Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Circadian regulation of prefrontal cortex dependent emotional memories

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Psychiatric disorders, especially those marked by dysregulated mood and emotional control, such as depression, bipolar disorder, post traumatic stress disorder (PTSD) and schizophrenia, are associated with physiological and cognitive features of disrupted circadian function. Circadian regulation is necessary for appropriate anchoring of the optimal performance of virtually every cell and system of the body to fluctuating daily demands. Although the suprachiasmatic nucleus (SCN) of the hypothalamus serves as the body?s master circadian pacemaker, cells in other brain regions and in peripheral tissues express many of the same molecular clock elements (i.e. clock genes) as those found in the SCN. Recent advances have been made in determining the functional role and regulation of cellular clocks in peripheral tissues. Those studies demonstrate an important circadian entraining influence of the endogenous glucocorticoid hormones (CORT) on peripheral tissue cellular clock function. However, there is very little understanding of the function and regulatory processes of cellular clocks in extra-SCN brain regions. The prefrontal cortex (PFC) is a brain region that plays a central role in organizing and coordinating physiological, behavioral and emotional responses. Animal and human studies show that there is rhythmic clock gene expression in the PFC. Recent studies have found that normal clock gene expression in the PFC of rats depends on appropriate profiles of CORT secretion. Moreover, disruption of CORT-entrained PFC clock gene expression results in impaired diurnal patterns of conditioned fear extinction memory. PTSD is associated with impaired circadian function, compromised PFC function and dysregulation of CORT secretion. In addition, individuals with PTSD suffer from persistent conditioned fear responses. Improving conditioned fear extinction learning is a primary therapeutic objective for treating PTSD. Consequently, this project will use a rat animal model to determine the mechanistic basis by which PFC clock gene expression and CORT interdependently regulate conditioned fear extinction memory. The project is organized around 3 specific aims: Aim 1] To determine how time of day, circadian CORT and ventral medial PFC (vmPFC) clock gene expression modulate the activity of neuronal projections from the vmPFC to the basal medial amygdala (BMA) during conditioned fear extinction training and recall. Aim 2] To determine how time of day, circadian CORT and vmPFC clock gene expression modulate neuroplasticity- related processes in the vmPFC that support conditioned fear extinction recall. Aim 3] To test the necessity and sufficiency of vmPFC to BMA projections for mediating time of day, circadian CORT and vmPFC clock gene expression regulation of conditioned fear extinction recall. The proposed studies will provide new understanding of how circadian and CORT factors dynamically interact to regulate PFC function. These studies will also lead to better understanding of the underlying mechanisms of conditioned fear extinction memory, a neuroprocess that has important clinical relevance for circadian and stress-related disorders.
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