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1.
Nat Commun ; 12(1): 2304, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863916

RESUMO

Mitochondria play a pivotal role in the generation of signals coupling metabolism with neurotransmitter release, but a role for mitochondrial-produced ROS in regulating neurosecretion has not been described. Here we show that endogenously produced hydrogen peroxide originating from axonal mitochondria (mtH2O2) functions as a signaling cue to selectively regulate the secretion of a FMRFamide-related neuropeptide (FLP-1) from a pair of interneurons (AIY) in C. elegans. We show that pharmacological or genetic manipulations that increase mtH2O2 levels lead to increased FLP-1 secretion that is dependent upon ROS dismutation, mitochondrial calcium influx, and cysteine sulfenylation of the calcium-independent PKC family member PKC-1. mtH2O2-induced FLP-1 secretion activates the oxidative stress response transcription factor SKN-1/Nrf2 in distal tissues and protects animals from ROS-mediated toxicity. mtH2O2 levels in AIY neurons, FLP-1 secretion and SKN-1 activity are rapidly and reversibly regulated by exposing animals to different bacterial food sources. These results reveal a previously unreported role for mtH2O2 in linking diet-induced changes in mitochondrial homeostasis with neuropeptide secretion.


Assuntos
Adaptação Fisiológica , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Peróxido de Hidrogênio/metabolismo , Mitocôndrias/metabolismo , Neuropeptídeos/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Comportamento Alimentar/fisiologia , Regulação da Expressão Gênica , Interneurônios/citologia , Interneurônios/metabolismo , Oxirredução , Estresse Oxidativo/fisiologia , Fatores de Transcrição/metabolismo
2.
Sheng Li Xue Bao ; 73(2): 295-305, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33903891

RESUMO

Cortical GABAergic inhibitory neurons are composed of three major classes, each expressing parvalbumin (PV), somatostatin (SOM) and 5-hydroxytryptamine receptor 3A (Htr3a), respectively. Htr3a+ inhibitory neurons are mainly derived from the caudal ganglionic eminence (CGE). This highly heterogeneous group of inhibitory neurons are comprised of many different subtypes with distinct molecular signatures, morphological and electrophysiological properties and connectivity patterns. In this review, we summarized recent research progress regarding cortical Htr3a+ inhibitory neurons, focusing on their molecular, morphological and electrophysiological diversity, and introduced some genetic mouse tools that were used to study Htr3a+ inhibitory neurons.


Assuntos
Interneurônios , Serotonina , Animais , Interneurônios/metabolismo , Camundongos , Neurônios/metabolismo , Parvalbuminas/genética , Parvalbuminas/metabolismo , Receptores 5-HT3 de Serotonina/genética , Somatostatina/metabolismo
3.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806936

RESUMO

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.


Assuntos
Comportamento Animal , Imunomodulação , Interneurônios/metabolismo , Lipopolissacarídeos/imunologia , Parvalbuminas/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Feminino , Imuno-Histoquímica , Masculino , Exposição Materna , Microglia/imunologia , Microglia/metabolismo , Gravidez , Ratos , Fatores Sexuais , Comportamento Social
4.
Nat Commun ; 12(1): 1731, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741962

RESUMO

Mutations in KCNC3, which encodes the Kv3.3 potassium channel, cause degeneration of the cerebellum, but exactly how the activity of an ion channel is linked to the survival of cerebellar neurons is not understood. Here, we report that Kv3.3 channels bind and stimulate Tank Binding Kinase 1 (TBK1), an enzyme that controls trafficking of membrane proteins into multivesicular bodies, and that this stimulation is greatly increased by a disease-causing Kv3.3 mutation. TBK1 activity is required for the binding of Kv3.3 to its auxiliary subunit Hax-1, which prevents channel inactivation with depolarization. Hax-1 is also an anti-apoptotic protein required for survival of cerebellar neurons. Overactivation of TBK1 by the mutant channel leads to the loss of Hax-1 by its accumulation in multivesicular bodies and lysosomes, and also stimulates exosome release from neurons. This process is coupled to activation of caspases and increased cell death. Our studies indicate that Kv3.3 channels are directly coupled to TBK1-dependent biochemical pathways that determine the trafficking of cellular constituents and neuronal survival.


