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1.
Nat Commun ; 11(1): 4819, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968048

RESUMO

In many parts of the nervous system, experience-dependent refinement of neuronal circuits predominantly involves synapse elimination. The role of sleep in this process remains unknown. We investigated the role of sleep in experience-dependent dendritic spine elimination of layer 5 pyramidal neurons in the visual (V1) and frontal association cortex (FrA) of 1-month-old mice. We found that monocular deprivation (MD) or auditory-cued fear conditioning (FC) caused rapid spine elimination in V1 or FrA, respectively. MD- or FC-induced spine elimination was significantly reduced after total sleep or REM sleep deprivation. Total sleep or REM sleep deprivation also prevented MD- and FC-induced reduction of neuronal activity in response to visual or conditioned auditory stimuli. Furthermore, dendritic calcium spikes increased substantially during REM sleep, and the blockade of these calcium spikes prevented MD- and FC-induced spine elimination. These findings reveal an important role of REM sleep in experience-dependent synapse elimination and neuronal activity reduction.


Assuntos
Córtex Cerebral/fisiologia , Espinhas Dendríticas/fisiologia , Sono REM/fisiologia , Animais , Condicionamento Clássico , Medo/fisiologia , Camundongos , Camundongos Transgênicos , Modelos Animais , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Células Piramidais/fisiologia , Privação Sensorial/fisiologia , Privação do Sono , Sinapses , Córtex Visual/fisiologia
2.
Nat Commun ; 11(1): 4395, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879322

RESUMO

The formation and maintenance of spatial representations within hippocampal cell assemblies is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at distinct inhibitory synapses and its regulation of hippocampal network activity is not well understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type calcium channel activation to confer synapse specificity but otherwise employ distinct mechanisms. Since parvalbumin and somatostatin interneurons preferentially target perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to stabilise place cells while facilitating representation of multiple unique environments within the hippocampal network.


Assuntos
Hipocampo/fisiologia , Interneurônios/metabolismo , Células Piramidais/fisiologia , Potenciais de Ação , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Canais de Cálcio Tipo T/metabolismo , Channelrhodopsins/metabolismo , Hipocampo/citologia , Camundongos , Optogenética/métodos , Parvalbuminas/metabolismo , Técnicas de Patch-Clamp , Transdução de Sinais , Somatostatina/metabolismo , Sinapses/metabolismo
3.
Nat Commun ; 11(1): 4276, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848151

RESUMO

The structural organization of excitatory inputs supporting spike-timing-dependent plasticity (STDP) remains unknown. We performed a spine STDP protocol using two-photon (2P) glutamate uncaging (pre) paired with postsynaptic spikes (post) in layer 5 pyramidal neurons from juvenile mice. Here we report that pre-post pairings that trigger timing-dependent LTP (t-LTP) produce shrinkage of the activated spine neck and increase in synaptic strength; and post-pre pairings that trigger timing-dependent LTD (t-LTD) decrease synaptic strength without affecting spine shape. Furthermore, the induction of t-LTP with 2P glutamate uncaging in clustered spines (<5 µm apart) enhances LTP through a NMDA receptor-mediated spine calcium accumulation and actin polymerization-dependent neck shrinkage, whereas t-LTD was dependent on NMDA receptors and disrupted by the activation of clustered spines but recovered when separated by >40 µm. These results indicate that synaptic cooperativity disrupts t-LTD and extends the temporal window for the induction of t-LTP, leading to STDP only encompassing LTP.


