RESUMEN

Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca2+ imaging in hippocampal area CA1 of wild-type and Df(16)A+/- mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A+/- mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction.

Asunto(s)

Síndrome de DiGeorge/genética , Síndrome de DiGeorge/fisiopatología , Modelos Animales de Enfermedad , Hipocampo/fisiopatología , Aprendizaje/fisiología , Células de Lugar/fisiología , Animales , Femenino , Objetivos , Hipocampo/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células de Lugar/patología , Distribución Aleatoria

RESUMEN

The mammalian hippocampus is critical for spatial information processing and episodic memory. Its primary output cells, CA1 pyramidal cells (CA1 PCs), vary in genetics, morphology, connectivity, and electrophysiological properties. It is therefore possible that distinct CA1 PC subpopulations encode different features of the environment and differentially contribute to learning. To test this hypothesis, we optically monitored activity in deep and superficial CA1 PCs segregated along the radial axis of the mouse hippocampus and assessed the relationship between sublayer dynamics and learning. Superficial place maps were more stable than deep during head-fixed exploration. Deep maps, however, were preferentially stabilized during goal-oriented learning, and representation of the reward zone by deep cells predicted task performance. These findings demonstrate that superficial CA1 PCs provide a more stable map of an environment, while their counterparts in the deep sublayer provide a more flexible representation that is shaped by learning about salient features in the environment. VIDEO ABSTRACT.

Asunto(s)

Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiología , Aprendizaje/fisiología , Navegación Espacial/fisiología , Potenciales de Acción/fisiología , Animales , Región CA1 Hipocampal/anatomía & histología , Femenino , Masculino , Ratones , Células Piramidales/fisiología , Recompensa

RESUMEN

We present a model for neural circuit mechanisms underlying hippocampal memory. Central to this model are nonlinear interactions between anatomically and functionally segregated inputs onto dendrites of pyramidal cells in hippocampal areas CA3 and CA1. We study the consequences of such interactions using model neurons in which somatic burst-firing and synaptic plasticity are controlled by conjunctive processing of these separately integrated input pathways. We find that nonlinear dendritic input processing enhances the model's capacity to store and retrieve large numbers of similar memories. During memory encoding, CA3 stores heavily decorrelated engrams to prevent interference between similar memories, while CA1 pairs these engrams with information-rich memory representations that will later provide meaningful output signals during memory recall. While maintaining mathematical tractability, this model brings theoretical study of memory operations closer to the hippocampal circuit's anatomical and physiological properties, thus providing a framework for future experimental and theoretical study of hippocampal function.

Asunto(s)

Potenciales de Acción/fisiología , Región CA1 Hipocampal/fisiología , Región CA3 Hipocampal/fisiología , Dendritas/fisiología , Células Piramidales/fisiología , Animales , Humanos , Memoria/fisiología , Modelos Neurológicos , Vías Nerviosas/fisiología , Sinapsis/fisiología

RESUMEN

Adult-born granule cells (abGCs) have been implicated in cognition and mood; however, it remains unknown how these cells behave in vivo. Here, we have used two-photon calcium imaging to monitor the activity of young abGCs in awake behaving mice. We find that young adult-born neurons fire at a higher rate in vivo but paradoxically exhibit less spatial tuning than their mature counterparts. When presented with different contexts, mature granule cells underwent robust remapping of their spatial representations, and the few spatially tuned adult-born cells remapped to a similar degree. We next used optogenetic silencing to confirm the direct involvement of abGCs in context encoding and discrimination, consistent with their proposed role in pattern separation. These results provide the first in vivo characterization of abGCs and reveal their participation in the encoding of novel information.

