Genetic targeting of hippocampal CA2 pyramidal neurons

Neuropsychiatric disorders, such as schizophrenia and bipolar disorder, are often associated with changes in social behavior. Recent studies from our laboratory and others have identified the hippocampal CA2 region, a relatively unexplored brain area, as critical for both social memory and social aggression. Moreover, alterations in CA2 have been found in individuals with schizophrenia and bipolar disorder, and we have recently discovered similar changes in a mouse model of schizophrenia that is deficient in social memory. In this competitive renewal application we propose to extend our previous findings on the role of CA2 in social behavior in two important ways. Previous studies on CA2, including those from our laboratory, have focused on the dorsal region of CA2. However, CA2 extends along the dorsal-ventral longitudinal axis of the hippocampus yet nothing is known about the role of ventral regions of CA2. Such studies are important because whereas dorsal hippocampus has been implicated in spatial cognition and spatial memory, ventral hippocampus is thought to be more important for emotional behaviors, such as anxiety and depression Thus, our first goal is to explore the behavioral role and neural circuitry of ventral CA2. We will use a mouse line expressing Cre relatively selectively throughout the CA2 longitudinal axis to label ventral CA2 inputs and outputs and to silence ventral CA2 through optogenetic or chemogenetic approaches,similar to those used to explore dorsal CA2. We will assess the functional strength of ventral CA2 inputs and outputs using brain slice electrophysiological recordings. We will compare the behavioral role of ventral and dorsal CA2 in social memory, social aggression, anxiety and depression. We are particularly interested in testing the hypothesis, suggested by our preliminary anatomical tracing, that ventral CA2 may suppress social aggression, opposite to the effect of dorsal CA2 to promote aggression. Our second goal is to explore the in vivo role of CA2 in coordinating network activity important for memory. In the current funding period we examined the effect of acute optogenetic and chemogenetic CA2 silencing, which revealed that CA2 is critical for encoding, consolidation and recall of social memory. It has recently been suggested that CA2 is important for generating sharp wave ripples (SWRs), a synchronous form of hippocampal network activity observed during sleep and quiet wakefulness that is thought to be important for memory encoding and consolidation. However, neither the causal role of CA2 in generating sharp wave ripples nor the role of CA2 ripples in social memory have yet been examined. Moreover, there have been no studies of the importance of ventral CA2 in SWRs in ventral hippocampus. We will thus examine the role of dorsal and ventral CA2 in SWR generation, as well as the role of these events in social and non-social memory.