Assuntos
Espinhas Dendríticas/fisiologia , Plasticidade Neuronal/fisiologia , Potenciais de Ação/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Técnicas In Vitro , Potenciação de Longa Duração/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência por Excitação Multifotônica , Modelos Neurológicos , Células Piramidais/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia
4.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 40(7): 972-980, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32701228

RESUMO

OBJECTIVE: To investigate the effects of acid-sensing ion channels (ASICs) on electrophysiological epileptic activities of mouse hippocampal pyramidal neurons in the extracellular acidotic condition. METHODS: We investigated effects of extracellular acidosis on epileptic activities induced by elevated extracellular K + concentration or the application of an antagonist of GABAA receptors in perfusate of mouse hippocampal slices under field potential recordings. We also tested the effects of extracellular acidosis on neuronal excitability under field potential recording and evaluated the changes in epileptic activities of the neurons in response to pharmacological inhibition of ASICs using a specific inhibitor of ASICs. RESULTS: Extracellular acidosis significantly suppressed epileptic activities of the hippocampal neurons by converting ictal-like epileptic activities to non-ictal-like epileptic activities in both high [K +]o and disinhibition models, and also suppressed the intrinsic excitability of the neurons. ASICs inhibitor did not antagonize the inhibitory effect of extracellular acidosis on ictal epileptic activities and intrinsic neuronal excitability, but exacerbated non-ictal epileptic activities of the neurons in extracellular acidotic condition in both high [K+]o and disinhibition models. CONCLUSIONS: ASICs can differentially modulate ictal-like and non-ictallike epileptic activities via its direct actions on excitatory neurons.


Assuntos
Canais Iônicos Sensíveis a Ácido , Acidose , Epilepsia , Células Piramidais , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Epilepsia/fisiopatologia , Concentração de Íons de Hidrogênio , Camundongos , Células Piramidais/patologia , Células Piramidais/fisiologia
5.
Proc Natl Acad Sci U S A ; 117(29): 17278-17287, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32631999

RESUMO

The prefrontal cortex (PFC) plays a critical role in curbing impulsive behavior, but the underlying circuit mechanism remains incompletely understood. Here we show that a subset of dorsomedial PFC (dmPFC) layer 5 pyramidal neurons, which project to the subthalamic nucleus (STN) of the basal ganglia, play a key role in inhibiting impulsive responses in a go/no-go task. Projection-specific labeling and calcium imaging showed that the great majority of STN-projecting neurons were preferentially active in no-go trials when the mouse successfully withheld licking responses, but lateral hypothalamus (LH)-projecting neurons were more active in go trials with licking; visual cortex (V1)-projecting neurons showed only weak task-related activity. Optogenetic activation and inactivation of STN-projecting neurons reduced and increased inappropriate licking, respectively, partly through their direct innervation of the STN, but manipulating LH-projecting neurons had the opposite effects. These results identify a projection-defined subtype of PFC pyramidal neurons as key mediators of impulse control.


Assuntos
Comportamento Impulsivo/fisiologia , Inibição Psicológica , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Animais , Gânglios da Base/fisiologia , Comportamento Animal/fisiologia , Interneurônios/fisiologia , Camundongos , Neurônios/fisiologia , Optogenética , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/patologia , Células Piramidais/patologia , Núcleo Subtalâmico/diagnóstico por imagem , Núcleo Subtalâmico/fisiologia , Córtex Visual
6.
Neuron ; 107(3): 509-521.e7, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32492366

RESUMO

Post-tetanic potentiation (PTP) is an attractive candidate mechanism for hippocampus-dependent short-term memory. Although PTP has a uniquely large magnitude at hippocampal mossy fiber-CA3 pyramidal neuron synapses, it is unclear whether it can be induced by natural activity and whether its lifetime is sufficient to support short-term memory. We combined in vivo recordings from granule cells (GCs), in vitro paired recordings from mossy fiber terminals and postsynaptic CA3 neurons, and "flash and freeze" electron microscopy. PTP was induced at single synapses and showed a low induction threshold adapted to sparse GC activity in vivo. PTP was mainly generated by enlargement of the readily releasable pool of synaptic vesicles, allowing multiplicative interaction with other plasticity forms. PTP was associated with an increase in the docked vesicle pool, suggesting formation of structural "pool engrams." Absence of presynaptic activity extended the lifetime of the potentiation, enabling prolonged information storage in the hippocampal network.


