1] What is the neural representation of stressfulness?
Most people state with certainty that they frequently, if not daily, experience stress. Yet, our bodies do not have any stress detectors/receptors. We are studying the neural response in rats to psychological stress—situations that by themselves do not produce any direct physical harm or physiologic disturbance but, nevertheless, elicit stress responses. Our objective is to determine whether there are specific neural circuits that are necessary for the organism to: 1) interpret a situation as stressful, 2) generate a central stress state, and 3) coordinate behavioral and physiological stress responses. Identification of such circuits could be a key for understanding and developing treatments for stress-related disorders, such as anxiety disorders or depression.Recent supporting papers:
*Pace, TWW, Gaylord, R, Topczewski, F, Girotti, M, Rubin, B and RL Spencer. Immediate early gene induction in hippocampus and cortex as a result of novel experience is not directly related to the stressfulness of that experience. European Journal of Neuroscience, 22:1679-1690, 2005. *T.W.W.P and R.G contributed equally to this work.2] What are the mechanisms of stress adaptation?
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.Recent supporting papers:
Weinberg, MS, Johnson, DC, Bhatt, AP and RL Spencer. Medial prefrontal cortex activity can disrupt the expression of stress response habituation. Neuroscience 168:744-756, 2010.Weinberg, MS, Bhatt, AP, Girotti, M, Masini, CV, Day, HEW, Campeau, S and RL Spencer. Repeated ferret odor exposure induces different temporal patterns of same-stressor habituation and novel-stressor sensitization in both HPA-axis activity and forebrain c-fos expression in the rat. Endocrinology, 150: 749-761, 2009.
Girotti, M, Pace, TWW, Gaylord, RI, Rubin, BA, Herman, JP and RL Spencer. Habituation to repeated restraint stress is associated with lack of stress-induced c-fos expression in primary sensory processing areas of the rat brain. Neuroscience, 138: 1067-1081, 2006.
3] What are the mechanisms of glucocorticoid negative feedback regulation of the HPA axis?
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. We currently have a 5 year grant from the National Institutes of Health to study the molecular, cellular and systems-level mechanisms of glucocorticoid negative feedback.Recent supporting papers:
Pace, TWW, Gaylord, RI, Jarvis, E, Girotti, M and RL Spencer. Differential glucocorticoid effects on stress-induced gene expression in the paraventricular nucleus of the hypothalamus and ACTH secretion. Stress, 12:400-411, 2009.Girotti, M, Weinberg, MS and RL Spencer. Differential responses of HPA axis immediate early genes to corticosterone and circadian drive. Endocrinology, 148: 2542-2552, 2007.
Francis, AB, Pace, TWW, Ginsberg, AB, Rubin, BA and RL Spencer. Limited brain diffusion of the glucocorticoid receptor agonist RU28362 following i.c.v. administration: implications for i.c.v. drug delivery and glucocorticoid negative feedback in the hypothalamic-pituitary-adrenal axis. Neuroscience, 141(3):1503-15, 2006.
Ginsberg, AB, Frank, MG, Francis, AB, Rubin, BA, O'Connor, KA and RL Spencer. Specific and time-dependent effects of glucocorticoid receptor agonist RU28362 on stress-induced POMC hnRNA, c-fos mRNA and zif268 mRNA in the pituitary. Journal of Neuroendocrinology, 18(2):129-38, 2006.
4] What is the role of Clock Gene expression in the anatomical components of the HPA axis?
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 exploring the role and regulation of clock gene expression within the anatomical components of the HPA axis (hypothalamic paraventricular nucleus, anterior pituitary and adrenal cortex). These studies may lead to a better understanding of the mechanisms underlying the disruptive effects that stress can have on circadian and sleep patterns.Recent supporting papers:
Girotti, M, Weinberg, MS and RL Spencer. Diurnal expression of functional and clock-related genes in the rat hypothalamic-pituitary-adrenal axis. System-wide shifts in response to a restricted feeding schedule. American Journal of Physiology: Endocrinology and Metabolism, 296:888-897, 2009.Girotti, M, Weinberg, MS and RL Spencer. Differential responses of HPA axis immediate early genes to corticosterone and circadian drive. Endocrinology, 148: 2542-2552, 2007.
5] What does immediate early gene expression in the brain tell us about recent brain activity?
The human genome contains approximately 30,000 genes. A small number of th0se genes (approximately 30-50) have the unique ability to be rapidly induced in neurons by experience-dependent extracellular signals. The prototypical “immediate early gene” is the c-fos gene. Its expression level is almost undetectable in the rat brain under resting conditions, however within a few minutes of exposing a rat to a novel experience there is extensive expression of that gene in many different brain regions. Thus, c-fos gene induction, to some extent serves as a marker of increased neuronal activity. We are studying the expression of multiple immediate early genes and examining the degree to which their expression changes in parallel or differentially during various experiences. Since each immediate early gene has a unique DNA promoter sequence, we believe that with careful systematic characterization we can identify different aspects of neuronal function that are “marked” by the expression of these different genes.Recent supporting papers:
VanElzakker, M, Fevurly, RD, Breindel, T and RL Spencer. Environmental novelty is associated with a selective increase in Fos expression in the output elements of the hippocampal formation and the perirhinal cortex. Learning and Memory, 15:899-908, 2008.Pace, TWW, Gaylord, RI, Jarvis, E, Girotti, M and RL Spencer. Differential glucocorticoid effects on stress-induced gene expression in the paraventricular nucleus of the hypothalamus and ACTH secretion. Stress, 12:400-411, 2009.
*Pace, TWW, Gaylord, R, Topczewski, F, Girotti, M, Rubin, B and RL Spencer. Immediate early gene induction in hippocampus and cortex as a result of novel experience is not directly related to the stressfulness of that experience. European Journal of Neuroscience, 22:1679-1690, 2005. *T.W.W.P and R.G contributed equally to this work.