RESUMO
Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.
Assuntos
Microglia/metabolismo , Inibição Neural/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal , Regulação da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Parvalbuminas/metabolismo , Fenótipo , Receptores de GABA-B/metabolismo , Sinapses/fisiologia , Transcrição GênicaRESUMO
Hardwired circuits encoding innate responses have emerged as an essential feature of the mammalian brain. Sweet and bitter evoke opposing predetermined behaviors. Sweet drives appetitive responses and consumption of energy-rich food sources, whereas bitter prevents ingestion of toxic chemicals. Here we identified and characterized the neurons in the brainstem that transmit sweet and bitter signals from the tongue to the cortex. Next we examined how the brain modulates this hardwired circuit to control taste behaviors. We dissect the basis for bitter-evoked suppression of sweet taste and show that the taste cortex and amygdala exert strong positive and negative feedback onto incoming bitter and sweet signals in the brainstem. Finally we demonstrate that blocking the feedback markedly alters responses to ethologically relevant taste stimuli. These results illustrate how hardwired circuits can be finely regulated by top-down control and reveal the neural basis of an indispensable behavioral response for all animals.
Assuntos
Tonsila do Cerebelo/fisiologia , Encéfalo/fisiologia , Mamíferos/fisiologia , Paladar/fisiologia , Animais , Tronco Encefálico/fisiologia , Calbindina 2/metabolismo , Córtex Cerebral/fisiologia , Retroalimentação Fisiológica , Camundongos Endogâmicos C57BL , Mutação/genética , Inibição Neural/fisiologia , Neurônios/fisiologia , Núcleo Solitário/fisiologia , Somatostatina/metabolismoRESUMO
Cortical layer 1 (L1) interneurons have been proposed as a hub for attentional modulation of underlying cortex, but the transformations that this circuit implements are not known. We combined genetically targeted voltage imaging with optogenetic activation and silencing to study the mechanisms underlying sensory processing in mouse barrel cortex L1. Whisker stimuli evoked precisely timed single spikes in L1 interneurons, followed by strong lateral inhibition. A mild aversive stimulus activated cholinergic inputs and evoked a bimodal distribution of spiking responses in L1. A simple conductance-based model that only contained lateral inhibition within L1 recapitulated the sensory responses and the winner-takes-all cholinergic responses, and the model correctly predicted that the network would function as a spatial and temporal high-pass filter for excitatory inputs. Our results demonstrate that all-optical electrophysiology can reveal basic principles of neural circuit function in vivo and suggest an intuitive picture for how L1 transforms sensory and modulatory inputs. VIDEO ABSTRACT.
Assuntos
Eletrofisiologia/métodos , Potenciais Somatossensoriais Evocados/fisiologia , Interneurônios/fisiologia , Inibição Neural/fisiologia , Imagem Óptica/métodos , Córtex Somatossensorial/citologia , Potenciais de Ação/fisiologia , Animais , Neurônios Colinérgicos/fisiologia , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Patch-Clamp/métodos , Potenciais Sinápticos/fisiologia , Vibrissas/fisiologiaRESUMO
Distinct brain and behavioural states are associated with organized neural population dynamics that are thought to serve specific cognitive functions1-3. Memory replay events, for example, occur during synchronous population events called sharp-wave ripples in the hippocampus while mice are in an 'offline' behavioural state, enabling cognitive mechanisms such as memory consolidation and planning4-11. But how does the brain re-engage with the external world during this behavioural state and permit access to current sensory information or promote new memory formation? Here we found that the hippocampal dentate spike, an understudied population event that frequently occurs between sharp-wave ripples12, may underlie such a mechanism. We show that dentate spikes are associated with distinctly elevated brain-wide firing rates, primarily observed in higher order networks, and couple to brief periods of arousal. Hippocampal place coding during dentate spikes aligns to the mouse's current spatial location, unlike the memory replay accompanying sharp-wave ripples. Furthermore, inhibiting neural activity during dentate spikes disrupts associative memory formation. Thus, dentate spikes represent a distinct brain state and support memory during non-locomotor behaviour, extending the repertoire of cognitive processes beyond the classical offline functions.
