RESUMEN
In the hippocampus, spatial maps are formed by place cells while contextual memories are thought to be encoded as engrams1-6. Engrams are typically identified by expression of the immediate early gene Fos, but little is known about the neural activity patterns that drive, and are shaped by, Fos expression in behaving animals7-10. Thus, it is unclear whether Fos-expressing hippocampal neurons also encode spatial maps and whether Fos expression correlates with and affects specific features of the place code11. Here we measured the activity of CA1 neurons with calcium imaging while monitoring Fos induction in mice performing a hippocampus-dependent spatial learning task in virtual reality. We find that neurons with high Fos induction form ensembles of cells with highly correlated activity, exhibit reliable place fields that evenly tile the environment and have more stable tuning across days than nearby non-Fos-induced cells. Comparing neighbouring cells with and without Fos function using a sparse genetic loss-of-function approach, we find that neurons with disrupted Fos function have less reliable activity, decreased spatial selectivity and lower across-day stability. Our results demonstrate that Fos-induced cells contribute to hippocampal place codes by encoding accurate, stable and spatially uniform maps and that Fos itself has a causal role in shaping these place codes. Fos ensembles may therefore link two key aspects of hippocampal function: engrams for contextual memories and place codes that underlie cognitive maps.
Asunto(s)
Hipocampo , Proteínas Proto-Oncogénicas c-fos , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiología , Calcio/metabolismo , Hipocampo/citología , Hipocampo/fisiología , Ratones , Neuronas/fisiología , Células de Lugar/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Neural activity in the mammalian cortex has been studied extensively during decision tasks, and recent work aims to identify under what conditions cortex is actually necessary for these tasks. We discovered that mice with distinct cognitive experiences, beyond sensory and motor learning, use different cortical areas and neural activity patterns to solve the same navigation decision task, revealing past learning as a critical determinant of whether cortex is necessary for goal-directed navigation. We used optogenetics and calcium imaging to study the necessity and neural activity of multiple cortical areas in mice with different training histories. Posterior parietal cortex and retrosplenial cortex were mostly dispensable for accurate performance of a simple navigation task. In contrast, these areas were essential for the same simple task when mice were previously trained on complex tasks with delay periods or association switches. Multiarea calcium imaging showed that, in mice with complex-task experience, single-neuron activity had higher selectivity and neuron-neuron correlations were weaker, leading to codes with higher task information. Therefore, past experience is a key factor in determining whether cortical areas have a causal role in goal-directed navigation.
Asunto(s)
Calcio , Objetivos , Animales , Cognición , Mamíferos , Ratones , Optogenética , Lóbulo Parietal/fisiologíaRESUMEN
As animals explore an environment, the hippocampus is thought to automatically form and maintain a place code by combining sensory and self-motion signals. Instead, we observed an extensive degradation of the place code when mice voluntarily disengaged from a virtual navigation task, remarkably even as they continued to traverse the identical environment. Internal states, therefore, can strongly gate spatial maps and reorganize hippocampal activity even without sensory and self-motion changes.
Asunto(s)
Navegación Espacial , Animales , Hipocampo , Ratones , Percepción EspacialRESUMEN
Behavioural experiences activate the FOS transcription factor in sparse populations of neurons that are critical for encoding and recalling specific events1-3. However, there is limited understanding of the mechanisms by which experience drives circuit reorganization to establish a network of Fos-activated cells. It is also not known whether FOS is required in this process beyond serving as a marker of recent neural activity and, if so, which of its many gene targets underlie circuit reorganization. Here we demonstrate that when mice engage in spatial exploration of novel environments, perisomatic inhibition of Fos-activated hippocampal CA1 pyramidal neurons by parvalbumin-expressing interneurons is enhanced, whereas perisomatic inhibition by cholecystokinin-expressing interneurons is weakened. This bidirectional modulation of inhibition is abolished when the function of the FOS transcription factor complex is disrupted. Single-cell RNA-sequencing, ribosome-associated mRNA profiling and chromatin analyses, combined with electrophysiology, reveal that FOS activates the transcription of Scg2, a gene that encodes multiple distinct neuropeptides, to coordinate these changes in inhibition. As parvalbumin- and cholecystokinin-expressing interneurons mediate distinct features of pyramidal cell activity4-6, the SCG2-dependent reorganization of inhibitory synaptic input might be predicted to affect network function in vivo. Consistent with this prediction, hippocampal gamma rhythms and pyramidal cell coupling to theta phase are significantly altered in the absence of Scg2. These findings reveal an instructive role for FOS and SCG2 in establishing a network of Fos-activated neurons via the rewiring of local inhibition to form a selectively modulated state. The opposing plasticity mechanisms acting on distinct inhibitory pathways may support the consolidation of memories over time.
Asunto(s)
Red Nerviosa/citología , Red Nerviosa/fisiología , Inhibición Neural , Plasticidad Neuronal/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Colecistoquinina/metabolismo , Conducta Exploratoria/fisiología , Femenino , Ritmo Gamma , Interneuronas/metabolismo , Masculino , Consolidación de la Memoria , Ratones , Parvalbúminas/metabolismo , Células Piramidales/metabolismo , Secretogranina II/genética , Secretogranina II/metabolismo , Navegación Espacial/fisiología , Ritmo TetaRESUMEN
Neuronal representations change as associations are learned between sensory stimuli and behavioral actions. However, it is poorly understood whether representations for learned associations stabilize in cortical association areas or continue to change following learning. We tracked the activity of posterior parietal cortex neurons for a month as mice stably performed a virtual-navigation task. The relationship between cells' activity and task features was mostly stable on single days but underwent major reorganization over weeks. The neurons informative about task features (trial type and maze locations) changed across days. Despite changes in individual cells, the population activity had statistically similar properties each day and stable information for over a week. As mice learned additional associations, new activity patterns emerged in the neurons used for existing representations without greatly affecting the rate of change of these representations. We propose that dynamic neuronal activity patterns could balance plasticity for learning and stability for memory.