Local Circuit Control of Rapid Plasticity and Tunable Ensemble Formation in the Hippocampus

Project Summary/Abstract Neural representations supporting spatial and episodic learning form, and transform rapidly in the mammalian hippocampus. Individual hippocampal pyramidal cells each fire at a specific location in an environment and together these place cells provide a striking substrate for a cognitive map. A critical step in achieving a mechanistic understanding of how place cell dynamics support hippocampal learning and memory is to be able to re-create endogenous neuronal representations experimentally, and test their behavioral relevance. However, it has not previously been possible to generate lasting hippocampal place cell maps through controlled manipulations of hippocampal plasticity. Our groups have recently identified key potential controllers of hippocampal ensemble formation, raising the intriguing possibility that stable place cell maps can be synthetically generated and allocated by manipulating these controllers. In particular, we demonstrated that any individual, arbitrarily chosen pyramidal cell in the mouse hippocampal area CA1 can be reliably induced to become lasting place cells, using all-optical plasticity induction. Here, we propose to determine if targeted in vivo manipulations of feedback inhibitory (Aim 1), recurrent excitatory (Aim 2), and cell-intrinsic retrograde (Aim 3) local circuit control mechanisms enable the specific generation and allocation of behaviorally relevant neural representation by scaling single-cell optogenetic place cell induction to multi-cellular ensembles. We will test our hypothesis in the hippocampal area CA1 of mice navigating and learning in a virtual reality environment, utilizing a variety of innovative in vivo calcium-imaging, optogenetic, electrophysiology, statistical data analysis, and modeling approaches. We anticipate that our project will have a significant, potentially translatable impact by overcoming major knowledge gaps about cellular and local circuit determinants of neuronal plasticity, while also supporting rapid induced plasticity of neuronal representations. Our research can thereby accelerate the development of neural modulation strategies to study, modify, or improve memory-related behaviors.