Assuntos
Ondas Encefálicas , Cognição , Hipocampo , Animais , Camundongos , Hipocampo/fisiologia , Consolidação da Memória/fisiologia , Nível de Alerta/fisiologia , Potenciais de Ação , Inibição Neural , Cognição/fisiologia , Ondas Encefálicas/fisiologia , Masculino , FemininoRESUMO
Astrocytes are heterogeneous glial cells of the central nervous system1-3. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. Here we show that a specific population of astrocytes in the central striatum expresses µ-crystallin (encoded by Crym in mice and CRYM in humans) that is associated with several human diseases, including neuropsychiatric disorders4-7. In adult mice, reducing the levels of µ-crystallin in striatal astrocytes through CRISPR-Cas9-mediated knockout of Crym resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory-inhibitory synaptic balance. Increased perseveration stemmed from the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics8, and that this treatment also corrected the synaptic deficits. Together, our findings reveal converging molecular, synaptic, circuit and behavioural mechanisms by which a molecularly defined and allocated population of striatal astrocytes gates perseveration phenotypes that accompany neuropsychiatric disorders9-12. Our data show that Crym-positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte-neuron interaction mechanisms that could be targeted in treatments for perseveration.
Assuntos
Astrócitos , Corpo Estriado , Ruminação Cognitiva , Cristalinas mu , Animais , Humanos , Camundongos , Astrócitos/metabolismo , Corpo Estriado/citologia , Corpo Estriado/fisiologia , Edição de Genes , Técnicas de Inativação de Genes , Cristalinas mu/deficiência , Cristalinas mu/genética , Cristalinas mu/metabolismo , Ruminação Cognitiva/fisiologia , Transmissão Sináptica , Sistemas CRISPR-Cas , Neurônios Espinhosos Médios/metabolismo , Sinapses/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Terminações Pré-Sinápticas/metabolismo , Inibição NeuralRESUMO
The posterior parietal cortex exhibits choice-selective activity during perceptual decision-making tasks1-10. However, it is not known how this selective activity arises from the underlying synaptic connectivity. Here we combined virtual-reality behaviour, two-photon calcium imaging, high-throughput electron microscopy and circuit modelling to analyse how synaptic connectivity between neurons in the posterior parietal cortex relates to their selective activity. We found that excitatory pyramidal neurons preferentially target inhibitory interneurons with the same selectivity. In turn, inhibitory interneurons preferentially target pyramidal neurons with opposite selectivity, forming an opponent inhibition motif. This motif was present even between neurons with activity peaks in different task epochs. We developed neural-circuit models of the computations performed by these motifs, and found that opponent inhibition between neural populations with opposite selectivity amplifies selective inputs, thereby improving the encoding of trial-type information. The models also predict that opponent inhibition between neurons with activity peaks in different task epochs contributes to creating choice-specific sequential activity. These results provide evidence for how synaptic connectivity in cortical circuits supports a learned decision-making task.
Assuntos
Tomada de Decisões , Vias Neurais , Lobo Parietal , Sinapses , Cálcio/análise , Cálcio/metabolismo , Tomada de Decisões/fisiologia , Interneurônios/metabolismo , Interneurônios/ultraestrutura , Aprendizagem/fisiologia , Microscopia Eletrônica , Inibição Neural , Vias Neurais/fisiologia , Vias Neurais/ultraestrutura , Lobo Parietal/citologia , Lobo Parietal/fisiologia , Lobo Parietal/ultraestrutura , Células Piramidais/metabolismo , Células Piramidais/ultraestrutura , Sinapses/metabolismo , Sinapses/ultraestrutura , Realidade Virtual , Modelos NeurológicosRESUMO
Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition, which is essential for neuronal computation1,2. Deviations from a balanced state have been linked to neurodevelopmental disorders, and severe disruptions result in epilepsy3-5. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here we identify a signalling pathway in the adult mouse neocortex that is activated in response to increased neuronal network activity. Overactivation of excitatory neurons is signalled to the network through an increase in the levels of BMP2, a growth factor that is well known for its role as a morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of perineuronal nets. PV-interneuron-specific disruption of BMP2-SMAD1 signalling is accompanied by a loss of glutamatergic innervation in PV cells, underdeveloped perineuronal nets and decreased excitability. Ultimately, this impairment of the functional recruitment of PV interneurons disrupts the cortical excitation-inhibition balance, with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signalling is repurposed to stabilize cortical networks in the adult mammalian brain.