Asunto(s)

Calcio/metabolismo , Giro Dentado/metabolismo , Neurogénesis , Neuronas/metabolismo , Animales , Diferenciación Celular , Giro Dentado/citología , Hipocampo/citología , Hipocampo/metabolismo , Ratones , Microscopía de Fluorescencia por Excitación Multifotónica , Optogenética

RESUMEN

Animals must distinguish behaviorally relevant patterns of sensory stimulation from those that are attributable to their own movements. In principle, this distinction could be made based on internal signals related to motor commands, known as corollary discharge (CD), sensory feedback, or some combination of both. Here we use an advantageous model system--the electrosensory lobe (ELL) of weakly electric mormyrid fish--to directly examine how CD and proprioceptive feedback signals are transformed into negative images of the predictable electrosensory consequences of the fish's motor commands and/or movements. In vivo recordings from ELL neurons and theoretical modeling suggest that negative images are formed via anti-Hebbian plasticity acting on random, nonlinear mixtures of CD and proprioception. In support of this, we find that CD and proprioception are randomly mixed in spinal mossy fibers and that properties of granule cells are consistent with a nonlinear recoding of these signals. The mechanistic account provided here may be relevant to understanding how internal models of movement consequences are implemented in other systems in which similar components (e.g., mixed sensory and motor signals and synaptic plasticity) are found.

Asunto(s)

Retroalimentación Fisiológica/fisiología , Movimiento/fisiología , Propiocepción/fisiología , Células Receptoras Sensoriales/fisiología , Transducción de Señal/fisiología , Animales , Pez Eléctrico , Femenino , Predicción , Masculino , Distribución Aleatoria

RESUMEN

Fluorescence imaging is a powerful method for monitoring dynamic signals in the nervous system. However, analysis of dynamic fluorescence imaging data remains burdensome, in part due to the shortage of available software tools. To address this need, we have developed SIMA, an open source Python package that facilitates common analysis tasks related to fluorescence imaging. Functionality of this package includes correction of motion artifacts occurring during in vivo imaging with laser-scanning microscopy, segmentation of imaged fields into regions of interest (ROIs), and extraction of signals from the segmented ROIs. We have also developed a graphical user interface (GUI) for manual editing of the automatically segmented ROIs and automated registration of ROIs across multiple imaging datasets. This software has been designed with flexibility in mind to allow for future extension with different analysis methods and potential integration with other packages. Software, documentation, and source code for the SIMA package and ROI Buddy GUI are freely available at http://www.losonczylab.org/sima/.

RESUMEN

Whether morphology tailors functional properties of pyramidal neurons is not completely understood. In this issue of Neuron, Thome et al. (2014) show that, in hippocampal pyramidal neurons, axons frequently originate from basal dendrites rather than the soma, constituting a "privileged" channel for synaptic inputs located in these axon-carrying dendrites.

Asunto(s)

Axones/fisiología , Dendritas/fisiología , Hipocampo/fisiología , Células Piramidales/fisiología , Transmisión Sináptica/fisiología , Animales , Femenino , Masculino

RESUMEN

Mormyrid electric fish are a model system for understanding how neural circuits predict the sensory consequences of motor acts. Medium ganglion cells in the electrosensory lobe create negative images that predict sensory input resulting from the fish's electric organ discharge (EOD). Previous studies have shown that negative images can be created through plasticity at granule cell-medium ganglion cell synapses, provided that granule cell responses to the brief EOD command are sufficiently varied and prolonged. Here we show that granule cells indeed provide such a temporal basis and that it is well-matched to the temporal structure of self-generated sensory inputs, allowing rapid and accurate sensory cancellation and explaining paradoxical features of negative images. We also demonstrate an unexpected and critical role of unipolar brush cells (UBCs) in generating the required delayed responses. These results provide a mechanistic account of how copies of motor commands are transformed into sensory predictions.

Asunto(s)

Pez Eléctrico/fisiología , Órgano Eléctrico/fisiología , Neuronas/fisiología , Sensación/fisiología , Potenciales de Acción/fisiología , Animales , Encéfalo/citología , Encéfalo/fisiología , Electrofisiología/instrumentación , Electrofisiología/métodos , Microelectrodos , Factores de Tiempo

RESUMEN

Fear memories guide adaptive behavior in contexts associated with aversive events. The hippocampus forms a neural representation of the context that predicts aversive events. Representations of context incorporate multisensory features of the environment, but must somehow exclude sensory features of the aversive event itself. We investigated this selectivity using cell type-specific imaging and inactivation in hippocampal area CA1 of behaving mice. Aversive stimuli activated CA1 dendrite-targeting interneurons via cholinergic input, leading to inhibition of pyramidal cell distal dendrites receiving aversive sensory excitation from the entorhinal cortex. Inactivating dendrite-targeting interneurons during aversive stimuli increased CA1 pyramidal cell population responses and prevented fear learning. We propose subcortical activation of dendritic inhibition as a mechanism for exclusion of aversive stimuli from hippocampal contextual representations during fear learning.

