Chronic stress-induced REDD1 expression in prefrontal cortex and cognitive inflexibility - PROJECT SUMMARY Flexible behavior-- the ability to adapt behavior in response to changing environmental contingencies --is a critical component of everyday life. Deficits in cognitive flexibility, a subconstruct in the cognitive systems domain of the NIMH Research Domain Criteria (RDoC), are evident in many stress-associated neuropsychiatric conditions, including major depressive disorder (MDD). Such deficits are debilitating, as they manifest as ineffective problem solving and cognitive reappraisal as well as ruminating thought patterns that come at the expense of healthy coping responses. Our preliminary data in mice demonstrate that a chronic unpredictable stress (CUS) regimen produces deficits in strategy shifting (cognitive flexibility), akin to those observed in people with MDD, assessed using an operant-based strategy set-shifting task. These effects are sex-dependent, as they are more readily observed in males relative to females. The human prefrontal cortex (PFC) has been implicated in flexible cognitive control, and stress-related psychopathology is associated with functional and structural deficits in the PFC. However, the cortical output pathways, affected pyramidal neuron subpopulations, and underlying cellular mechanisms are not well-understood. In this proposal, we test the hypothesis that CUS produces sex-dependent reductions in dendritic spine number and size in a subpopulation of pyramidal neurons in the prelimbic cortex that express D2 dopamine receptors and project to the nucleus accumbens (NAc) core to produce deficits in behavioral/cognitive flexibility. Based on observations that the protein REDD1 is increased in prelimbic cortex following CUS and is elevated postmortem in the dorsolateral PFC of individuals diagnosed with MDD and that overexpression of REDD1 in the prelimbic cortex produces deficits in set shifting, excitatory synaptic transmission, and dendritic spine morphology, the proposal examines a mechanism wherein CUS increases REDD1 expression in D2-expressing pyramidal neurons resulting in dysregulation of mTORC1 signaling and disrupted actin cycling in dendritic spines. Aim 1 of the proposal will examine sex-dependent effects of CUS on cognitive flexibility as assessed in our set shifting task and corresponding effects on synaptic regulation and activity of NAc core-projecting D1 and D2 pyramidal neurons in the prelimbic PFC in mice. Aim 2 will examine the contribution of increased REDD1 expression and disrupted TORC1 function in pyramidal neuron subpopulations in the prelimbic PFC to CUS-induced deficits in cognitive flexibility. Aim 3 will examine the contribution of disrupted actin cycling in prelimbic PFC neuronal subpopulations to CUS-induced deficits. To pursue this project, we have brought together a team with complementary expertise in behavioral assessment, stress neurobiology, systems neuroscience, in vivo and ex vivo physiological and morphometric measures to assess alterations in neuronal activation, synaptic regulation, and dendritic spine structure. Understanding how CUS dysregulates the prelimbic PFC to produce deficits in cognitive flexibility has implications for understanding and treating a range of debilitating stress-related neuropsychiatric conditions.