Assuntos
Proteína Morfogenética Óssea 2 , Interneurônios , Neocórtex , Rede Nervosa , Inibição Neural , Neurônios , Transdução de Sinais , Proteína Smad1 , Animais , Feminino , Humanos , Masculino , Camundongos , Proteína Morfogenética Óssea 2/metabolismo , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Interneurônios/metabolismo , Neocórtex/metabolismo , Neocórtex/citologia , Rede Nervosa/metabolismo , Neurônios/metabolismo , Parvalbuminas/metabolismo , Proteína Smad1/metabolismo , Sinapses/metabolismo , Ácido Glutâmico/metabolismoRESUMO
Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain1-7. Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior-posterior axis precedes restriction in the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain.
Assuntos
Linhagem da Célula , Células Clonais , Mosaicismo , Neurônios , Prosencéfalo , Idoso , Feminino , Humanos , Alelos , Linhagem da Célula/genética , Células Clonais/citologia , Células Clonais/metabolismo , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/metabolismo , Hipocampo/citologia , Proteínas de Homeodomínio/metabolismo , Neocórtex/citologia , Inibição Neural , Neurônios/citologia , Neurônios/metabolismo , Lobo Parietal/citologia , Prosencéfalo/anatomia & histologia , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Análise de Célula Única , Transcriptoma/genéticaRESUMO
Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people's cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22-97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing-two conditions that involve declines in cognitive flexibility and plasticity1,2-cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.
Assuntos
Envelhecimento , Astrócitos , Neurônios , Córtex Pré-Frontal , Esquizofrenia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Envelhecimento/metabolismo , Envelhecimento/patologia , Astrócitos/citologia , Astrócitos/metabolismo , Astrócitos/patologia , Colesterol/metabolismo , Cognição , Neurônios GABAérgicos/metabolismo , Predisposição Genética para Doença , Glutamina/metabolismo , Saúde , Individualidade , Inibição Neural , Plasticidade Neuronal , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Análise da Expressão Gênica de Célula Única , Sinapses/genética , Sinapses/metabolismo , Sinapses/patologia , Membranas Sinápticas/química , Membranas Sinápticas/metabolismoRESUMO
Changes in patterns of activity within the medial prefrontal cortex enable rodents, non-human primates and humans to update their behaviour to adapt to changes in the environment-for example, during cognitive tasks1-5. Parvalbumin-expressing inhibitory neurons in the medial prefrontal cortex are important for learning new strategies during a rule-shift task6-8, but the circuit interactions that switch prefrontal network dynamics from maintaining to updating task-related patterns of activity remain unknown. Here we describe a mechanism that links parvalbumin-expressing neurons, a new callosal inhibitory connection, and changes in task representations. Whereas nonspecifically inhibiting all callosal projections does not prevent mice from learning rule shifts or disrupt the evolution of activity patterns, selectively inhibiting only callosal projections of parvalbumin-expressing neurons impairs rule-shift learning, desynchronizes the gamma-frequency activity that is necessary for learning8 and suppresses the reorganization of prefrontal activity patterns that normally accompanies rule-shift learning. This dissociation reveals how callosal parvalbumin-expressing projections switch the operating mode of prefrontal circuits from maintenance to updating by transmitting gamma synchrony and gating the ability of other callosal inputs to maintain previously established neural representations. Thus, callosal projections originating from parvalbumin-expressing neurons represent a key circuit locus for understanding and correcting the deficits in behavioural flexibility and gamma synchrony that have been implicated in schizophrenia and related conditions9,10.
