Glucocorticoids and Psychiatric Disorders: Mechanisms of Stress Induced Cognitive Deficits

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Chronic stress is a major risk factor for psychiatric illnesses such as depression and anxiety disorders. Cognitive deficits are an important consequence of these disorders, because they severely compromise functioning in daily life. Chronic stress causes the release of glucocorticoids (GCs), which bind to glucocorticoid receptors (GR) throughout the brain. A number of studies suggest that stress-induced GC release has detrimental effects on cognition and that these effects are mediated via GR activation in the prefrontal cortex (PFC), a structure that plays a key role in cognitive processes. Yet it is not well understood whether and how the effects of GCs are mediated by GRs in distinct cell populations within PFC microcircuits. Here, we propose to address this by manipulating GR expression in pyramidal neurons and parvalbumin-expressing inhibitory nterneurons within the PFC using a combination of genetic and viral strategies. We will then examine how these cell-specific manipulations affect responses to chronic stress. By using the combined technical expertise of the applicants, we will take a comprehensive multi-level approach to examine how cell-specific GR manipulations modulate the effects of stress on gene transcription, cellular morphology and physiology, as well as inter-areal network interactions and cognitive behavior. We will first study the behavioral consequences of cell-specific GR manipulations on stress-induced cognitive deficits using a battery of PFC-dependent cognitive tasks. We will then use multi-site, multi-unit recordings to ask how stress affects a neural circuit involving the hippocampus and PFC, which is central for cognitive function in rodents. We will also address the role of GR in modulating the effects of stress in this circuit. Finally, by combining histology, in vitro recordings and transcriptome analysis, we will assess the morphological, physiological and molecular impact of GR gene manipulation on PFC microcircuits. Taken together, these studies will help reveal the mechanisms by which chronic stress alters PFC circuit function and causes the cognitive deficits that are observed in stress-induced psychiatric illnesses.