Prefrontal CRF and the Regulation of Goal Directed Behavior

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.

Grant Number: 5R01MH116526-08
NIH Institute/Center: NIH
Principal Investigator: CRAIG BERRIDGE