Assuntos
Memória de Curto Prazo/fisiologia , Fibras Musgosas Hipocampais/metabolismo , Plasticidade Neuronal/fisiologia , Células Piramidais/metabolismo , Sinapses/metabolismo , Vesículas Sinápticas/metabolismo , Potenciais de Ação/fisiologia , Animais , Região CA3 Hipocampal/citologia , Giro Denteado/citologia , Camundongos , Microscopia Eletrônica , Fibras Musgosas Hipocampais/fisiologia , Fibras Musgosas Hipocampais/ultraestrutura , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Células Piramidais/ultraestrutura , Ratos , Sinapses/fisiologia , Potenciais Sinápticos/fisiologia
7.
PLoS Comput Biol ; 16(5): e1007932, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453795

RESUMO

Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.


Assuntos
Cloretos/química , Dendritos/fisiologia , Neurônios/fisiologia , Receptores de GABA/fisiologia , Sinapses/fisiologia , Potenciais de Ação , Animais , Encéfalo/fisiologia , Simulação por Computador , Hipocampo/fisiologia , Humanos , Cinética , Masculino , Modelos Neurológicos , Técnicas de Cultura de Órgãos , Ligação Proteica , Células Piramidais/fisiologia , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia
8.
Nat Commun ; 11(1): 2388, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404907

RESUMO

Deep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson's disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics, behavioral tasks and mathematical modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A computational model highlights that a decrease in pyramidal neuron activity induced by DBS or by a stimulation of cortical somatostatin interneurons can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation.


Assuntos
Estimulação Encefálica Profunda/métodos , Levodopa/uso terapêutico , Transtornos Parkinsonianos/terapia , Somatostatina/metabolismo , Algoritmos , Animais , Antiparkinsonianos/uso terapêutico , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Motor/efeitos dos fármacos , Córtex Motor/metabolismo , Córtex Motor/fisiopatologia , Optogenética/métodos , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Núcleo Subtalâmico/efeitos dos fármacos , Núcleo Subtalâmico/metabolismo , Núcleo Subtalâmico/fisiopatologia
9.
Nat Commun ; 11(1): 2217, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32371879

RESUMO

Theta oscillations play a major role in temporarily defining the hippocampal rate code by translating behavioral sequences into neuronal representations. However, mechanisms constraining phase timing and cell-type-specific phase preference are unknown. Here, we employ computational models tuned with evolutionary algorithms to evaluate phase preference of individual CA1 pyramidal cells recorded in mice and rats not engaged in any particular memory task. We applied unbiased and hypothesis-free approaches to identify effects of intrinsic and synaptic factors, as well as cell morphology, in determining phase preference. We found that perisomatic inhibition delivered by complementary populations of basket cells interacts with input pathways to shape phase-locked specificity of deep and superficial pyramidal cells. Somatodendritic integration of fluctuating glutamatergic inputs defined cycle-by-cycle by unsupervised methods demonstrated that firing selection is tuneable across sublayers. Our data identify different mechanisms of phase-locking selectivity that are instrumental for flexible dynamical representations of theta sequences.


Assuntos
Região CA1 Hipocampal/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Ritmo Teta/fisiologia , Potenciais de Ação/fisiologia , Algoritmos , Animais , Região CA1 Hipocampal/citologia , Simulação por Computador , Feminino , Cinética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Neurológicos , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Ratos Wistar
10.
Neuron ; 107(3): 522-537.e6, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32464088

RESUMO

Dendritic spinules are thin protrusions, formed by neuronal spines, not adequately resolved by diffraction-limited light microscopy, which has limited our understanding of their behavior. Here we performed rapid structured illumination microscopy and enhanced resolution confocal microscopy to study spatiotemporal spinule dynamics in cortical pyramidal neurons. Spinules recurred at the same locations on mushroom spine heads. Most were short-lived, dynamic, exploratory, and originated near simple PSDs, whereas a subset was long-lived, elongated, and associated with complex PSDs. These subtypes were differentially regulated by Ca2+ transients. Furthermore, the postsynaptic Rac1-GEF kalirin-7 regulated spinule formation, elongation, and recurrence. Long-lived spinules often contained PSD fragments, contacted distal presynaptic terminals, and formed secondary synapses. NMDAR activation increased spinule number, length, and contact with distal presynaptic elements. Spinule subsets, dynamics, and recurrence were validated in cortical neurons of acute brain slices. Thus, we identified unique properties, regulatory mechanisms, and functions of spinule subtypes, supporting roles in neuronal connectivity.


