Friday, April 26, 2024
4/26/2024
Project Summary The prefrontal cortex (PFC) supports a constellation of ‘executive’ cognitive processes that guide goal-directed behavior. Dysregulation of PFC-dependent cognition is associated with numerous behavioral disorders. Currently there is a strong need for improved treatments for PFC- dependent cognitive dysfunction. However, the development of novel treatments is hindered by our limited understanding of the neurobiology underlying PFC-dependent cognition. In recent studies we demonstrated that corticotropin-releasing factor (CRF) neurons in the caudal, but not rostral, dorsomedial PFC (dmPFC) of male and female rats (outside proestrus) impair two distinct cognitive processes: working memory and sustained attention. Conversely, inhibition of PFC CRF neuronal activity or blockade of CRF receptors, locally or globally in the brain, improved PFC- dependent cognition. Interestingly, the regulatory actions of CRF across these distinct cognitive processes involve distinct pathways: local release for working memory and extra-PFC release for sustained attention. The mediodorsal nucleus of the thalamus (MDthal) plays a central role in the regulation of PFC-dependent function. Preliminary studies indicate that MDthal plays a prominent role in the sustained attention actions of PFC CRF neurons. We recently demonstrated that the PFC CRF neurons are comprised of both glutamatergic (CRFGlu, 85%) and GABAergic (CRFGABA, 15%) subpopulations. The proposed multidisciplinary studies will provide a better understanding of neural mechanisms that underlie the cognitive actions of PFC CRF neurons. Aim 1 uses recently developed viral vector-based chemogenetic manipulations to determine the cognitive actions of CRFGlu and CRFGABA neurons. Aim 2, building on preliminary observations tests the hypothesis that the sustained attention (an possibly working memory) actions of PFC CRF neurons involve projections to the MDthal. Aim 3 examines the neural coding actions of caudal dmPFC CRFGlu and CRFGABA across the PFC-MDthal circuit. Collectively, these studies will provide novel insight into the neurobiology of PFC-dependent cognition. In doing so, these studies may provide a better understanding of the neural bases of PFC cognitive dysfunction and lead to novel treatment strategies for PFC-dependent cognitive dysfunction.
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