Odor-Reward Association Encoding in CA2 and its Contribution to Social Memory

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PROJECT SUMMARY Impairments in social memories are central to many neuropsychiatric disorders, including Schizophrenia (SZD). This application investigates olfactory processing in the CA2 region of the rodent hippocampus and its contribution to social memory—the ability to encode and recall another conspecific. CA2 is necessary for social memory in rodents; inhibiting dorsal CA2 (dCA2) during an initial social interaction disrupts a mouse’s ability to form and recall that social memory. But how CA2 precisely contributes to encoding and retrieval remains unclear. Since mice rely on olfaction to investigate social targets, I hypothesize that murine CA2 is vital to the integration and discrimination of social olfactory cues that provide valent information about different conspecifics. In a pilot study using water-restricted female mice, I found that silencing CA2 activity with inhibitory opsins showed a trend towards impairing the mice’s abilities to distinguish one male mouse urine from another in a head-fixed, Go/No- Go Odor Discrimination Task, in which GO odors are paired with a water reward. Using 2-photon calcium imaging in seven mice, a collaborator and I have discovered that dCA2 processes both social and nonsocial odors. Moving forward, I am using 2-photon imaging to test how CA2 uses olfactory information to discriminate between odor stimuli and to associate odors with conditioned or unconditioned valences, and how perturbation of this processing affects social memory in disease. In Aim 1, I am identifying sex differences, if any, in CA2 function with respect to the encoding of five odors—two naturally valent male urines (social odors), methyl butyrate and ethyl acetate (nonvalent nonsocial odors), and a mock odor (water)—in a “three-phase paradigm” (TPP) involving passive odor delivery before and after active odor discrimination. In Aim 2, I will compare the social and nonsocial odor processing functions of dCA2 and dCA1 (known to process nonsocial odor-reward associations) in the TPP odor task. I will also train multiple decoders to predict stimulus identity from 2-photon calcium imaging data, looking for what kinds of stimuli are important to each region (social, nonsocial, rewarded, or nonrewarded odors) based on decoder performance. Aim 3 examines an SZD genetic mouse model of the human 22q11.2 deletion syndrome—Df(16)A+/- mice—which shows a profound deficit in social memory. In a second odor discrimination pilot study, I found that Df(16)A+/- female mice resemble the performance of the CA2-silenced mice in their impaired ability to distinguish between two social odors. Hence, I will use 2-photon imaging to compare CA2 responses to odor stimuli in this mouse model to that of their neurotypical cagemates. Furthermore, I will attempt to rescue this social odor discrimination deficit with injection of a TREK-1 dominant-negative virus, which has been shown to improve neuronal firing in the pathologically hyperpolarized CA2 neurons harbored by these heterozygous mice. All in all, the results of my research will provide insight into how mice use sensory cues to discriminate between social subjects and facilitate social recognition. My findings will initiate investigations into how other social sensory modalities—like vision, hearing, and touch—are processed through CA2 in humans.