS), and NOR-treated versus CSDS (NORCSDS) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NORCSDS groups and NORIMI groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NORCSDS and NORIMI, revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.
Assuntos
Antidepressivos , Modelos Animais de Doenças , Mitocôndrias , Córtex Pré-Frontal , Proteômica , Estresse Psicológico , Animais , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Camundongos Endogâmicos C57BL , Proteína Duplacortina , Depressão/tratamento farmacológico , Depressão/metabolismo , Comportamento Animal/efeitos dos fármacos , Derrota SocialRESUMO
The optimization of brain circuit connectivity based on initial environmental input occurs during critical periods characterized by sensory experience-dependent, temporally restricted, and transiently reversible synapse elimination. This precise, targeted synaptic pruning mechanism is mediated by glial phagocytosis. Serotonin signaling has prominent, foundational roles in the brain, but functions in glia, or in experience-dependent brain circuit synaptic connectivity remodeling, have been relatively unknown. Here, we discover that serotonergic signaling between glia is essential for olfactory experience-dependent synaptic glomerulus pruning restricted to a well-defined Drosophila critical period. We find that experience-dependent serotonin signaling is restricted to the critical period, with both (1) serotonin production and (2) 5-HT2A receptors specifically in glia, but not neurons, absolutely required for targeted synaptic glomerulus pruning. We discover that glial 5-HT2A receptor signaling limits the experience-dependent synaptic connectivity pruning in the critical period and that conditional reexpression of 5-HT2A receptors within adult glia reestablishes "critical period-like" experience-dependent synaptic glomerulus pruning at maturity. These results reveal an essential requirement for glial serotonergic signaling mediated by 5-HT2A receptors for experience-dependent synapse elimination.
Assuntos
Neuroglia , Receptor 5-HT2A de Serotonina , Serotonina , Transdução de Sinais , Sinapses , Animais , Neuroglia/metabolismo , Sinapses/metabolismo , Sinapses/fisiologia , Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Plasticidade Neuronal/fisiologia , Drosophila melanogaster/metabolismo , Drosophila/metabolismoRESUMO
Many animals use visual information to navigate1-4, but how such information is encoded and integrated by the navigation system remains incompletely understood. In Drosophila melanogaster, EPG neurons in the central complex compute the heading direction5 by integrating visual input from ER neurons6-12, which are part of the anterior visual pathway (AVP)10,13-16. Here we densely reconstruct all neurons in the AVP using electron-microscopy data17. The AVP comprises four neuropils, sequentially linked by three major classes of neurons: MeTu neurons10,14,15, which connect the medulla in the optic lobe to the small unit of the anterior optic tubercle (AOTUsu) in the central brain; TuBu neurons9,16, which connect the AOTUsu to the bulb neuropil; and ER neurons6-12, which connect the bulb to the EPG neurons. On the basis of morphologies, connectivity between neural classes and the locations of synapses, we identify distinct information channels that originate from four types of MeTu neurons, and we further divide these into ten subtypes according to the presynaptic connections in the medulla and the postsynaptic connections in the AOTUsu. Using the connectivity of the entire AVP and the dendritic fields of the MeTu neurons in the optic lobes, we infer potential visual features and the visual area from which any ER neuron receives input. We confirm some of these predictions physiologically. These results provide a strong foundation for understanding how distinct sensory features can be extracted and transformed across multiple processing stages to construct higher-order cognitive representations.