Assuntos
Sobrevivência Celular/fisiologia , Cerebelo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transporte Proteico/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Potássio Shaw/metabolismo , Animais , Exossomos/metabolismo , Feminino , Interneurônios/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Mutação , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Canais de Potássio Shaw/genética , Transdução de Sinais
5.
Nat Commun ; 12(1): 1932, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771998

RESUMO

The physical distance between presynaptic Ca2+ channels and the Ca2+ sensors triggering the release of neurotransmitter-containing vesicles regulates short-term plasticity (STP). While STP is highly diversified across synapse types, the computational and behavioral relevance of this diversity remains unclear. In the Drosophila brain, at nanoscale level, we can distinguish distinct coupling distances between Ca2+ channels and the (m)unc13 family priming factors, Unc13A and Unc13B. Importantly, coupling distance defines release components with distinct STP characteristics. Here, we show that while Unc13A and Unc13B both contribute to synaptic signalling, they play distinct roles in neural decoding of olfactory information at excitatory projection neuron (ePN) output synapses. Unc13A clusters closer to Ca2+ channels than Unc13B, specifically promoting fast phasic signal transfer. Reduction of Unc13A in ePNs attenuates responses to both aversive and appetitive stimuli, while reduction of Unc13B provokes a general shift towards appetitive values. Collectively, we provide direct genetic evidence that release components of distinct nanoscopic coupling distances differentially control STP to play distinct roles in neural decoding of sensory information.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Animais Geneticamente Modificados , Comportamento Apetitivo/fisiologia , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Feminino , Interneurônios/metabolismo , Interneurônios/fisiologia , Proteínas de Membrana/genética , Microscopia Confocal , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferência de RNA , Sinapses/metabolismo , Transmissão Sináptica/genética , Vesículas Sinápticas/metabolismo
6.
Molecules ; 26(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668529

RESUMO

Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, ICh, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited ICh with the order: norfluoxetine ~ mirtazapine ~ imipramine < bupropion ~ fluoxetine ~ venlafaxine ~ escitalopram. The constructed homology model of the rat α7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion-channel of the α7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of ICh and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the α7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion-channel.


Assuntos
Antidepressivos/química , Antidepressivos/farmacologia , Canais Iônicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/química , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Antidepressivos/classificação , Colina/farmacologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ratos , Homologia Estrutural de Proteína , Relação Estrutura-Atividade , Termodinâmica
7.
Nat Neurosci ; 24(3): 401-411, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33619404

RESUMO

Pyramidal cells and GABAergic interneurons fire together in balanced cortical networks. In contrast to this general rule, we describe a distinct neuron type in mice and rats whose spiking activity is anti-correlated with all principal cells and interneurons in all brain states but, most prevalently, during the down state of non-REM (NREM) sleep. We identify these down state-active (DSA) neurons as deep-layer neocortical neurogliaform cells that express ID2 and Nkx2.1 and are weakly immunoreactive to neuronal nitric oxide synthase. DSA neurons are weakly excited by deep-layer pyramidal cells and strongly inhibited by several other GABAergic cell types. Spiking of DSA neurons modified the sequential firing order of other neurons at down-up transitions. Optogenetic activation of ID2+Nkx2.1+ interneurons in the posterior parietal cortex during NREM sleep, but not during waking, interfered with consolidation of cue discrimination memory. Despite their sparsity, DSA neurons perform critical physiological functions.


Assuntos
Potenciais de Ação/fisiologia , Proteína 2 Inibidora de Diferenciação/metabolismo , Interneurônios/fisiologia , Lobo Parietal/fisiologia , Células Piramidais/fisiologia , Sono/fisiologia , Fator Nuclear 1 de Tireoide/metabolismo , Animais , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Vias Neurais/fisiologia , Óxido Nítrico Sintase Tipo I/metabolismo , Optogenética , Lobo Parietal/metabolismo
8.
Nature ; 591(7848): 99-104, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33627875

RESUMO

Neuropil is a fundamental form of tissue organization within the brain1, in which densely packed neurons synaptically interconnect into precise circuit architecture2,3. However, the structural and developmental principles that govern this nanoscale precision remain largely unknown4,5. Here we use an iterative data coarse-graining algorithm termed 'diffusion condensation'6 to identify nested circuit structures within the Caenorhabditis elegans neuropil, which is known as the nerve ring. We show that the nerve ring neuropil is largely organized into four strata that are composed of related behavioural circuits. The stratified architecture of the neuropil is a geometrical representation of the functional segregation of sensory information and motor outputs, with specific sensory organs and muscle quadrants mapping onto particular neuropil strata. We identify groups of neurons with unique morphologies that integrate information across strata and that create neural structures that cage the strata within the nerve ring. We use high resolution light-sheet microscopy7,8 coupled with lineage-tracing and cell-tracking algorithms9,10 to resolve the developmental sequence and reveal principles of cell position, migration and outgrowth that guide stratified neuropil organization. Our results uncover conserved structural design principles that underlie the architecture and function of the nerve ring neuropil, and reveal a temporal progression of outgrowth-based on pioneer neurons-that guides the hierarchical development of the layered neuropil. Our findings provide a systematic blueprint for using structural and developmental approaches to understand neuropil organization within the brain.


