Role of GABAergic inhibition in the hippocampal contribution to stress susceptibility

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A fundamental question in the field of stress neurobiology is why we respond to stress differently. Investigating the biological mechanism of individual differences in stress susceptibility has important implications for the impact of stress on memory. One of the brain regions that is imperative for stress susceptibility is the hippocampus. The hippocampus not only is well-known for its roles in memory, but also is highly sensitive to stress. Although stress susceptibility has been associated with high hippocampal activity, mechanisms underlying this hippocampal change remain unclear. The long-term goal of this research program is to investigate the role of hippocampal GABAergic inhibition in stress susceptibility. Hippocampal activity is regulated by the balance between excitatory and inhibitory synaptic transmission. Apart from neural inhibition, activity of GABAergic neurons is crucial for the processing of sensory information for memory formation. Since GABAergic inhibition is highly sensitive to stress, we hypothesize that stress susceptibility is regulated by the activity of GABAergic neurons in the hippocampus. Our short-term goal is to examine changes in the functional property of two types of GABAergic interneurons: parvalbumin- (PV neurons) and somatostatin-expressing neurons (SOM neurons) in mice that are either susceptible or resilient to chronic social defeat stress. In the first objective, we will use in vitro techniques to examine changes in GABAergic inhibition in mice with different stress susceptibilities. We will first use electrophysiology to examine changes in synaptic transmission in these mice. Next, we will study the excitability of and synaptic inputs onto PV and SOM neurons in mice with different stress susceptibilities. We will also examine if modulating PV or SOM neuronal activity by optogenetic approaches rescues the reduction of GABAergic transmission in susceptible mice. Finally, we will investigate if changes in GABAergic transmission are responsible for the higher stress susceptibility in female mice. In the second objective, we will use the UCLA miniscope to monitor PV and SOM neuronal activity in freely moving mice. Changes in the activity of these neurons will be examined before, during and after chronic social defeat stress in mice that are either susceptible or resilient to this stressor. We will also use the chemogenetic technique to study the effect of modulating PV or SOM neuronal activity on stress susceptibility. This research program will advance our understanding of how stress susceptibility is regulated by hippocampal GABAergic neurons. Our findings will also reveal how these GABAergic interneurons contribute to the processing of repeated aversive experiences, a mechanism that underlies the impact of chronic stress on memory.