Circuits underlying overgeneralization

Overgeneralization is a cognitive impairment commonly associated with post-traumatic stress disorder as well as mood and anxiety disorders. Over the past 10 years of this grant, we have accumulated several lines of evidence indicating that the dentate gyrus (DG) contributes to a range of negative valence related behaviors including fear overgeneralization, as well as to some of the behavioral effects of antidepressant medications. Specifically, we and others have shown that the dentate gyrus is critical for contextual fear discrimination learning, a form a learning that has been proposed to be mediated by pattern separation, a computational process by which similar experiences are transformed into discrete non-overlapping neural representations. In the current proposal we aim at bringing together these behavioral and physiological lines of research by showing that the DG is critical for pattern separation and that deficits in pattern separation underlie the contextual discrimination deficits often observed in mood and anxiety disorders. Based on our preliminary results we hypothesize that strategies aimed at improving pattern separation in the DG will be beneficial for the treatment of mood and anxiety disorders. Unlike most other brain regions, the adult DG contains not only mature developmentally-born neurons but also adult-born neurons generated via a process termed adult neurogenesis. We and others have shown that both mature granule cells (mGCs) and young adult-born granule cells (abGCs) are critical for contextual fear discrimination learning (CFD). In the proposed studies we will image the activity of both abGCs as well as mGCs in the DG during a contextual fear discrimination task by using calcium imaging and miniature microscopes (miniscopes). This imaging will be done in baseline conditions (Aim 1), after optogenetic manipulation of abGCs to modulate DG activity (Aim 2), and after early life stress and adult manipulations of DG activity (Aim 3).