Assuntos
Conectoma , Drosophila melanogaster , Neurônios , Neurópilo , Navegação Espacial , Sinapses , Vias Visuais , Animais , Drosophila melanogaster/fisiologia , Drosophila melanogaster/citologia , Vias Visuais/fisiologia , Navegação Espacial/fisiologia , Neurônios/fisiologia , Neurópilo/citologia , Masculino , Feminino , Lobo Óptico de Animais não Mamíferos/citologia , Microscopia EletrônicaRESUMO
The recent assembly of the adult Drosophila melanogaster central brain connectome, containing more than 125,000 neurons and 50 million synaptic connections, provides a template for examining sensory processing throughout the brain1,2. Here we create a leaky integrate-and-fire computational model of the entire Drosophila brain, on the basis of neural connectivity and neurotransmitter identity3, to study circuit properties of feeding and grooming behaviours. We show that activation of sugar-sensing or water-sensing gustatory neurons in the computational model accurately predicts neurons that respond to tastes and are required for feeding initiation4. In addition, using the model to activate neurons in the feeding region of the Drosophila brain predicts those that elicit motor neuron firing5-a testable hypothesis that we validate by optogenetic activation and behavioural studies. Activating different classes of gustatory neurons in the model makes accurate predictions of how several taste modalities interact, providing circuit-level insight into aversive and appetitive taste processing. Additionally, we applied this model to mechanosensory circuits and found that computational activation of mechanosensory neurons predicts activation of a small set of neurons comprising the antennal grooming circuit, and accurately describes the circuit response upon activation of different mechanosensory subtypes6-10. Our results demonstrate that modelling brain circuits using only synapse-level connectivity and predicted neurotransmitter identity generates experimentally testable hypotheses and can describe complete sensorimotor transformations.
Assuntos
Encéfalo , Drosophila melanogaster , Modelos Neurológicos , Paladar , Animais , Drosophila melanogaster/fisiologia , Encéfalo/fisiologia , Encéfalo/citologia , Paladar/fisiologia , Comportamento Alimentar/fisiologia , Asseio Animal/fisiologia , Sinapses/fisiologia , Simulação por Computador , Optogenética , Neurônios Motores/fisiologia , Feminino , Masculino , ConectomaRESUMO
As connectomics advances, it will become commonplace to know far more about the structure of a nervous system than about its function. The starting point for many investigations will become neuronal wiring diagrams, which will be interpreted to make theoretical predictions about function. Here I demonstrate this emerging approach with the Drosophila optic lobe, analysing its structure to predict that three Dm3 (refs. 1-4) and three TmY (refs. 2,4) cell types are part of a circuit that serves the function of form vision. Receptive fields are predicted from connectivity, and suggest that the cell types encode the local orientation of a visual stimulus. Extraclassical5,6 receptive fields are also predicted, with implications for robust orientation tuning7, position invariance8,9 and completion of noisy or illusory contours10,11. The TmY types synapse onto neurons that project from the optic lobe to the central brain12,13, which are conjectured to compute conjunctions and disjunctions of oriented features. My predictions can be tested through neurophysiology, which would constrain the parameters and biophysical mechanisms in neural network models of fly vision14.
Assuntos
Drosophila melanogaster , Modelos Neurológicos , Neurônios , Lobo Óptico de Animais não Mamíferos , Animais , Lobo Óptico de Animais não Mamíferos/citologia , Lobo Óptico de Animais não Mamíferos/fisiologia , Drosophila melanogaster/fisiologia , Drosophila melanogaster/citologia , Neurônios/fisiologia , Visão Ocular/fisiologia , Vias Visuais/fisiologia , Sinapses/fisiologia , Orientação/fisiologiaRESUMO
Connections between neurons can be mapped by acquiring and analysing electron microscopic brain images. In recent years, this approach has been applied to chunks of brains to reconstruct local connectivity maps that are highly informative1-6, but nevertheless inadequate for understanding brain function more globally. Here we present a neuronal wiring diagram of a whole brain containing 5 × 107 chemical synapses7 between 139,255 neurons reconstructed from an adult female Drosophila melanogaster8,9. The resource also incorporates annotations of cell classes and types, nerves, hemilineages and predictions of neurotransmitter identities10-12. Data products are available for download, programmatic access and interactive browsing and have been made interoperable with other fly data resources. We derive a projectome-a map of projections between regions-from the connectome and report on tracing of synaptic pathways and the analysis of information flow from inputs (sensory and ascending neurons) to outputs (motor, endocrine and descending neurons) across both hemispheres and between the central brain and the optic lobes. Tracing from a subset of photoreceptors to descending motor pathways illustrates how structure can uncover putative circuit mechanisms underlying sensorimotor behaviours. The technologies and open ecosystem reported here set the stage for future large-scale connectome projects in other species.
