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One of the most exciting discoveries in Neuroscience over the last 30 years has been the molecular and neural systems basis of the endogenous circadian Master Clock in the mammalian hypothalamic suprachiasmatic nucleus. Very recently it has become clear that the molecular components of this Master Clock are operational in tissues throughout the body. We are studying the role and regulation of clock gene expression within the prefrontal cortex, a brain region instrumental for emotion-related learning. Our recent studies support the presence of an operational molecular clock intrinsic to the prefrontal cortex that depends on appropriately timed daily circadian corticosterone hormone signals for normal function. Moreover, disruption of this prefrontal cortex molecular clock results in impaired conditioned fear extinction learning, an adaptive emotional learning task that is often disrupted in individuals with post traumatic stress disorder. These studies may lead to a better understanding of the mechanisms underlying the disruptive effects that stress and circadian disruption can have on prefrontal cortex function.

• Woodruff ER, Chun LE, Hinds LR, *Varra NM, *Tirado D, Morton SJ, McClung CA and RL Spencer. Coordination between prefrontal cortex clock gene expression and corticosterone contributes to enhanced conditioned fear extinction recall. eNeuro, 2018.��.
• Hartsock MJ, Spencer RL. Memory and the circadian system: identifying candidate mechanisms by which local clocks in the brain may regulate synaptic plasticity.��Neuroscience and Biobehavioral Reviews.��118:134-162, 2020.
• Spencer RL, Chun LE, Hartsock MJ, Woodruff ER. Glucocorticoid hormones are both a major circadian signal and major stress signal: How this shared signal contributes to a dynamic relationship between the circadian and stress systems.��Frontiers in Neuroendocrinology,��49, 52-71, 2018.
• Spencer RL, Deak T.��A users guide to HPA axis research.��Physiol Behav,��178, 43-65, 2017.

The glucocorticoid stress hormones, cortisol and corticosterone, have potent widespread effects throughout the body. These glucocorticoid effects can be beneficial in helping the organism combat the effects of physical stress. It is not clear, however, if they are beneficial in combating psychological stress. In addition, chronic over exposure of the body to glucocorticoids can have adverse physiological effects including exacerbation of diabetes, osteoporsis and cardiac disease as well as decreased resistance to infection and increased fatigue. The secretion of glucocorticoid hormones is normally minimized by a negative feedback effect of the hormone on the HPA axis. There is some evidence, however, that the high cortisol levels (HPA axis disregulation) associated with clinical depression are due to impaired glucocorticoid negative feedback function. We are studying the mechanisms of glucocorticoid negative feedback. Two key components of our approach to these studies is 1) identification of the specific glucocorticoid actions at different anatomical sites within the brain, as well as the pituitary gland, that impacts on HPA axis activity, and 2) determination of the effect of glucocorticoids on signal transduction pathways within those anatomical elements responsible for coupling cell excitation with (neuro)hormone secretion and gene expression.

All organisms display the ability to adjust their responses to repeated or chronic stress. This adaptation is often manifest as a change over time in the magnitude of response, and the nature of this adaptation may be either reduced levels of responding (stress habituation ) or increased levels of responding (stress sensitization). We are studying the molecular, cellular and systems-level mechanisms that underlie stress adaptation. Understanding these mechanisms may have important clinical applications. Some of the symptoms of post-traumatic stress disorder are characterized by persistent and in some cases progressively increased generalized stress responsiveness (sensitization) . Some of the clinical features of depression may be characterized as an impaired ability to habituate to daily hassles. Our studies have led us to explore the possibility that adaptation to psychological stress depends on a “top-down” neural-systems level control of the widespread neural response to familiar vs. novel stressors. Our most recent studies indicate that the medial prefrontal cortex regulates the expression of stress response habituation.

Our research is fundamentally an example of Systems Neuroscience. We believe that psychological stress is a systems-level state, but we recognize that stress adaptation ultimately depends on cellular and molecular changes. Utilizing the rat as an in vivo model, we use endocrine, pharmacological and behavioral manipulations to study organismic stress responses and the underlying neural-systems, cellular and molecular changes associated with those responses.