Prefrontal Cortical Microcircuit Mechanisms of Working Memory Deficits in Chronic Stress

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 DESCRIPTION (provided by applicant): Prefrontal cortical (PFC) circuit dysfunction has emerged as a central pathological finding in depression and other stress-related neuropsychiatric disorders, and has been linked to characteristic deficits in regulating attention, reward processing, and executive control. All of these functions depend on working memory: a process that supports the short-term storage and manipulation of information, despite interference from competing, task-irrelevant information. Working memory is mediated in part by PFC pyramidal neurons, which exhibit sustained activity during active maintenance of a memory trace. This unusual capacity for sustained, internally generated activity is thought to emerge from the precisely coordinated activity of excitatory pyramidal cells and inhibitory interneurons, but the microcircuit-level mechanisms remain incompletely understood. Understanding how these cells interact in the service of working memory-and how they are disrupted in psychiatric and neurodevelopmental disorders-are fundamental challenges for systems neuroscience. Here, we will use optogenetic tools and two-photon (2P) calcium imaging to quantify and manipulate neural activity in awake, behaving mice and investigate how pyramidal cells interact with two interneuron subtypes to support working memory. Next, we will test the hypothesis that chronic stress disrupts these interactions, altering the balance of excitation and inhibition in PF microcircuits and impairing working memory. Finally, we will test the hypothesis that these effects are driven at the molecular level by deficits in BDNF-mediated plasticity mechanisms for maintaining synaptic homeostasis. The results of this work will advance our understanding of how prefrontal microcircuits support working memory, a core component of multiple psychiatric and neurodevelopmental disorders. They may also inform future efforts to design new interventions targeting dysfunction in specific neuronal subtypes in mood and anxiety disorders.