Assuntos
Encéfalo , Conectoma , Drosophila melanogaster , Neurônios , Sinapses , Animais , Drosophila melanogaster/fisiologia , Drosophila melanogaster/citologia , Feminino , Encéfalo/citologia , Encéfalo/fisiologia , Neurônios/fisiologia , Neurônios/citologia , Vias Neurais/fisiologia , Vias Neurais/citologia , Neurotransmissores/metabolismo , Lobo Óptico de Animais não Mamíferos/citologia , Lobo Óptico de Animais não Mamíferos/fisiologia , Vias Eferentes/fisiologia , Vias Eferentes/citologia , Células Fotorreceptoras de Invertebrados/fisiologia , Células Fotorreceptoras de Invertebrados/citologiaRESUMO
Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, accompanied by chemotherapy and radiotherapy. Malignant cells escape surgical resection by migrating into the surrounding healthy brain tissue, where they give rise to the recurrent tumor. Based on gene expression, tumor cores can be subtyped into mesenchymal, proneural, and classical tumors, each being associated with differences in genetic alterations and cellular composition. In contrast, the adjacent brain parenchyma where infiltrating malignant cells escape surgical resection is less characterized in patients. Using spatial transcriptomics (n = 11), we show that malignant cells within proneural or mesenchymal tumor cores display spatially organized differences in gene expression, although such differences decrease within the infiltrated brain tissue. Malignant cells residing in infiltrated brain tissue have increased expression of genes related to neurodevelopmental pathways and glial cell differentiation. Our findings provide an updated view of the spatial landscape of glioblastomas and further our understanding of the malignant cells that infiltrate the healthy brain, providing new avenues for the targeted therapy of these cells after surgical resection.
Assuntos
Neoplasias Encefálicas , Encéfalo , Regulação Neoplásica da Expressão Gênica , Glioblastoma , Receptores Notch , Transdução de Sinais , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Receptores Notch/metabolismo , Receptores Notch/genética , Encéfalo/metabolismo , Encéfalo/patologia , Transcriptoma , Sinapses/metabolismo , Masculino , Feminino , Linhagem Celular Tumoral , Neuroglia/metabolismo , Neuroglia/patologia , Diferenciação Celular/genéticaRESUMO
Response gain is a crucial means by which modulatory systems control the impact of sensory input. In the visual cortex, the serotonergic 5-HT2A receptor is key in such modulation. However, due to its expression across different cell types and lack of methods that allow for specific activation, the underlying network mechanisms remain unsolved. Here we optogenetically activate endogenous G protein-coupled receptor (GPCR) signaling of a single receptor subtype in distinct mouse neocortical subpopulations in vivo. We show that photoactivation of the 5-HT2A receptor pathway in pyramidal neurons enhances firing of both excitatory neurons and interneurons, whereas 5-HT2A photoactivation in parvalbumin interneurons produces bidirectional effects. Combined photoactivation in both cell types and cortical network modelling demonstrates a conductance-driven polysynaptic mechanism that controls the gain of visual input without affecting ongoing baseline levels. Our study opens avenues to explore GPCRs neuromodulation and its impact on sensory-driven activity and ongoing neuronal dynamics.
Assuntos
Interneurônios , Optogenética , Células Piramidais , Receptor 5-HT2A de Serotonina , Córtex Visual , Animais , Córtex Visual/metabolismo , Córtex Visual/fisiologia , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/genética , Camundongos , Interneurônios/metabolismo , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Parvalbuminas/metabolismo , Sinapses/metabolismo , Sinapses/fisiologia , FemininoRESUMO
Stimulus-specific adaptation is a hallmark of sensory processing in which a repeated stimulus results in diminished successive neuronal responses, but a deviant stimulus will still elicit robust responses from the same neurons. Recent work has established that synaptically released zinc is an endogenous mechanism that shapes neuronal responses to sounds in the auditory cortex. Here, to understand the contributions of synaptic zinc to deviance detection of specific neurons, we performed wide-field and 2-photon calcium imaging of multiple classes of cortical neurons. We find that intratelencephalic (IT) neurons in both layers 2/3 and 5 as well as corticocollicular neurons in layer 5 all demonstrate deviance detection; however, we find a specific enhancement of deviance detection in corticocollicular neurons that arises from ZnT3-dependent synaptic zinc in layer 2/3 IT neurons. Genetic deletion of ZnT3 from layer 2/3 IT neurons removes the enhancing effects of synaptic zinc on corticocollicular neuron deviance detection and results in poorer acuity of detecting deviant sounds by behaving mice.
