Cognitive deficits are hallmark features of a variety of psychiatric diseases. While body of evidences pointed to the prefrontal cortex (PFC) as a key structure for cognition, recent studies further suggested that abnormalities in the interaction between inhibitory interneurons and glutamatergic pyramidal cells within PFC microcircuit could be involved in the pathogenesis of cognitive deficits in psychiatric disorders. Thus, intensive effort has been made to understand the mechanisms underlying PFC microcircuit dysfunction and the ensuing cognitive impairment. Stress-induced release of glucocorticoids (GCs) has been associated with cognitive symptoms in multiple mental disorders. GCs modulate behavioral responses to stress via their binding to the glucocorticoid receptor (GR), a nuclear receptor expressed in heterogeneous cell populations throughout the brain. Although it has been suggested that GCs could alter cognition through their action within the PFC, it is still unknown whether and how the GCs via their action on distinct cell types within the PFC can alter cognition, prefrontal microcircuit function and larger brain circuits. Only a genetic approach offering spatial resolution and cell-type specificity can precisely address these issues. Given their key role in cognition and their potential involvement in the pathophysiology of psychiatric disorders, I propose to manipulate GR expression within PFC pyramidal neurons and Parvalbumin-expressing interneurons. Using a battery of PFC-dependant cognitive tasks, I will study the behavioral consequences of these manipulations. Finally, combining whole cell patch-clamp and in vivo multisite recordings in behaving mice, I will assess the functional impact of GR gene manipulation on PFC microcircuit and hippocampo-frontal network during working memory. This study should shed light on mechanisms involved in stress-induced cognitive deficit and potentially lead to the finding of new treatment against cognitive symptoms.
Field of science
- /medical and health sciences/basic medicine/physiology/pathophysiology
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