Assuntos
Caenorhabditis elegans/embriologia , Caenorhabditis elegans/metabolismo , Neurópilo/química , Neurópilo/metabolismo , Algoritmos , Animais , Encéfalo/citologia , Encéfalo/embriologia , Caenorhabditis elegans/química , Caenorhabditis elegans/citologia , Movimento Celular , Difusão , Interneurônios/metabolismo , Neurônios Motores/metabolismo , Neuritos/metabolismo , Neurópilo/citologia , Células Receptoras Sensoriais/metabolismo
9.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445678

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid ß (Aß) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Região CA1 Hipocampal/patologia , Potenciação de Longa Duração/fisiologia , Rede Nervosa/patologia , Neurônios/patologia , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Cognição/fisiologia , Modelos Animais de Doenças , Feminino , Interneurônios/metabolismo , Interneurônios/patologia , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Camundongos , Camundongos Transgênicos , Rede Nervosa/metabolismo , Neuregulina-1/metabolismo , Neurônios/metabolismo , Parvalbuminas/metabolismo , Receptor ErbB-4/metabolismo , Transdução de Sinais/fisiologia , Transmissão Sináptica/fisiologia
10.
PLoS Genet ; 17(1): e1009295, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33428618

RESUMO

Environmental factors such as temperature affect neuronal activity and development. However, it remains unknown whether and how they affect synaptic subcellular specificity. Here, using the nematode Caenorhabditis elegans AIY interneurons as a model, we found that high cultivation temperature robustly induces defects in synaptic subcellular specificity through glutamatergic neurotransmission. Furthermore, we determined that the functional glutamate is mainly released by the ASH sensory neurons and sensed by two conserved inhibitory glutamate-gated chloride channels GLC-3 and GLC-4 in AIY. Our work not only presents a novel neurotransmission-dependent mechanism underlying the synaptic subcellular specificity, but also provides a potential mechanistic insight into high-temperature-induced neurological defects.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Canais de Cloreto/genética , Ácido Glutâmico/metabolismo , Interneurônios/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Ácido Glutâmico/genética , Transdução de Sinais/genética , Sinapses/genética , Sinapses/metabolismo , Transmissão Sináptica/genética , Temperatura
11.
J Neurosci ; 41(5): 845-854, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472820

RESUMO

Spinal interneurons are important facilitators and modulators of motor, sensory, and autonomic functions in the intact CNS. This heterogeneous population of neurons is now widely appreciated to be a key component of plasticity and recovery. This review highlights our current understanding of spinal interneuron heterogeneity, their contribution to control and modulation of motor and sensory functions, and how this role might change after traumatic spinal cord injury. We also offer a perspective for how treatments can optimize the contribution of interneurons to functional improvement.


Assuntos
Interneurônios/metabolismo , Doenças do Sistema Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Agonistas GABAérgicos/farmacologia , Agonistas GABAérgicos/uso terapêutico , Humanos , Interneurônios/efeitos dos fármacos , Interneurônios/patologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/patologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia
12.
Epilepsia ; 62(2): 542-556, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33452820

RESUMO

OBJECTIVE: Many antiseizure drugs (ASDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood. METHODS: In the present study, we determined the effects of eslicarbazepine (S-Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated rats. RESULTS: We found that S-Lic causes an unexpected reduction of feed-forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 300 but not 100 µM S-Lic significantly reduced maximal firing rates in putative feed-forward interneurons located in the CA1 stratum radiatum of sham-control and epileptic animals. In contrast, feedback inhibition was not inhibited by S-Lic. Instead, application of S-Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post-synaptic currents (IPSCs) only in epileptic and not in sham-control animals, which persisted after washout of S-Lic. We hypothesized that this plasticity of inhibition might rely on anti-Hebbian potentiation of excitatory feedback inputs onto oriens-lacunosum moleculare (OLM) interneurons, which is dependent on Ca2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Indeed, we show that blocking Ca2+ -permeable AMPA receptors completely prevents upmodulation of feedback inhibition. SIGNIFICANCE: These results suggest that S-Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account.