Assuntos
Córtex Auditivo , Neurônios , Sinapses , Zinco , Animais , Zinco/metabolismo , Córtex Auditivo/metabolismo , Córtex Auditivo/fisiologia , Camundongos , Sinapses/metabolismo , Sinapses/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Estimulação Acústica , Camundongos Knockout , Percepção Auditiva/fisiologia , Camundongos Endogâmicos C57BL , MasculinoRESUMO
Progressive supranuclear palsy (PSP) is an incurable neurodegenerative disease characterized by 4-repeat (0N/4R)-Tau protein accumulation in CNS neurons. We generated transgenic zebrafish expressing human 0N/4R-Tau to investigate PSP pathophysiology. Tau zebrafish replicated multiple features of PSP, including: decreased survival; hypokinesia; impaired optokinetic responses; neurodegeneration; neuroinflammation; synapse loss; and Tau hyperphosphorylation, misfolding, mislocalization, insolubility, truncation, and oligomerization. Using automated assays, we screened 147 small molecules for activity in rescuing neurological deficits in Tau zebrafish. (+)JQ1, a bromodomain inhibitor, improved hypokinesia, survival, microgliosis, and brain synapse elimination. A heterozygous brd4+/- mutant reducing expression of the bromodomain protein Brd4 similarly rescued these phenotypes. Microglial phagocytosis of synaptic material was decreased by (+)JQ1 in both Tau zebrafish and rat primary cortical cultures. Microglia in human PSP brains expressed Brd4. Our findings implicate Brd4 as a regulator of microglial synaptic elimination in tauopathy and provide an unbiased approach for identifying mechanisms and therapeutic targets in PSP.
Assuntos
Animais Geneticamente Modificados , Modelos Animais de Doenças , Microglia , Paralisia Supranuclear Progressiva , Sinapses , Fatores de Transcrição , Peixe-Zebra , Proteínas tau , Animais , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas tau/metabolismo , Proteínas tau/genética , Microglia/metabolismo , Microglia/patologia , Sinapses/metabolismo , Paralisia Supranuclear Progressiva/metabolismo , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Azepinas/farmacologia , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Triazóis/farmacologia , Ratos , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Encéfalo/metabolismo , Encéfalo/patologia , Fagocitose , Neurônios/metabolismo , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo CelularRESUMO
Changes in synaptic strength across timescales are integral to algorithmic operations of neural circuits. However, pinpointing synaptic loci that undergo plasticity in intact brain circuits and delineating contributions of synaptic plasticity to circuit function remain challenging. The whole-mount retina preparation provides an accessible platform for measuring plasticity at specific synapses while monitoring circuit-level behaviors during visual processing ex vivo. In this review, we discuss insights gained from retina studies into the versatile roles of short-term synaptic plasticity in context-dependent circuit functions. Plasticity at single synapse level greatly expands the algorithms of common microcircuit motifs and contributes to diverse circuit-level behaviors such as gain modulation, selective gating, and stimulus-dependent excitatory/inhibitory balance. Examples in retinal circuitry offer unequivocal support that synaptic plasticity increases the computational capacity of hardwired neural circuitry.
Assuntos
Plasticidade Neuronal , Retina , Sinapses , Plasticidade Neuronal/fisiologia , Retina/fisiologia , Animais , Humanos , Sinapses/fisiologia , Rede Nervosa/fisiologiaRESUMO
Ischemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modeled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the mouse hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed unexpected differences in the vulnerability of the investigated cellular mechanisms. Axonal action potential firing and glutamate uptake were surprisingly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.
