RESUMEN
Animals can choose to act upon, or to ignore, sensory stimuli, depending on circumstance and prior knowledge. This flexibility is thought to depend on neural inhibition, through suppression of inappropriate and disinhibition of appropriate actions. Here, we identified the ventral lateral geniculate nucleus (vLGN), an inhibitory prethalamic area, as a critical node for control of visually evoked defensive responses in mice. The activity of vLGN projections to the medial superior colliculus (mSC) is modulated by previous experience of threatening stimuli, tracks the perceived threat level in the environment, and is low prior to escape from a visual threat. Optogenetic stimulation of the vLGN abolishes escape responses, and suppressing its activity lowers the threshold for escape and increases risk-avoidance behavior. The vLGN most strongly affects visual threat responses, potentially via modality-specific inhibition of mSC circuits. Thus, inhibitory vLGN circuits control defensive behavior, depending on an animal's prior experience and its anticipation of danger in the environment.
Asunto(s)
Cuerpos Geniculados , Vías Visuales , Animales , Cuerpos Geniculados/fisiología , Ratones , Formación Reticular , Colículos Superiores/fisiología , Transmisión Sináptica , Vías Visuales/fisiologíaRESUMEN
Subplate neurons (SPNs) are thought to play a role in nascent sensory processing in neocortex. To better understand how heterogeneity within this population relates to emergent function, we investigated the synaptic connectivity of Lpar1-EGFP SPNs through the first postnatal week in whisker somatosensory cortex (S1BF). These SPNs comprise of two morphological subtypes: fusiform SPNs with local axons and pyramidal SPNs with axons that extend through the marginal zone. The former receive translaminar synaptic input up until the emergence of the whisker barrels, a timepoint coincident with significant cell death. In contrast, pyramidal SPNs receive local input from the subplate at early ages but then - during the later time window - acquire input from overlying cortex. Combined electrical and optogenetic activation of thalamic afferents identified that Lpar1-EGFP SPNs receive sparse thalamic innervation. These data reveal components of the postnatal network that interpret sparse thalamic input to direct the emergent columnar structure of S1BF.
Asunto(s)
Proteínas Fluorescentes Verdes/metabolismo , Neuronas/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Corteza Somatosensorial/metabolismo , Animales , Animales Recién Nacidos , Axones/metabolismo , Estimulación Eléctrica/métodos , GABAérgicos/metabolismo , Ratones , Optogenética/métodos , Tálamo/metabolismo , Vibrisas/metabolismoRESUMEN
How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.
Asunto(s)
Corteza Cerebral/fisiología , Interneuronas/fisiología , Sinapsis/genética , Sinapsis/fisiología , Animales , Dendritas/genética , Dendritas/fisiología , Regulación del Desarrollo de la Expresión Génica , Ratones , Células Piramidales/fisiología , Análisis de Secuencia de ARN , Transcripción Genética , TranscriptomaRESUMEN
Neural circuit assembly relies on the precise synchronization of developmental processes, such as cell migration and axon targeting, but the cell-autonomous mechanisms coordinating these events remain largely unknown. Here we found that different classes of interneurons use distinct routes of migration to reach the embryonic cerebral cortex. Somatostatin-expressing interneurons that migrate through the marginal zone develop into Martinotti cells, one of the most distinctive classes of cortical interneurons. For these cells, migration through the marginal zone is linked to the development of their characteristic layer 1 axonal arborization. Altering the normal migratory route of Martinotti cells by conditional deletion of Mafb-a gene that is preferentially expressed by these cells-cell-autonomously disrupts axonal development and impairs the function of these cells in vivo. Our results suggest that migration and axon targeting programs are coupled to optimize the assembly of inhibitory circuits in the cerebral cortex.
Asunto(s)
Axones/fisiología , Movimiento Celular/fisiología , Corteza Cerebral/fisiología , Interneuronas/fisiología , Animales , Corteza Cerebral/citología , Neuronas GABAérgicas/citología , Neuronas GABAérgicas/fisiología , Interneuronas/citología , Factor de Transcripción MafB/genética , Ratones NoqueadosRESUMEN
An important consideration when probing the function of any neuron is to uncover the source of synaptic input onto the cell, its intrinsic physiology and efferent targets. Over the years, electrophysiological approaches have generated considerable insight into these properties in a variety of cortical neuronal subtypes and circuits. However, as researchers explore neuronal function in greater detail, they are increasingly turning to optical techniques to bridge the gap between local network interactions and behaviour. The application of optical methods has increased dramatically over the past decade, spurred on by the optogenetic revolution. In this review, we provide an account of recent innovations, providing researchers with a primer detailing circuit mapping strategies in the cerebral cortex. We will focus on technical aspects of performing neurotransmitter uncaging and channelrhodopsin-assisted circuit mapping, with the aim of identifying common pitfalls that can negatively influence the collection of reliable data.
Asunto(s)
Mapeo Encefálico/métodos , Corteza Cerebral/fisiología , Neuronas/fisiología , Optogenética , Animales , Corteza Cerebral/citología , Humanos , Neuronas/citología , Transmisión SinápticaRESUMEN
Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive. We show that the PNN protein Brevican is a critical regulator of interneuron plasticity. We find that Brevican simultaneously controls cellular and synaptic forms of plasticity in PV+ cells by regulating the localization of potassium channels and AMPA receptors, respectively. By modulating Brevican levels, experience introduces precise molecular and cellular modifications in PV+ cells that are required for learning and memory. These findings uncover a molecular program through which a PNN protein facilitates appropriate behavioral responses to experience by dynamically gating PV+ interneuron function.