Assuntos
Aprendizagem , Inibição Neural , Vias Neurais , Neurônios , Parvalbuminas , Córtex Pré-Frontal , Animais , Camundongos , Aprendizagem/fisiologia , Neurônios/metabolismo , Parvalbuminas/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Esquizofrenia/fisiopatologia , Corpo Caloso/citologia , Corpo Caloso/fisiologia , Inibição Neural/fisiologiaRESUMO
Neurons in the posterior parietal cortex contribute to the execution of goal-directed navigation1 and other decision-making tasks2-4. Although molecular studies have catalogued more than 50 cortical cell types5, it remains unclear what distinct functions they have in this area. Here we identified a molecularly defined subset of somatostatin (Sst) inhibitory neurons that, in the mouse posterior parietal cortex, carry a cell-type-specific error-correction signal for navigation. We obtained repeatable experimental access to these cells using an adeno-associated virus in which gene expression is driven by an enhancer that functions specifically in a subset of Sst cells6. We found that during goal-directed navigation in a virtual environment, this subset of Sst neurons activates in a synchronous pattern that is distinct from the activity of surrounding neurons, including other Sst neurons. Using in vivo two-photon photostimulation and ex vivo paired patch-clamp recordings, we show that nearby cells of this Sst subtype excite each other through gap junctions, revealing a self-excitation circuit motif that contributes to the synchronous activity of this cell type. These cells selectively activate as mice execute course corrections for deviations in their virtual heading during navigation towards a reward location, for both self-induced and experimentally induced deviations. We propose that this subtype of Sst neurons provides a self-reinforcing and cell-type-specific error-correction signal in the posterior parietal cortex that may help with the execution and learning of accurate goal-directed navigation trajectories.
Assuntos
Neurônios , Lobo Parietal , Animais , Camundongos , Aprendizagem , Neurônios/metabolismo , Lobo Parietal/citologia , Lobo Parietal/metabolismo , Objetivos , Somatostatina/metabolismo , Inibição Neural , Navegação Espacial , Técnicas de Patch-Clamp , Junções Comunicantes/metabolismoRESUMO
Communication between neurons and glia has an important role in establishing and maintaining higher-order brain function1. Astrocytes are endowed with complex morphologies, placing their peripheral processes in close proximity to neuronal synapses and directly contributing to their regulation of brain circuits2-4. Recent studies have shown that excitatory neuronal activity promotes oligodendrocyte differentiation5-7; whether inhibitory neurotransmission regulates astrocyte morphogenesis during development is unclear. Here we show that inhibitory neuron activity is necessary and sufficient for astrocyte morphogenesis. We found that input from inhibitory neurons functions through astrocytic GABAB receptor (GABABR) and that its deletion in astrocytes results in a loss of morphological complexity across a host of brain regions and disruption of circuit function. Expression of GABABR in developing astrocytes is regulated in a region-specific manner by SOX9 or NFIA and deletion of these transcription factors results in region-specific defects in astrocyte morphogenesis, which is conferred by interactions with transcription factors exhibiting region-restricted patterns of expression. Together, our studies identify input from inhibitory neurons and astrocytic GABABR as universal regulators of morphogenesis, while further revealing a combinatorial code of region-specific transcriptional dependencies for astrocyte development that is intertwined with activity-dependent processes.
Assuntos
Astrócitos , Forma Celular , Inibição Neural , Neurônios , Receptores de GABA-B , Astrócitos/citologia , Astrócitos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Neurônios/metabolismo , Sinapses/metabolismo , Receptores de GABA-B/metabolismo , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição NFI/metabolismo , Regulação da Expressão GênicaRESUMO
Associating multiple sensory cues with objects and experience is a fundamental brain process that improves object recognition and memory performance. However, neural mechanisms that bind sensory features during learning and augment memory expression are unknown. Here we demonstrate multisensory appetitive and aversive memory in Drosophila. Combining colours and odours improved memory performance, even when each sensory modality was tested alone. Temporal control of neuronal function revealed visually selective mushroom body Kenyon cells (KCs) to be required for enhancement of both visual and olfactory memory after multisensory training. Voltage imaging in head-fixed flies showed that multisensory learning binds activity between streams of modality-specific KCs so that unimodal sensory input generates a multimodal neuronal response. Binding occurs between regions of the olfactory and visual KC axons, which receive valence-relevant dopaminergic reinforcement, and is propagated downstream. Dopamine locally releases GABAergic inhibition to permit specific microcircuits within KC-spanning serotonergic neurons to function as an excitatory bridge between the previously 'modality-selective' KC streams. Cross-modal binding thereby expands the KCs representing the memory engram for each modality into those representing the other. This broadening of the engram improves memory performance after multisensory learning and permits a single sensory feature to retrieve the memory of the multimodal experience.
