TY - JOUR T1 - COORDINATION BETWEEN PREFRONTAL CORTEX CLOCK GENE EXPRESSION AND CORTICOSTERONE CONTRIBUTES TO ENHANCED CONDITIONED FEAR EXTINCTION RECALL JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0455-18.2018 SP - ENEURO.0455-18.2018 AU - Elizabeth R. Woodruff AU - Lauren E. Chun AU - Laura R. Hinds AU - Nicholas M. Varra AU - Daniel Tirado AU - Sarah J Morton AU - Colleen A. McClung AU - Robert L. Spencer Y1 - 2018/12/06 UR - http://www.eneuro.org/content/early/2018/12/06/ENEURO.0455-18.2018.abstract N2 - PTSD is associated with impaired conditioned fear extinction learning, a ventromedial prefrontal cortex (vmPFC) dependent process. PTSD is also associated with dysregulation of vmPFC, circadian and glucocorticoid hormone function. Rats have rhythmic clock gene expression in the vmPFC that requires appropriate diurnal circulatory patterns of corticosterone (CORT), suggesting the presence of CORT-entrained intrinsic circadian clock function within the PFC. We examined the role of vmPFC clock gene expression and its interaction with CORT profiles in regulation of auditory conditioned fear extinction learning. Extinction learning and recall were examined in male rats trained and tested either in the night (active phase) or in the day (inactive phase). Using a viral vector strategy, Per1 and Per2 clock gene expression were selectively knocked down within the vmPFC. Circulating CORT profiles were manipulated via adrenalectomy (ADX) ± diurnal and acute CORT replacement. Rats trained and tested during the night exhibited superior conditioned fear extinction recall that was absent in rats that had knockdown of vmPFC clock gene expression. Similarly, the superior nighttime extinction recall was absent in ADX rats, but restored in ADX rats given a combination of a diurnal pattern of CORT and acute elevation of CORT during the post-extinction training consolidation period. Thus, conditioned fear extinction learning is regulated in a diurnal fashion that requires normal vmPFC clock gene expression and a combination of circadian and training-associated CORT. Strategic manipulation of these factors may enhance the therapeutic outcome of conditioned fear extinction related treatments in the clinical setting.SIGNIFICANCE STATEMENT Post Traumatic Stress Disorder is associated with deficits in conditioned fear extinction learning, a prefrontal cortex (PFC)-dependent process, as well as dysregulation of circadian and glucocorticoid hormone function. We examined the role of glucocorticoid-entrained clock gene expression within the PFC on conditioned fear extinction learning, and its interaction with glucocorticoid hormone profiles. We found a prominent time of day difference in extinction recall—superior recall in rats trained and tested at night. This superior recall required normal PFC clock gene expression as well as a combination of a diurnal pattern of circulating glucocorticoids and an acute elevation of glucocorticoids during the extinction learning memory consolidation period. Appropriate alignment of these factors in the clinical setting may enhance extinction learning related outcomes. ER -