Assuntos
Espinhas Dendríticas/ultraestrutura , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Densidade Pós-Sináptica/ultraestrutura , Células Piramidais/ultraestrutura , Sinapses/ultraestrutura , Animais , Cálcio/metabolismo , Córtex Cerebral/citologia , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/fisiologia , Imageamento Tridimensional , Camundongos , Microscopia Confocal , Densidade Pós-Sináptica/fisiologia , Células Piramidais/fisiologia , Receptores de N-Metil-D-Aspartato/agonistas , Análise Espaço-Temporal , Sinapses/fisiologia
11.
PLoS Comput Biol ; 16(4): e1007175, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32310936

RESUMO

Analytical forms for neuronal firing rates are important theoretical tools for the analysis of network states. Since the 1960s, the majority of approaches have treated neurons as being electrically compact and therefore isopotential. These approaches have yielded considerable insight into how single-cell properties affect network activity; however, many neuronal classes, such as cortical pyramidal cells, are electrically extended objects. Calculation of the complex flow of electrical activity driven by stochastic spatio-temporal synaptic input streams in these structures has presented a significant analytical challenge. Here we demonstrate that an extension of the level-crossing method of Rice, previously used for compact cells, provides a general framework for approximating the firing rate of neurons with spatial structure. Even for simple models, the analytical approximations derived demonstrate a surprising richness including: independence of the firing rate to the electrotonic length for certain models, but with a form distinct to the point-like leaky integrate-and-fire model; a non-monotonic dependence of the firing rate on the number of dendrites receiving synaptic drive; a significant effect of the axonal and somatic load on the firing rate; and the role that the trigger position on the axon for spike initiation has on firing properties. The approach necessitates only calculating the mean and variances of the non-thresholded voltage and its rate of change in neuronal structures subject to spatio-temporal synaptic fluctuations. The combination of simplicity and generality promises a framework that can be built upon to incorporate increasing levels of biophysical detail and extend beyond the low-rate firing limit treated in this paper.


Assuntos
Potenciais de Ação , Axônios/fisiologia , Neurônios/fisiologia , Células Piramidais/fisiologia , Sinapses/fisiologia , Transmissão Sináptica , Animais , Biologia Computacional , Dendritos/fisiologia , Modelos Neurológicos , Distribuição Normal , Optogenética , Linguagens de Programação , Processos Estocásticos
12.
J Neurosci ; 40(17): 3385-3407, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32241837

RESUMO

Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, using in vitro whole-cell patch-clamp recording and intracellular filling in acute slices of ventral premotor cortex (vPMC) from rhesus monkeys (Macaca mulatta) of either sex, we demonstrate that MSC-EVs reduce injury-related physiological and morphologic changes in perilesional layer 3 pyramidal neurons. At 14-16 weeks after injury, vPMC neurons from both vehicle- and EV-treated lesioned monkeys exhibited significant hyperexcitability and predominance of inhibitory synaptic currents, compared with neurons from nonlesioned control brains. However, compared with vehicle-treated monkeys, neurons from EV-treated monkeys showed lower firing rates, greater spike frequency adaptation, and excitatory:inhibitory ratio. Further, EV treatment was associated with greater apical dendritic branching complexity, spine density, and inhibition, indicative of enhanced dendritic plasticity and filtering of signals integrated at the soma. Importantly, the degree of EV-mediated reduction of injury-related pathology in vPMC was significantly correlated with measures of behavioral recovery. These data show that EV treatment dampens injury-related hyperexcitability and restores excitatory:inhibitory balance in vPMC, thereby normalizing activity within cortical networks for motor function.SIGNIFICANCE STATEMENT Neuronal plasticity can facilitate recovery of function after cortical injury, but the underlying mechanisms and efficacy of therapeutic interventions promoting this plasticity in primates are not well understood. Our recent work has shown that intravenous infusions of mesenchymal-derived extracellular vesicles (EVs) that are involved in cell-to-cell inflammatory and trophic signaling can enhance recovery of motor function after injury in monkey primary motor cortex. This study shows that this EV-mediated enhancement of recovery is associated with amelioration of injury-related hyperexcitability and restoration of excitatory-inhibitory balance in perilesional ventral premotor cortex. These findings demonstrate the efficacy of mesenchymal EVs as a therapeutic to reduce injury-related pathologic changes in the physiology and structure of premotor pyramidal neurons and support recovery of function.


