Sensitive periods for interneuron development supporting cognitive flexibility

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Cognitive flexibility is a core component of executive functioning that is impaired in a range of neuropsychiatric disorders. The prefrontal cortex (PFC) supports cognitive flexibility in the adult, and alterations in prefrontal function likely contribute to impairments in this cognitive process. Cognitive flexibility, like other aspects of executive functioning, develops slowly across postnatal development. Developmental refinement of prefrontal circuitry and function is theorized to underlie the protracted acquisition of cognitive abilities, and abnormalities in this refinement may contribute to deficits in prefrontal circuitry and function in the context of psychiatric disorders. While the early stages of prefrontal circuit development are largely governed by genetic programs, subsequent circuit refinement is heavily dependent on activity. Postnatal maturation of GABAergic tone is poised to powerfully regulate cortical activity—providing a source of excitability during the first postnatal week that rapidly changes to inhibition thereafter. Importantly, developmental dysfunction of interneurons, especially those expressing parvalbumin (PV) or somatostatin (SST), is linked with impaired set-shifting behavior and prefrontal circuit function in adulthood. Yet, how activity in PV and SST interneurons influences prefrontal circuit development—including the development of the interneurons themselves—during different developmental time windows is a fundamental gap in our knowledge. Further, once mature connectivity is established, how SST and PV interneurons work together to engage cortical activity to support cognitive flexibility in adulthood, remains unknown. We hypothesize that during early postnatal development, prefrontal SST activity is required for establishing increasing thalamocortical drive onto PV cells that, in turn, sustains and augments the strength of the connections these PV cells make onto pyramidal cells, and that PV activity subsequently iteratively refines the strength of incoming excitatory drive from cortical and subcortical sources. This developmental maturation in activity establishes proper connectivity of PV and SST interneurons in adulthood, whose activity is essential for mature prefrontal network function supporting cognitive flexibility. To test this hypothesis, in Aim 1 we will examine how PV and SST interneurons organize PFC network activity to support extra dimensional attentional set shifting in adult mice. In Aim 2, we will test how inhibiting activity of prefrontal PV or SST interneurons during different developmental windows using the DREADD receptor, hM4DGi, affects adult network function and behavior using the physiological and behavioral outcomes assessed in Aim 1. Understanding how PV and SST interneurons support cognition, and how developmental perturbations of these cells affect adult PFC function, will provide insight into neurobiological origins of cognitive deficits in psychiatric disorders and more broadly into the role of cell-type selective GABA release in sculpting the developing PFC.