Assuntos
Encéfalo , Percepção de Cores , Drosophila melanogaster , Aprendizagem , Memória , Neurônios , Percepção Olfatória , Animais , Encéfalo/citologia , Encéfalo/fisiologia , Dopamina/metabolismo , Aprendizagem/fisiologia , Corpos Pedunculados/citologia , Corpos Pedunculados/fisiologia , Neurônios/fisiologia , Drosophila melanogaster/citologia , Drosophila melanogaster/fisiologia , Neurônios GABAérgicos/metabolismo , Neurônios Serotoninérgicos/metabolismo , Memória/fisiologia , Percepção Olfatória/fisiologia , Neurônios Dopaminérgicos/metabolismo , Inibição Neural , Percepção de Cores/fisiologia , Odorantes/análiseRESUMO
The cerebral cortex is a cellularly complex structure comprising a rich diversity of neuronal and glial cell types. Cortical neurons can be broadly categorized into two classes-excitatory neurons that use the neurotransmitter glutamate, and inhibitory interneurons that use γ-aminobutyric acid (GABA). Previous developmental studies in rodents have led to a prevailing model in which excitatory neurons are born from progenitors located in the cortex, whereas cortical interneurons are born from a separate population of progenitors located outside the developing cortex in the ganglionic eminences1-5. However, the developmental potential of human cortical progenitors has not been thoroughly explored. Here we show that, in addition to excitatory neurons and glia, human cortical progenitors are also capable of producing GABAergic neurons with the transcriptional characteristics and morphologies of cortical interneurons. By developing a cellular barcoding tool called 'single-cell-RNA-sequencing-compatible tracer for identifying clonal relationships' (STICR), we were able to carry out clonal lineage tracing of 1,912 primary human cortical progenitors from six specimens, and to capture both the transcriptional identities and the clonal relationships of their progeny. A subpopulation of cortically born GABAergic neurons was transcriptionally similar to cortical interneurons born from the caudal ganglionic eminence, and these cells were frequently related to excitatory neurons and glia. Our results show that individual human cortical progenitors can generate both excitatory neurons and cortical interneurons, providing a new framework for understanding the origins of neuronal diversity in the human cortex.
Assuntos
Linhagem da Célula , Córtex Cerebral , Interneurônios , Inibição Neural , Neurônios , Córtex Cerebral/citologia , Neurônios GABAérgicos/citologia , Humanos , Interneurônios/citologia , Neurônios/citologiaRESUMO
Transcriptomics has revealed that cortical inhibitory neurons exhibit a great diversity of fine molecular subtypes1-6, but it is not known whether these subtypes have correspondingly diverse patterns of activity in the living brain. Here we show that inhibitory subtypes in primary visual cortex (V1) have diverse correlates with brain state, which are organized by a single factor: position along the main axis of transcriptomic variation. We combined in vivo two-photon calcium imaging of mouse V1 with a transcriptomic method to identify mRNA for 72 selected genes in ex vivo slices. We classified inhibitory neurons imaged in layers 1-3 into a three-level hierarchy of 5 subclasses, 11 types and 35 subtypes using previously defined transcriptomic clusters3. Responses to visual stimuli differed significantly only between subclasses, with cells in the Sncg subclass uniformly suppressed, and cells in the other subclasses predominantly excited. Modulation by brain state differed at all hierarchical levels but could be largely predicted from the first transcriptomic principal component, which also predicted correlations with simultaneously recorded cells. Inhibitory subtypes that fired more in resting, oscillatory brain states had a smaller fraction of their axonal projections in layer 1, narrower spikes, lower input resistance and weaker adaptation as determined in vitro7, and expressed more inhibitory cholinergic receptors. Subtypes that fired more during arousal had the opposite properties. Thus, a simple principle may largely explain how diverse inhibitory V1 subtypes shape state-dependent cortical processing.