Assuntos
Ácido Glutâmico , Hipocampo , Transmissão Sináptica , Animais , Ácido Glutâmico/metabolismo , Camundongos , Hipocampo/metabolismo , Transdução de Sinais , Masculino , Sinapses/metabolismo , Sinapses/fisiologia , Camundongos Endogâmicos C57BLRESUMO
This study aims to reveal the protective effect and mechanism of Zuogui Jiangtang Jieyu Formula on the damage to hippo-campal synaptic microenvironment in rats with diabetes-related depression(DD) via regulating microglia immune receptor molecule-like family member f(CD300f)/Toll-like receptor 4(TLR4) signal. Firstly, the model of DD rats was established by a two-week high-fat diet+STZ injection+chronic mild and unpredictable stress plus isolation for 28 days. The rats were randomly divided into normal group, model group, CD300f blocker(CLM1, 2 µg·kg~(-1)) group, CD300f agonist(Fcγ, 5 µg·kg~(-1)) group, positive drug(0.18 g·kg~(-1) metformin+1.8 mg·kg~(-1) fluoxetine) group, and high-dose and low-dose(20.52 and 10.26 g·kg~(-1)) Zuogui Jiangtang Jieyu Formula groups. Depression-like behavior of rats was evaluated by open field and forced swimming experiments. The levels of blood glucose and insulin were detected by biochemical analysis. The levels of tumor necrosis factor α(TNF-α), interleukin-1ß(IL-1ß), indoleamine 2, 3-dioxygenase(IDO), 5-hydroxytryptamine(5-HT), and dopamine(DA) in the hippocampus were detected by enzyme-linked immunosorbent assay. The changes in the synaptic ultrastructure in hippocampal neurons of rats were observed by transmission electron microscopy. The protein expressions of CD300f, TLR4, synaptophysin(SYN), and postsynaptic density protein 95(PSD-95) in microglial cells of the hippocampus were detected by immunofluorescence and Western blot. The results indicated that compared with that in the normal group, the total movement distance in open field experiments was reduced in the model group, and the immobility time in forced swimming experiments increased, with an elevated insulin level in serum, as well as TNF-α, IL-1ß, and IDO levels in the hippocampus. The 5-HT and DA levels in the hippocampus were reduced. In addition, the CD300f expression was down-regulated in microglial cells of the hippocampus, and the TLR4 expression was up-regulated. Moreover, the expression of synapse-related proteins SYN and PSD-95 in hippocampal neurons decreased, and the synaptic ultrastructure of hippocampal neurons was significantly damaged. Compared with the model group, the CD300f blocker and agonist aggravated and alleviated the above abnormal changes, respectively. High-dose and low-dose Zuogui Jiangtang Jieyu Formula could significantly improve the above depression-like beha-vior in rats, inhibit the abnormal increase of TNF-α, IL-1ß, and IDO and the decrease of 5-HT and DA, effectively increase the expression of CD300f in microglial cells, and decrease the expression of TLR4. They could up-regulate the protein expression of presyna-ptic membrane SYN and postsynaptic membrane PSD-95 in hippocampal neurons and finally improve the damage to the hippocampal synaptic microenvironment. In conclusion, this research confirmed that Zuogui Jiangtang Jieyu Formula effectively alleviated the depression-like behavior and inhibited inflammatory activation of microglial cells in the hippocampus of rats with DD, and the mechanism might be related to the regulation of CD300f/TLR4 signal to alleviate the damage to hippocampal synaptic microenvironment.