Assuntos
Lesões Encefálicas/terapia , Vesículas Extracelulares , Células-Tronco Mesenquimais , Córtex Motor/patologia , Células Piramidais/patologia , Recuperação de Função Fisiológica/fisiologia , Animais , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Modelos Animais de Doenças , Feminino , Macaca mulatta , Masculino , Córtex Motor/fisiopatologia , Plasticidade Neuronal/fisiologia , Células Piramidais/fisiologia
13.
J Neurosci ; 40(19): 3694-3706, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277041

RESUMO

Persistent alterations in neuronal activity elicit homeostatic plastic changes in synaptic transmission and/or intrinsic excitability. However, it is unknown whether these homeostatic processes operate in concert or at different temporal scales to maintain network activity around a set-point value. Here we show that chronic neuronal hyperactivity, induced by M-channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in cultured hippocampal pyramidal neurons from mice of either sex. Homeostatic changes of intrinsic excitability occurred at a fast timescale (1-4 h) and depended on ongoing spiking activity. This fast intrinsic adaptation included plastic changes in the threshold current and a distal relocation of FGF14, a protein physically bridging Nav1.6 and Kv7.2 channels along the axon initial segment. In contrast, synaptic adaptations occurred at a slower timescale (∼2 d) and involved decreases in miniature EPSC amplitude. To examine how these temporally distinct homeostatic responses influenced hippocampal network activity, we quantified the rate of spontaneous spiking measured by multielectrode arrays at extended timescales. M-Channel blockade triggered slow homeostatic renormalization of the mean firing rate (MFR), concomitantly accompanied by a slow synaptic adaptation. Thus, the fast intrinsic adaptation of excitatory neurons is not sufficient to account for the homeostatic normalization of the MFR. In striking contrast, homeostatic adaptations of intrinsic excitability and spontaneous MFR failed in hippocampal GABAergic inhibitory neurons, which remained hyperexcitable following chronic M-channel blockage. Our results indicate that a single perturbation such as M-channel inhibition triggers multiple homeostatic mechanisms that operate at different timescales to maintain network mean firing rate.SIGNIFICANCE STATEMENT Persistent alterations in synaptic input elicit homeostatic plastic changes in neuronal activity. Here we show that chronic neuronal hyperexcitability, induced by M-type potassium channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in hippocampal excitatory neurons. The data indicate that the fast adaptation of intrinsic excitability depends on ongoing spiking activity but is not sufficient to provide homeostasis of the mean firing rate. Our results show that a single perturbation such as M-channel inhibition can trigger multiple homeostatic processes that operate at different timescales to maintain network mean firing rate.