Assuntos
Anticonvulsivantes/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Dibenzazepinas/farmacologia , Epilepsia/fisiopatologia , Interneurônios/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Cálcio/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Epilepsia/induzido quimicamente , Retroalimentação Fisiológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Interneurônios/metabolismo , Potenciação de Longa Duração , Agonistas Muscarínicos/toxicidade , Plasticidade Neuronal , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pilocarpina/toxicidade , Ratos , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/metabolismo
13.
PLoS One ; 16(1): e0238799, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33434191

RESUMO

Exposure to volatile anesthetics during the neonatal period results in acute neuron death. Prior work suggests that apoptosis is the dominant mechanism mediating neuron death. We show that Bax deficiency blocks neuronal death following exposure to isoflurane during the neonatal period. Blocking Bax-mediated neuron death attenuated the neuroinflammatory response of microglia following isoflurane exposure. We find that GABAergic interneurons are disproportionately overrepresented among dying neurons. Despite the increase in neuronal apoptosis induced by isoflurane exposure during the neonatal period, seizure susceptibility, spatial memory retention, and contextual fear memory were unaffected later in life. However, Bax deficiency alone led to mild deficiencies in spatial memory and contextual fear memory, suggesting that normal developmental apoptotic death is important for cognitive function. Collectively, these findings show that while GABAergic neurons in the neonatal brain undergo elevated Bax-dependent apoptotic cell death following exposure to isoflurane, this does not appear to have long-lasting consequences on overall neurological function later in life.


Assuntos
Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Isoflurano/efeitos adversos , Anestésicos Inalatórios/farmacologia , Animais , Animais Recém-Nascidos/metabolismo , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Feminino , Hipocampo/metabolismo , Interneurônios/metabolismo , Isoflurano/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Microglia/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/fisiologia
14.
Br J Anaesth ; 126(4): 835-844, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33386125

RESUMO

BACKGROUND: Propofol, a commonly used intravenous anaesthetic, binds to type A gamma aminobutyric acid (GABA) receptors in mammalian brain. Previous work on its anaesthetic action has characterised either the biochemistry underlying propofol binding or the associated changes in brain network dynamics during sedation. Despite these advances, no study has focused on understanding how propofol action at the cellular level results in changes in brain network connectivity. METHODS: We used human whole-brain microarray data to generate distribution maps for genes that mark the primary GABAergic cortical interneurone subtypes (somatostatin, parvalbumin [PV], and 5-hydroxytryptamine 3A. Next, 25 healthy participants underwent propofol-induced sedation during resting state functional MRI scanning. We used partial least squares analysis to identify the brain regions in which connectivity patterns were most impacted by propofol sedation. We then correlated these multimodal cortical patterns to determine if a specific interneurone subtype was disproportionately expressed in brain regions in which connectivity patterns were altered during sedation. RESULTS: Brain networks that were significantly altered by propofol sedation had a high density of PV-expressing GABAergic interneurones. Brain networks that anticorrelated during normal wakefulness, namely the default mode network and attentional and frontoparietal control networks, increased in correlation during sedation. CONCLUSIONS: PV-expressing interneurones are highly expressed in brain regions with altered connectivity profiles during propofol-induced sedation. This study also demonstrates the utility of leveraging multiple datasets to address multiscale neurobiological problems.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Interneurônios/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Parvalbuminas , Propofol/farmacologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Feminino , Neurônios GABAérgicos/metabolismo , Humanos , Interneurônios/metabolismo , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Parvalbuminas/metabolismo , Análise Serial de Proteínas/métodos
15.
Nat Commun ; 12(1): 108, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398060

RESUMO

The diversity reflected by >100 different neural cell types fundamentally contributes to brain function and a central idea is that neuronal identity can be inferred from genetic information. Recent large-scale transcriptomic assays seem to confirm this hypothesis, but a lack of morphological information has limited the identification of several known cell types. In this study, we used single-cell RNA-seq in morphologically identified parvalbumin interneurons (PV-INs), and studied their transcriptomic states in the morphological, physiological, and developmental domains. Overall, we find high transcriptomic similarity among PV-INs, with few genes showing divergent expression between morphologically different types. Furthermore, PV-INs show a uniform synaptic cell adhesion molecule (CAM) profile, suggesting that CAM expression in mature PV cells does not reflect wiring specificity after development. Together, our results suggest that while PV-INs differ in anatomy and in vivo activity, their continuous transcriptomic and homogenous biophysical landscapes are not predictive of these distinct identities.