Assuntos
Depressão , Medicamentos de Ervas Chinesas , Hipocampo , Microglia , Neurônios , Ratos Sprague-Dawley , Receptor 4 Toll-Like , Animais , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Humanos , Receptores Imunológicos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
Abnormalities in gamma-aminobutyric acid (GABA)ergic neurotransmission play a role in the pathogenesis of autism, although the mechanisms responsible for alterations in specific brain regions remain unclear. Deficits in social motivation and interactions are core symptoms of autism, likely due to defects in dopaminergic neural pathways. Therefore, investigating the morphology and functional roles of GABAergic neurons within dopaminergic projection areas could elucidate the underlying etiology of autism. The aim of this study was to (1) compare the morphology and arborization of glutamate decarboxylase (GAD)-positive neurons from the midbrain tegmentum; (2) evaluate synaptic activity in primary neurons from the striatum; and (3) assess GABAergic postsynaptic puncta in the ventral striatum of wild-type (WT) and Shank3-deficient mice. We found a significant decrease in the number of short neurites in GAD positive primary neurons from the midbrain tegmentum in Shank3-deficient mice. The application of a specific blocker of GABAA receptors (GABAAR) revealed significantly increased frequency of spontaneous postsynaptic currents (sPSCs) in Shank3-deficient striatal neurons compared to their WT counterparts. The mean absolute amplitude of the events was significantly higher in striatal neurons from Shank3-deficient compared to WT mice. We also observed a significant reduction in gephyrin/GABAAR γ2 colocalization in the striatum of adult male Shank3-deficient mice. The gene expression of collybistin was significantly lower in the nucleus accumbens while gephyrin and GABAAR γ2 were lower in the ventral tegmental area (VTA) in male Shank3-deficient compared to WT mice. In conclusion, Shank3 deficiency leads to alterations in GABAergic neurons and impaired GABAergic function in dopaminergic brain areas. These changes may underlie autistic symptoms, and potential interventions modulating GABAergic activity in dopaminergic pathways may represent new treatment modality.
Assuntos
Corpo Estriado , Neurônios GABAérgicos , Mesencéfalo , Proteínas do Tecido Nervoso , Sinapses , Animais , Neurônios GABAérgicos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/deficiência , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Sinapses/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Biomarcadores/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas dos Microfilamentos/deficiência , Glutamato Descarboxilase/metabolismo , Forma Celular , Ácido gama-Aminobutírico/metabolismo , Camundongos Endogâmicos C57BL , Camundongos , Masculino , Camundongos Knockout , Receptores de GABA-A/metabolismo , Proteínas de MembranaRESUMO
Phenylketonuria (PKU) is the most common inherited disorder of amino acid metabolism, characterized by high levels of phenylalanine (Phe) in the blood and brain, leading to cognitive impairment without treatment. Nevertheless, Phe-mediated brain dysfunction is not fully understood. The objective of this study was to address gene expression alterations due to excessive Phe exposure in the human neuronal model and provide molecular advances in PKU pathophysiology. Hence, we performed NT2/D1 differentiation in culture, and, for the first time, we used Phe-treated NT2-derived neurons (NT2/N) as a novel model for Phe-mediated neuronal impairment. NT2/N were treated with 1.25 mM, 2.5 mM, 5 mM, 10 mM, and 30 mM Phe and subjected to whole-mRNA short-read sequencing. Differentially expressed genes (DEGs) were analyzed and enrichment analysis was performed. Under three different Phe concentrations (2.5 mM, 5 mM, and 10 mM), DEGs pointed to the PREX1, LRP4, CDC42BPG, GPR50, PRMT8, RASGRF2, and CDH6 genes, placing them in the context of PKU for the first time. Enriched processes included dendrite and axon impairment, synaptic transmission, and membrane assembly. In contrast to these groups, the 30 mM Phe treatment group clearly represented the neurotoxicity of Phe, exhibiting enrichment in apoptotic pathways. In conclusion, we established NT2/N as a novel model for Phe-mediated neuronal dysfunction and outlined the Phe-induced gene expression changes resulting in neurite impairment and altered synaptic connectivity.