Assuntos
Hipocampo/fisiologia , Homeostase/fisiologia , Plasticidade Neuronal/fisiologia , Células Piramidais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Canais de Potássio/metabolismo
14.
Nat Commun ; 11(1): 1172, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127543

RESUMO

von Economo neurons (VENs) are bipolar, spindle-shaped neurons restricted to layer 5 of human frontoinsula and anterior cingulate cortex that appear to be selectively vulnerable to neuropsychiatric and neurodegenerative diseases, although little is known about other VEN cellular phenotypes. Single nucleus RNA-sequencing of frontoinsula layer 5 identifies a transcriptomically-defined cell cluster that contained VENs, but also fork cells and a subset of pyramidal neurons. Cross-species alignment of this cell cluster with a well-annotated mouse classification shows strong homology to extratelencephalic (ET) excitatory neurons that project to subcerebral targets. This cluster also shows strong homology to a putative ET cluster in human temporal cortex, but with a strikingly specific regional signature. Together these results suggest that VENs are a regionally distinctive type of ET neuron. Additionally, we describe the first patch clamp recordings of VENs from neurosurgically-resected tissue that show distinctive intrinsic membrane properties relative to neighboring pyramidal neurons.


Assuntos
Neurônios/fisiologia , Lobo Temporal/citologia , Transcriptoma , Animais , Encéfalo/citologia , Encéfalo/fisiologia , Eletrofisiologia/métodos , Perfilação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Camundongos , Neurônios/citologia , Células Piramidais/fisiologia , Telencéfalo/citologia , Lobo Temporal/fisiologia
15.
Nat Commun ; 11(1): 1413, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179739

RESUMO

Clustering of functionally similar synapses in dendrites is thought to affect neuronal input-output transformation by triggering local nonlinearities. However, neither the in vivo impact of synaptic clusters on somatic membrane potential (sVm), nor the rules of cluster formation are elucidated. We develop a computational approach to measure the effect of functional synaptic clusters on sVm response of biophysical model CA1 and L2/3 pyramidal neurons to in vivo-like inputs. We demonstrate that small synaptic clusters appearing with random connectivity do not influence sVm. With structured connectivity,  ~10-20 synapses/cluster are optimal for clustering-based tuning via state-dependent mechanisms, but larger selectivity is achieved by 2-fold potentiation of the same synapses. We further show that without nonlinear amplification of the effect of random clusters, action potential-based, global plasticity rules cannot generate functional clustering. Our results suggest that clusters likely form via local synaptic interactions, and have to be moderately large to impact sVm responses.


Assuntos
Neurônios/fisiologia , Sinapses/fisiologia , Potenciais de Ação , Animais , Potenciais da Membrana , Camundongos , Modelos Neurológicos , Plasticidade Neuronal , Neurônios/química , Células Piramidais/fisiologia , Sinapses/química
16.
Neuron ; 106(4): 566-578.e8, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32169170

RESUMO

The balance between excitatory and inhibitory (E and I) synapses is thought to be critical for information processing in neural circuits. However, little is known about the spatial principles of E and I synaptic organization across the entire dendritic tree of mammalian neurons. We developed a new open-source reconstruction platform for mapping the size and spatial distribution of E and I synapses received by individual genetically-labeled layer 2/3 (L2/3) cortical pyramidal neurons (PNs) in vivo. We mapped over 90,000 E and I synapses across twelve L2/3 PNs and uncovered structured organization of E and I synapses across dendritic domains as well as within individual dendritic segments. Despite significant domain-specific variation in the absolute density of E and I synapses, their ratio is strikingly balanced locally across dendritic segments. Computational modeling indicates that this spatially precise E/I balance dampens dendritic voltage fluctuations and strongly impacts neuronal firing output.


Assuntos
Mapeamento Encefálico/métodos , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Sinapses , Animais , Dendritos/fisiologia , Dendritos/ultraestrutura , Humanos , Células Piramidais/fisiologia , Células Piramidais/ultraestrutura , Software , Sinapses/fisiologia , Sinapses/ultraestrutura
17.
Brain ; 143(3): 800-810, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32203578

RESUMO

Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Interneurônios/fisiologia , Córtex Motor/fisiologia , Inibição Neural/fisiologia , Adenoviridae , Animais , Progressão da Doença , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Destreza Motora/fisiologia , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Superóxido Dismutase-1/genética , Transfecção
18.
Neuron ; 106(5): 842-854.e4, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32213321