Assuntos
Interneurônios , Inibição Neural , Transcriptoma , Córtex Visual , Animais , Nível de Alerta , Axônios/fisiologia , Cálcio/análise , Interneurônios/fisiologia , Camundongos , Inibição Neural/genética , Receptores Colinérgicos , Transcriptoma/genética , Córtex Visual/citologia , Córtex Visual/metabolismo , Córtex Visual/fisiologiaRESUMO
When an animal moves through the world, its brain receives a stream of information about the body's translational velocity from motor commands and sensory feedback signals. These incoming signals are referenced to the body, but ultimately, they must be transformed into world-centric coordinates for navigation1,2. Here we show that this computation occurs in the fan-shaped body in the brain of Drosophila melanogaster. We identify two cell types, PFNd and PFNv3-5, that conjunctively encode translational velocity and heading as a fly walks. In these cells, velocity signals are acquired from locomotor brain regions6 and are multiplied with heading signals from the compass system. PFNd neurons prefer forward-ipsilateral movement, whereas PFNv neurons prefer backward-contralateral movement, and perturbing PFNd neurons disrupts idiothetic path integration in walking flies7. Downstream, PFNd and PFNv neurons converge onto hΔB neurons, with a connectivity pattern that pools together heading and translation direction combinations corresponding to the same movement in world-centric space. This network motif effectively performs a rotation of the brain's representation of body-centric translational velocity according to the current heading direction. Consistent with our predictions, we observe that hΔB neurons form a representation of translational velocity in world-centric coordinates. By integrating this representation over time, it should be possible for the brain to form a working memory of the path travelled through the environment8-10.
Assuntos
Encéfalo/fisiologia , Drosophila melanogaster/fisiologia , Locomoção/fisiologia , Modelos Neurológicos , Percepção Espacial/fisiologia , Memória Espacial/fisiologia , Navegação Espacial/fisiologia , Animais , Encéfalo/citologia , Drosophila melanogaster/citologia , Feminino , Cabeça , Memória de Curto Prazo , Inibição Neural , Vias Neurais , Neurônios/fisiologia , Rotação , Fatores de Tempo , CaminhadaRESUMO
Central oscillators are primordial neural circuits that generate and control rhythmic movements1,2. Mechanistic understanding of these circuits requires genetic identification of the oscillator neurons and their synaptic connections to enable targeted electrophysiological recording and causal manipulation during behaviours. However, such targeting remains a challenge with mammalian systems. Here we delimit the oscillator circuit that drives rhythmic whisking-a motor action that is central to foraging and active sensing in rodents3,4. We found that the whisking oscillator consists of parvalbumin-expressing inhibitory neurons located in the vibrissa intermediate reticular nucleus (vIRtPV) in the brainstem. vIRtPV neurons receive descending excitatory inputs and form recurrent inhibitory connections among themselves. Silencing vIRtPV neurons eliminated rhythmic whisking and resulted in sustained vibrissae protraction. In vivo recording of opto-tagged vIRtPV neurons in awake mice showed that these cells spike tonically when animals are at rest, and transition to rhythmic bursting at the onset of whisking, suggesting that rhythm generation is probably the result of network dynamics, as opposed to intrinsic cellular properties. Notably, ablating inhibitory synaptic inputs to vIRtPV neurons quenched their rhythmic bursting, impaired the tonic-to-bursting transition and abolished regular whisking. Thus, the whisking oscillator is an all-inhibitory network and recurrent synaptic inhibition has a key role in its rhythmogenesis.
Assuntos
Movimento , Vias Neurais , Neurônios , Periodicidade , Vibrissas , Animais , Tronco Encefálico/citologia , Tronco Encefálico/fisiologia , Camundongos , Movimento/fisiologia , Inibição Neural , Neurônios/fisiologia , Parvalbuminas/metabolismo , Descanso , Sinapses , Vibrissas/fisiologia , VigíliaRESUMO
The direct and indirect pathways of the basal ganglia are classically thought to promote and suppress action, respectively1. However, the observed co-activation of striatal direct and indirect medium spiny neurons2 (dMSNs and iMSNs, respectively) has challenged this view. Here we study these circuits in mice performing an interval categorization task that requires a series of self-initiated and cued actions and, critically, a sustained period of dynamic action suppression. Although movement produced the co-activation of iMSNs and dMSNs in the sensorimotor, dorsolateral striatum (DLS), fibre photometry and photo-identified electrophysiological recordings revealed signatures of functional opponency between the two pathways during action suppression. Notably, optogenetic inhibition showed that DLS circuits were largely engaged to suppress-and not promote-action. Specifically, iMSNs on a given hemisphere were dynamically engaged to suppress tempting contralateral action. To understand how such regionally specific circuit function arose, we constructed a computational reinforcement learning model that reproduced key features of behaviour, neural activity and optogenetic inhibition. The model predicted that parallel striatal circuits outside the DLS learned the action-promoting functions, generating the temptation to act. Consistent with this, optogenetic inhibition experiments revealed that dMSNs in the associative, dorsomedial striatum, in contrast to those in the DLS, promote contralateral actions. These data highlight how opponent interactions between multiple circuit- and region-specific basal ganglia processes can lead to behavioural control, and establish a critical role for the sensorimotor indirect pathway in the proactive suppression of tempting actions.