Assuntos
Perfilação da Expressão Gênica , Neuritos , Neurônios , Fenilalanina , Humanos , Fenilalanina/farmacologia , Neuritos/metabolismo , Neuritos/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Transcriptoma , Sinapses/metabolismo , Sinapses/efeitos dos fármacos , Fenilcetonúrias/metabolismo , Fenilcetonúrias/genética , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacosRESUMO
The primary pathological change in Parkinson's disease (PD) is the progressive degeneration of dopaminergic neurons in the substantia nigra. Additionally, excessive microglial activation and synaptic loss are also typical features observed in PD samples. Exercise trainings have been proven to improve PD symptoms, delay the disease progression as well as affect excessive microglial synaptic phagocytosis. In this study, we established a mouse model of PD by injecting mouse-derived α-synuclein preformed fibrils (M-α-syn PFFs) into the substantia nigra, and demonstrated that treadmill exercise inhibits microglial activation and synaptic phagocytosis in striatum. Using RNA-Seq and proteomics, we also found that PD involves excessive activation of the complement pathway which is closely related to over-activation of microglia and abnormal synaptic function. More importantly, exercise training can inhibit complement levels and complement-mediated microglial phagocytosis of synapses. It is probably triggered by CD55, as we observed that CD55 in the striatum significantly increased after exercise training and up-regulation of that molecule rescued motor deficits of PD mice, accompanied with reduced microglial synaptic phagocytosis in the striatum. This research elucidated the interplay among microglia, complement, and synapses, and analyzed the effects of exercise training on these factors. Our work also suggested CD55 as a complement-relevant candidate molecule for developing therapeutic strategies of PD.
Assuntos
Antígenos CD55 , Proteínas do Sistema Complemento , Camundongos Endogâmicos C57BL , Doença de Parkinson , Fagocitose , Condicionamento Físico Animal , Sinapses , Regulação para Cima , Animais , Fagocitose/fisiologia , Camundongos , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/métodos , Regulação para Cima/fisiologia , Sinapses/metabolismo , Sinapses/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Proteínas do Sistema Complemento/metabolismo , Antígenos CD55/metabolismo , Microglia/metabolismo , Masculino , alfa-Sinucleína/metabolismo , Modelos Animais de DoençasRESUMO
Cognitive impairment is a common issue among human patients undergoing surgery, yet the neural mechanism causing this impairment remains unidentified. Surgical procedures often lead to glial cell activation and neuronal hypoexcitability, both of which are known to contribute to postoperative cognitive dysfunction (POCD). However, the role of neuron-glia crosstalk in the pathology of POCD is still unclear. Through integrated transcriptomics and proteomics analyses, we found that the complement cascades and microglial phagocytotic signaling pathways are activated in a mouse model of POCD. Following surgery, there is a significant increase in the presence of complement C3, but not C1q, in conjunction with presynaptic elements. This triggers a reduction in excitatory synapses, a decline in excitatory synaptic transmission, and subsequent memory deficits in the mouse model. By genetically knockout out C3ar1 or inhibiting p-STAT3 signaling, we successfully prevented neuronal hypoexcitability and alleviated cognitive impairment in the mouse model. Therefore, targeting the C3aR and downstream p-STAT3 signaling pathways could serve as potential therapeutic approaches for mitigating POCD.
Assuntos
Complemento C3 , Modelos Animais de Doenças , Transtornos da Memória , Camundongos Knockout , Microglia , Animais , Camundongos , Microglia/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Complemento C3/metabolismo , Complemento C3/genética , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Receptores de Complemento/metabolismo , Receptores de Complemento/genética , Masculino , Complicações Cognitivas Pós-Operatórias/metabolismo , Complicações Cognitivas Pós-Operatórias/etiologia , Sinapses/metabolismo , Sinapses/patologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacosRESUMO
Recent studies have found dramatic cell-type-specific responses to stimulus novelty, highlighting the importance of analyzing the cortical circuitry at this granularity to understand brain function. Although initial work characterized activity by cell type, the alterations in cortical circuitry due to interacting novelty effects remain unclear. We investigated circuit mechanisms underlying the observed neural dynamics in response to novel stimuli using a large-scale public dataset of electrophysiological recordings in behaving mice and a population network model. The model was constrained by multi-patch synaptic physiology and electron microscopy data. We found generally weaker connections under novel stimuli, with shifts in the balance between somatostatin (SST) and vasoactive intestinal polypeptide (VIP) populations and increased excitatory influences on parvalbumin (PV) and SST populations. These findings systematically characterize how cortical circuits adapt to stimulus novelty.