RESUMO

Excitation in neural circuits must be carefully controlled by inhibition to regulate information processing and network excitability. During development, cortical inhibitory and excitatory inputs are initially mismatched but become co-tuned or balanced with experience. However, little is known about how excitatory-inhibitory balance is defined at most synapses or about the mechanisms for establishing or maintaining this balance at specific set points. Here we show how coordinated long-term plasticity calibrates populations of excitatory-inhibitory inputs onto mouse auditory cortical pyramidal neurons. Pairing pre- and postsynaptic activity induced plasticity at paired inputs and different forms of heterosynaptic plasticity at the strongest unpaired synapses, which required minutes of activity and dendritic Ca2+ signaling to be computed. Theoretical analyses demonstrated how the relative rate of heterosynaptic plasticity could normalize and stabilize synaptic strengths to achieve any possible excitatory-inhibitory correlation. Thus, excitatory-inhibitory balance is dynamic and cell specific, determined by distinct plasticity rules across multiple excitatory and inhibitory synapses.


Assuntos
Potenciais de Ação/fisiologia , Córtex Auditivo/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Células Piramidais/fisiologia , Animais , Sinalização do Cálcio , Potenciais Evocados , Potenciação de Longa Duração/fisiologia , Camundongos , Técnicas de Patch-Clamp , Sinapses/fisiologia
19.
Nat Neurosci ; 23(4): 520-532, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32123378

RESUMO

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B-/- mouse model of ASD. Male and female Shank3B-/- mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.


Assuntos
Potenciais de Ação/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Neurônios GABAérgicos/fisiologia , Proteínas do Tecido Nervoso/genética , Córtex Somatossensorial/fisiopatologia , Percepção do Tato/fisiologia , Animais , Transtorno do Espectro Autista/genética , Modelos Animais de Doenças , Camundongos , Estimulação Física , Células Piramidais/fisiologia , Limiar Sensorial/fisiologia , Tato/fisiologia
20.
PLoS One ; 15(2): e0228260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023274

RESUMO

The striatum is involved in the completion and optimization of sensorimotor tasks. In rodents, its dorsolateral part receives converging glutamatergic corticostriatal (CS) inputs from whisker-related primary somatosensory (S1) and motor (M1) cortical areas, which are interconnected at the cortical level. Although it has been demonstrated that the medium-spiny neurons (MSNs) from the dorsolateral striatum process sensory information from the whiskers via the S1 CS pathway, the functional impact of the corresponding M1 CS inputs onto the same striatal neurons remained unknown. Here, by combining in vivo S1 electrocorticogram with intracellular recordings from somatosensory MSNs in the rat, we first confirmed the heterogeneity of striatal responsiveness to whisker stimuli, encompassing MSNs responding exclusively by subthreshold synaptic depolarizations, MSNs exhibiting sub- and suprathreshold responses over successive stimulations, and non-responding cells. All recorded MSNs also exhibited clear-cut monosynaptic depolarizing potentials in response to electrical stimulations of the corresponding ipsilateral M1 cortex, which were efficient to fire striatal cells. Since M1-evoked responses in MSNs could result from the intra-cortical recruitment of S1 CS neurons, we performed intracellular recordings of S1 pyramidal neurons and compared their firing latency following M1 stimuli to the latency of striatal synaptic responses. We found that the onset of M1-evoked synaptic responses in MSNs significantly preceded the firing of S1 neurons, demonstrating a direct synaptic excitation of MSNs by M1. However, the firing of MSNs seemed to require the combined excitatory effects of S1 and M1 CS inputs. This study directly demonstrates that the same somatosensory MSNs can process excitatory synaptic inputs from two functionally-related sensory and motor cortical regions converging into the same striatal sector. The effectiveness of these convergent cortical inputs in eliciting action potentials in MSNs may represent a key mechanism of striatum-related sensorimotor behaviors.


Assuntos
Células Piramidais/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Estimulação Elétrica , Eletrodos Implantados , Masculino , Ratos , Ratos Sprague-Dawley , Potenciais Sinápticos
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