Assuntos
Corpo Estriado , Modelos Neurológicos , Inibição Neural , Vias Neurais , Neurônios , Animais , Simulação por Computador , Corpo Estriado/citologia , Corpo Estriado/fisiologia , Camundongos , Vias Neurais/citologia , Vias Neurais/fisiologia , Neurônios/citologia , Neurônios/fisiologia , OptogenéticaRESUMO
Local circuit architecture facilitates the emergence of feature selectivity in the cerebral cortex1. In the hippocampus, it remains unknown whether local computations supported by specific connectivity motifs2 regulate the spatial receptive fields of pyramidal cells3. Here we developed an in vivo electroporation method for monosynaptic retrograde tracing4 and optogenetics manipulation at single-cell resolution to interrogate the dynamic interaction of place cells with their microcircuitry during navigation. We found a local circuit mechanism in CA1 whereby the spatial tuning of an individual place cell can propagate to a functionally recurrent subnetwork5 to which it belongs. The emergence of place fields in individual neurons led to the development of inverse selectivity in a subset of their presynaptic interneurons, and recruited functionally coupled place cells at that location. Thus, the spatial selectivity of single CA1 neurons is amplified through local circuit plasticity to enable effective multi-neuronal representations that can flexibly scale environmental features locally without degrading the feedforward input structure.
Assuntos
Hipocampo/citologia , Hipocampo/fisiologia , Vias Neurais , Memória Espacial/fisiologia , Navegação Espacial/fisiologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Linhagem da Célula , Eletroporação , Feminino , Interneurônios/fisiologia , Masculino , Camundongos , Inibição Neural , Optogenética , Células de Lugar/fisiologia , Terminações Pré-Sinápticas/metabolismo , Células Piramidais/fisiologia , Análise de Célula ÚnicaRESUMO
Type A GABA (γ-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of α-, ß-, γ-, δ-, ε-, ρ-, θ- and π-subunits1. αß, α4ßδ, α6ßδ and α5ßγ receptors favour extrasynaptic localization, and mediate an essential persistent (tonic) inhibitory conductance in many regions of the mammalian brain1,2. Mutations of these receptors in humans are linked to epilepsy and insomnia3,4. Altered extrasynaptic receptor function is implicated in insomnia, stroke and Angelman and Fragile X syndromes1,5, and drugs targeting these receptors are used to treat postpartum depression6. Tonic GABAergic responses are moderated to avoid excessive suppression of neuronal communication, and can exhibit high sensitivity to Zn2+ blockade, in contrast to synapse-preferring α1ßγ, α2ßγ and α3ßγ receptor responses5,7-12. Here, to resolve these distinctive features, we determined structures of the predominantly extrasynaptic αß GABAA receptor class. An inhibited state bound by both the lethal paralysing agent α-cobratoxin13 and Zn2+ was used in comparisons with GABA-Zn2+ and GABA-bound structures. Zn2+ nullifies the GABA response by non-competitively plugging the extracellular end of the pore to block chloride conductance. In the absence of Zn2+, the GABA signalling response initially follows the canonical route until it reaches the pore. In contrast to synaptic GABAA receptors, expansion of the midway pore activation gate is limited and it remains closed, reflecting the intrinsic low efficacy that characterizes the extrasynaptic receptor. Overall, this study explains distinct traits adopted by αß receptors that adapt them to a role in tonic signalling.