Asunto(s)
Brevicano/metabolismo , Neuronas GABAérgicas/metabolismo , Interneuronas/metabolismo , Memoria/fisiología , Parvalbúminas/metabolismo , Animales , Matriz Extracelular/metabolismo , Ratones , Plasticidad Neuronal/fisiología , Corteza Visual/metabolismoRESUMEN
The function of cortical GABAergic interneurons is largely determined by their integration into specific neural circuits, but the mechanisms controlling the wiring of these cells remain largely unknown. This is particularly true for a major population of basket cells that express the neuropeptide cholecystokinin (CCK). Here we found that the tyrosine kinase receptor ErbB4 was required for the normal integration into cortical circuits of basket cells expressing CCK and vesicular glutamate transporter 3 (VGlut3). The number of inhibitory synapses made by CCK+VGlut3+ basket cells and the inhibitory drive they exerted on pyramidal cells were reduced in conditional mice lacking ErbB4. Developmental disruption of the connectivity of these cells diminished the power of theta oscillations during exploratory behavior, disrupted spatial coding by place cells, and caused selective alterations in spatial learning and memory in adult mice. These results suggest that normal integration of CCK+ basket cells in cortical networks is key to support spatial coding in the hippocampus.
Asunto(s)
Corteza Cerebral/fisiología , Colecistoquinina/fisiología , Neuronas GABAérgicas/fisiología , Aprendizaje Espacial/fisiología , Memoria Espacial/fisiología , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Corteza Cerebral/metabolismo , Colecistoquinina/genética , Colecistoquinina/metabolismo , Conducta Exploratoria/fisiología , Neuronas GABAérgicas/metabolismo , Interneuronas/metabolismo , Interneuronas/fisiología , Locomoción/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Inhibición Neural/fisiología , Vías Nerviosas/fisiología , Células de Lugar/fisiología , Inhibición Prepulso/fisiología , Células Piramidales/fisiología , Receptor ErbB-4/biosíntesis , Receptor ErbB-4/genética , Receptor ErbB-4/fisiología , Ritmo Teta/fisiologíaRESUMEN
Normative cortical processing depends on precise interactions between excitatory and inhibitory neurons. In this issue of Neuron, Lippi et al. (2016) identify miR-101 as a master regulator coordinating molecular programs during development that ultimately impact the activity of mature networks.
Asunto(s)
Corteza Cerebral/fisiología , Neuronas , Humanos , MicroARNsRESUMEN
GABAergic activity is thought to influence developing neocortical sensory circuits. Yet the late postnatal maturation of local layer (L)4 circuits suggests alternate sources of GABAergic control in nascent thalamocortical networks. We show that a population of L5b, somatostatin (SST)-positive interneuron receives early thalamic synaptic input and, using laser-scanning photostimulation, identify an early transient circuit between these cells and L4 spiny stellates (SSNs) that disappears by the end of the L4 critical period. Sensory perturbation disrupts the transition to a local GABAergic circuit, suggesting a link between translaminar and local control of SSNs. Conditional silencing of SST+ interneurons or conversely biasing the circuit toward local inhibition by overexpression of neuregulin-1 type 1 results in an absence of early L5b GABAergic input in mutants and delayed thalamic innervation of SSNs. These data identify a role for L5b SST+ interneurons in the control of SSNs in the early postnatal neocortex.
Asunto(s)
Interneuronas/fisiología , Corteza Somatosensorial/fisiología , Tálamo/citología , Tálamo/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Estimulación Eléctrica , Femenino , Masculino , Potenciales de la Membrana/fisiología , Ratones , Ratones Transgénicos , Vías Nerviosas , Neurregulina-1/biosíntesis , Estimulación Luminosa , Corteza Somatosensorial/citología , Corteza Somatosensorial/crecimiento & desarrollo , Somatostatina/fisiologíaRESUMEN
GABAergic interneurons play key roles in cortical circuits, yet little is known about their early connectivity. Here we use glutamate uncaging and a novel optogenetic strategy to track changes in the afferent and efferent synaptic connections of developing neocortical interneuron subtypes. We find that Nkx2-1-derived interneurons possess functional synaptic connections before emerging pyramidal cell networks. Subsequent interneuron circuit maturation is both subtype and layer dependent. Glutamatergic input onto fast spiking (FS), but not somatostatin-positive, non-FS interneurons increases over development. Interneurons of both subtype located in layers (L) 4 and 5b engage in transient circuits that disappear after the somatosensory critical period. These include a pathway mediated by L5b somatostatin-positive interneurons that specifically targets L4 during the first postnatal week. The innervation patterns of immature cortical interneuron circuits are thus neither static nor progressively strengthened but follow a layer-specific choreography of transient connections that differ from those of the adult brain.
Asunto(s)
Neuronas GABAérgicas , Interneuronas , Neocórtex/crecimiento & desarrollo , Red Nerviosa/crecimiento & desarrollo , Sinapsis , Animales , Animales Recién Nacidos , Análisis por Conglomerados , Proteínas Fluorescentes Verdes , Inmunohistoquímica , Ratones , Proteínas Nucleares , Optogenética , Técnicas de Placa-Clamp , Análisis de Componente Principal , Células Piramidales , Factor Nuclear Tiroideo 1 , Factores de TranscripciónRESUMEN
Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely-moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS-) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS- trials during training and early extinction. In contrast, they were lower during CS+ than CS- trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS- trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging.