Stress is an important factor in either eliciting or exacerbating many neuropsychiatric disorders. The goal of this proposal is to better understand the molecular mechanisms by which stress affects CNS physiology and behavior. Such knowledge will ultimately lead to more effective measures for preventing the deleterious effects of stress on behavior and health. A prominent mediator of stress is the neuroendocrine system that includes glucocorticoid signaling. Classic glucocorticoid signaling modulates gene expression via steroid hormone (glucocorticoid and mineralocorticoid) receptor transcription factors. This genomic mechanism is partly responsible for stress effects observed over hours to days. Acute stress effects occurring over minutes or longer can also be mediated by glucocorticoids. These effects of stress are thought to occur through non- genomic mechanisms, however, the identity of these mechanisms remains largely unknown. In a recent study examining the acute effects of stress on hippocampus-dependent memory retrieval, we identified the 22-adrenergic receptor (22AR) as a critical mediator of the impairing effects of stress and glucocorticoids. Based on these and other observations, we now hypothesize that there is a specific interaction between either the glucocorticoid receptor (GR) or its ligand (cort) and 22AR, and that many of the acute effects of glucocorticoids depend on this interaction and the downstream signaling activated by 22AR. Here we propose to identify additional systems in which this interaction is relevant to the stress response, characterize the interaction betwee cort and 22AR at the molecular level, and define the downstream signaling events that mediate this coincident signaling. Results from these aims will identify specific molecular mechanisms for the non-genomic effects of glucocorticoids and the acute effects of stress that can persist under conditions of chronic stress. Because stress can impair normal CNS physiology and behavior, as well as exacerbate many neurologic and psychiatric disorders, understanding the mechanisms that underlie stress effects may aid in their prevention.
Acute physiologic and/or psychologic stress elicits rapid, non-genomic as well as classic genomic adaptive responses that are mediated in part by the release of glucocorticoids and stimulation of cognate glucocorticoid receptors. However, acute and chronic stress can also result in maladaptive changes in cognition and other central processes through non-genomic as well as genomic mechanisms. Here we propose to characterize at the molecular level novel mechanisms for non-genomic glucocorticoid signaling mediated by the ?22-adrenergic receptor (?22AR), which appears to act as a coincidence detector for activation of the adrenergic and glucocorticoid systems. In addition, we will determine which effects of acute stress and glucocorticoids depend on this coincident signaling mechanism by ?22AR, as well as the downstream signaling mechanisms that are involved. Identification and characterization of these mechanisms may shed light o potential non-genomic mechanisms utilized by other steroid hormones, as well as lead to more efficacious treatment of psychiatric conditions such as post-traumatic stress disorder.
|Ross, Jennifer A; Reyes, Beverly A S; Thomas, Steven A et al. (2018) Localization of endogenous amyloid-? to the coeruleo-cortical pathway: consequences of noradrenergic depletion. Brain Struct Funct 223:267-284|
|Thomas, Steven A (2015) Neuromodulatory signaling in hippocampus-dependent memory retrieval. Hippocampus 25:415-31|