Inhibitory Control of Contextual Fear Memory and Memory Specificity

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August 2021
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The brain functions are supported by close interactions between excitation and inhibition. Inhibition contributes to neural computation by gating information flow, tuning the gain of the network, and modulating the output strength of the system. The inhibition in the brain is mainly achieved by GABAergic inhibitory neurons which exert their effect by acting on multiple types of GABA receptors. In this dissertation, I examined the roles of specific types of GABAergic neurons and GABA receptors in learning and memory. The study consists of three major components. In the first component (Chapter 2), I developed a novel technique to selectively target and control GABAergic interneurons (NDNF cells) distributed at the SLM of the hippocampus. With this technique, I found that the activities of NDNF cells increased during memory encoding and decreased during retrieval. Enhancing their activity improved memory encoding but impaired memory retrieval. I further discovered that NDNF cells coordinate memory encoding and retrieval by differentially regulating the two major excitatory inputs to the CA1 region of the hippocampus. In the second component (Chapter 3), I identified a single nucleotide deletion in the gene of a subunit of GABA receptors - Gabra2 that reduces contextual fear memory in C57BL/6J by using quantitative trait locus analysis. In the third component (Chapter 4), I found a change in GABAB receptor-mediated feedforward inhibition led to distinct hippocampal responses to environmental stimuli. This difference further led to distinct hippocampal representation and generalization of contextual fear memory. These studies were carried out at genetic, molecular, circuit, and behavioral levels, and involved a combination of techniques including genetic mapping, in vivo recording, circuit manipulation, and behavior analysis. They exemplify how inhibition shapes neuronal activity and animal behavior. They also provide valuable tools and ideas for future research on the function of inhibition in the brain. The knowledge gained through these studies on how the brain inhibitory network interacts with excitatory neurons to regulate memory facilitates our understanding of the cognitive processes in the brain.

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