Contributions of Hippocampal Area CA2 to Hippocampal Oscillatory Networks

Abstract

Complex cognitive abilities, such as memory, require synchronized neural activity across large populations of cells. The hippocampus is a region of the brain required for the formation of long term episodic memories, which is our memory for autobiographical information. The hippocampus itself consists of four sub-regions, the dentate gyrus (DG), CA1, CA2, and CA3, which can be viewed as functionally specialized processing hubs that uniquely contribute to memory formation based on their distinct molecular, synaptic, and anatomical properties. Only together; however, does the collective activity of all four sub-regions provide the neurobiological underpinnings necessary for a functional memory system. One mechanism for the coordination of neural networks is synchronization through oscillations. Neuronal oscillations reflect waves of synchronous action potentials and their presence in the hippocampus is strongly associated with episodic learning and memory. Although much progress been made towards understanding how different frequencies of activity are generated and how they support hippocampal-based memory, relatively little is known about the role of CA2 in organizing oscillations. In this dissertation work, I use combinatorial electrophysiological and chemogenetic approaches to genetically target and manipulate CA2 principal cells to investigate their role in coordinating hippocampal oscillatory networks in awake, behaving mice. In Chapter 2, I use Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to manipulate the endogenous G protein-coupled receptor (GPCR) signaling pathways in CA2 while animals explore a novel spatial environment. These experiments revealed that activation or inhibition of CA2 pyramidal cells through the endogenous Gq- and Gi-coupled pathways, respectively, is sufficient to bi-directionally modulate synchronized hippocampal activity in the slow gamma and beta frequency ranges. In Chapter 3, I further dissect the role of CA2 in coordinating hippocampal oscillations by inhibiting CA2 pyramidal cells while animals investigate novel social stimuli and record from CA2’s primary output region, CA1. These experiments revealed that the oscillatory structure observed in CA1 is organized in a layer- and frequency-specific manner that depends causally on CA2 output. These findings provide evidence that CA2 is an integral processing node capable of coordinating the hippocampal oscillatory networks that support long term episodic memory.Doctor of Philosoph