Hippocampal network mediating behavioral effects of social isolation in mice

Project Summary Major depressive disorder is a prevalent and debilitating mental illness associated with a high personal and socioeconomic burden, impacting nearly 10% of Americans. Depression is typically associated with decreased social interactions and reduced interest in novel events. Despite the widely accepted role of the hippocampus in depression, there remains no clear understanding or prevailing theory regarding how hippocampal function changes in this condition, nor is it understood how, or if, the rapid-acting antidepressant ketamine influences these hippocampal processes. The proposed research aims to address these issues using a novel hippocampal slice preparation to assess signal transformation across the polysynaptic prime hippocampal circuit and measure disrupted sociability and interest in social novelty as an index of depression-like behavior. The research will test the overarching hypothesis that lack of sociability and interest in social novelty is associated with impairments in hippocampal network function and that these changes can be offset by ketamine treatment. This hypothesis is supported by robust preliminary results showing that a short period of single housing of rodents still living in a busy colony produces impaired social behavior and disrupts hippocampal circuit function (i.e., reduces spontaneous sharp waves and hippocampal prime circuit throughput). Importantly, a single dose of ketamine normalizes measures of hippocampal circuit function and social behavior as assessed 6 hours post-treatment. Proposed studies will further validate these preliminary results in male and female mice and test if this lack of sociability and interest in social novelty quantified through the 3-Chamber Social Preference Test reflects changes in reverberatory activity in hippocampal field CA3, and if silencing of CA2 in wild-type rodents reproduces a similar behavior phenotype to single-housed animals as well as disrupts hippocampal throughput. Specifically, Aim 1 will test if a period of single housing leads to impaired social behavior and disruptions in hippocampal circuit function and if these changes are alleviated by ketamine treatment. Aim 2 will then test if partial chemogenetic (DREADDi) suppression of reverberatory activity in field CA3 replicates the effects of social isolation on mood and behavior, and if these measures are normalized by ketamine treatment. Together, this proposal will provide the first description of changes in hippocampal circuit function associated with the depression-like symptom of lack of sociability and interest in social novelty with novel insight as to why ketamine is an effective therapeutic. Importantly, these studies may identify a narrow cellular basis of hippocampal circuit dysfunction and, thus, a high-priority target for effective therapeutics.