Asunto(s)

Dendritas/fisiología , Miedo/fisiología , Hipocampo/fisiología , Aprendizaje/fisiología , Inhibición Neural , Amígdala del Cerebelo/metabolismo , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiología , Condicionamiento Psicológico , Hipocampo/citología , Interneuronas/metabolismo , Interneuronas/fisiología , Ratones , Receptores de Glicina/metabolismo , Receptores Nicotínicos/metabolismo , Somatostatina/metabolismo

RESUMEN

Hippocampal interneurons receive GABAergic input from the medial septum. Using two-photon Ca(2+) imaging of axonal boutons in hippocampal CA1 of behaving mice, we found that populations of septo-hippocampal GABAergic boutons were activated during locomotion and salient sensory events; sensory responses scaled with stimulus intensity and were abolished by anesthesia. We found similar activity patterns among boutons with common putative postsynaptic targets, with low-dimensional bouton population dynamics being driven primarily by presynaptic spiking.

Asunto(s)

Hipocampo/fisiología , Vías Nerviosas/fisiología , Tabique del Cerebro/citología , Transducción de Señal/fisiología , Vigilia/fisiología , Ácido gamma-Aminobutírico/metabolismo , Potenciales de Acción/fisiología , Anestésicos Locales/farmacología , Animales , Calmodulina/genética , Calmodulina/metabolismo , Channelrhodopsins , Colina O-Acetiltransferasa/metabolismo , Condicionamiento Psicológico , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Vías Nerviosas/efectos de los fármacos , Parvalbúminas/genética , Parvalbúminas/metabolismo , Lectinas de Plantas/metabolismo , Proteínas/genética , ARN no Traducido , Tabique del Cerebro/efectos de los fármacos , Tabique del Cerebro/fisiología , Tetrodotoxina/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo

RESUMEN

Transforming synaptic input into action potential output is a fundamental function of neurons. The pattern of action potential output from principal cells of the mammalian hippocampus encodes spatial and nonspatial information, but the cellular and circuit mechanisms by which neurons transform their synaptic input into a given output are unknown. Using a combination of optical activation and cell type-specific pharmacogenetic silencing in vitro, we found that dendritic inhibition is the primary regulator of input-output transformations in mouse hippocampal CA1 pyramidal cells, and acts by gating the dendritic electrogenesis driving burst spiking. Dendrite-targeting interneurons are themselves modulated by interneurons targeting pyramidal cell somata, providing a synaptic substrate for tuning pyramidal cell output through interactions in the local inhibitory network. These results provide evidence for a division of labor in cortical circuits, where distinct computational functions are implemented by subtypes of local inhibitory neurons.

Asunto(s)

Interneuronas/citología , Inhibición Neural/fisiología , Sinapsis/fisiología , Animales , Biofisica , Corteza Cerebral/citología , Channelrhodopsins , Proteínas de Unión al ADN/genética , Dependovirus/genética , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas del GABA/farmacología , Glutamato Descarboxilasa/genética , Ácido Glutámico/farmacología , Técnicas In Vitro , Interneuronas/fisiología , Canales Iónicos Activados por Ligandos/genética , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Neurológicos , Mutación/genética , Inhibición Neural/efectos de los fármacos , Inhibición Neural/genética , Parvalbúminas/genética , Técnicas de Placa-Clamp , Estimulación Luminosa , Células Piramidales/citología , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Piridazinas/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores de Glicina/genética , Sinapsis/genética , Transmisión Sináptica , Factores de Transcripción/genética , Transducción Genética , Valina/análogos & derivados , Valina/farmacología , Ácido gamma-Aminobutírico/farmacología