Assuntos
Perfilação da Expressão Gênica , Hipocampo/citologia , Interneurônios/citologia , Interneurônios/metabolismo , Parvalbuminas/metabolismo , Envelhecimento/genética , Animais , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular/genética , Fenômenos Eletrofisiológicos , Feminino , Regulação da Expressão Gênica , Hemoglobinas/genética , Hemoglobinas/metabolismo , Masculino , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma/genética
16.
Nat Commun ; 12(1): 278, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436636

RESUMO

Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Nav1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Nav currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders.


Assuntos
Interneurônios/metabolismo , Inibição Neural , Neuregulina-1/metabolismo , Córtex Pré-Frontal/metabolismo , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação , Animais , Comportamento Animal , Dependovirus/metabolismo , Genótipo , Ativação do Canal Iônico , Masculino , Camundongos Transgênicos , Rede Nervosa/metabolismo , Neuregulina-1/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Canais de Sódio/metabolismo
17.
Nat Commun ; 12(1): 314, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436635

RESUMO

Detecting the direction of frequency modulation (FM) is essential for vocal communication in both animals and humans. Direction-selective firing of neurons in the primary auditory cortex (A1) has been classically attributed to temporal offsets between feedforward excitatory and inhibitory inputs. However, it remains unclear how cortical recurrent circuitry contributes to this computation. Here, we used two-photon calcium imaging and whole-cell recordings in awake mice to demonstrate that direction selectivity is not caused by temporal offsets between synaptic currents, but by an asymmetry in total synaptic charge between preferred and non-preferred directions. Inactivation of cortical somatostatin-expressing interneurons (SOM cells) reduced direction selectivity, revealing its cortical contribution. Our theoretical models showed that charge asymmetry arises due to broad spatial topography of SOM cell-mediated inhibition which regulates signal amplification in strongly recurrent circuitry. Together, our findings reveal a major contribution of recurrent network dynamics in shaping cortical tuning to behaviorally relevant complex sounds.


Assuntos
Córtex Auditivo/fisiologia , Rede Nervosa/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores , Interneurônios/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Dinâmica não Linear , Somatostatina/metabolismo , Som , Sinapses/metabolismo
18.
Nature ; 590(7845): 315-319, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33328636

RESUMO

Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4-6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1-4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.


Assuntos
Antidepressivos/farmacologia , Fator de Iniciação 4E em Eucariotos/metabolismo , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Fatores de Iniciação em Eucariotos/genética , Fatores de Iniciação em Eucariotos/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Ketamina/análogos & derivados , Ketamina/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Mutação , Inibição Neural/efeitos dos fármacos , Inibição Neural/genética , Neurônios/classificação , Neurônios/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Transmissão Sináptica/efeitos dos fármacos
19.
Nat Neurosci ; 24(1): 24-33, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33349712

RESUMO

Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.


Assuntos
Química Encefálica/genética , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transcriptoma , Adulto , Autopsia , Estudos de Coortes , Transtorno Depressivo Maior/genética , Feminino , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Interneurônios/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Caracteres Sexuais , Adulto Jovem
20.
Methods Mol Biol ; 2191: 309-321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32865752

RESUMO

Optogenetic technology has enabled unparalleled insights into cellular and organ physiology by providing exquisite temporal and spatial control of biological pathways. Here, an optogenetic approach is presented for selective activation of the intrinsic cardiac nervous system in excised perfused mouse hearts. The breeding of transgenic mice that have selective expression of channelrhodopsin in either catecholaminergic or cholinergic neurons is described. An approach for perfusing hearts excised from those animals, recording the ECG to measure heart rate changes, and an illumination technique using a custom micro-LED light source to activate channelrhodopsin is explained. We have used these methods in ongoing studies of the kinetics of autonomic control of cardiac electrophysiology and contractility, demonstrating the proven utility of optogenetic technology to enable unparalleled spatiotemporal anatomic-functional probing of the intrinsic cardiac nervous system.


Assuntos
Channelrhodopsins/genética , Coração/fisiologia , Interneurônios/metabolismo , Optogenética/métodos , Potenciais de Ação/genética , Animais , Humanos , Interneurônios/patologia , Camundongos , Camundongos Transgênicos , Estimulação Luminosa/métodos
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