1985 — 2007 |
Dallman, Mary F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Brain-Pituitary-Adrenal Interrelationships @ University of California San Francisco
[unreadable] DESCRIPTION (provided by applicant): Obesity and chronic stress are major and growing societal and medical problems. Chronic stress may result in either decreased food intake and body weight or increased food intake and body weight in man. In rats, chronic stress usually decreases body weight. High glucocorticoids (B) in the presence of increased food intake and insulin increase body weight and abdominal obesity, whereas high glucocorticoids and decreased food intake and insulin decrease body weight. Our overall hypothesis is that stress-induced B levels act in brain in a feed-forward manner to stimulate amygdala corticotropin-releasing factor (CRF), increasing the autonomic, behavioral and neuroendocrine activity characteristic of chronic stress. However, chronic stress is required to recruit activity in this limbic network. In contrast, B acts in the periphery to increase body energy stores, which in turn inhibit the limbic stress response network. We will test 5 parts of this hypothesis: 1. Rats given high B and no stress will become fat and have inhibited responses to acute stress whereas rats given high B and repeatedly restrained will recruit the central stress-response network and become leaner. 2. Restricted feeding in rats given high B will increase stress responsivity in proportion to weight loss. 3. Denervation of the hindbrain catecholaminergic pathways will block the effects of restricted feeding in rats treated with high B. 4. Blockade of CRF receptors or treatment of CRF cell groups with CRF RNAi will block the recruited responses of the stress response network; and, 5. Sucrose, but not saccharin to drink will reduce activity in the recruited central stress response network. Measurements in each aim include: food intake, body weight, hormones, CRF and catecholaminergic mRNA/peptide expression; 2 tests of anxiety-like behavior, oxygen consumption, core temperature and acute temperature and hormonal response to a novel endotoxin stress. Manipulations will include toxin-induced lesions, CRF receptor pharmacology and specific CRF phenotypic knockouts. If it is so that eating 'comfort food' reduces activity of the chronic stress-recruited central stress response network through the combined negative actions of B and insulin on this network, we will provide new insight to those who are chronically stressed and eat 'comfort' food. The information should be useful for therapeutic advice for overweight, stressed people, and possibly provide insights into mechanisms underlying different types of depressive and anxiety disorders [unreadable] [unreadable]
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0.958 |
1994 — 1996 |
Dallman, Mary F |
R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Brain, Pituitary, Adrenal Interrelationships @ University of California San Francisco
The objectives of this work are to understand the neural control of ACTH secretion and the function of the adrenocortical system (ACS) in the overall physiology of the animal. Glucocorticoids secreted by the adrenals are necessary for normal mammalian life. In their absence, even minor stress may provoke collapse and death. Understanding of the regulation of function and the physiological effects of normal ACS activity is, therefore, of basic and clinical significance. The studies proposed are based on previous and current results from the lab, and are designed to further knowledge about brain control components of the system and the life saving effects of corticosterone (B). The grant has 4 specific aims: 1. Using streptozotocin-induced diabetes as a chronic stress in rats, the effects of this on hippocampus, hypothalamus, pituitary and adrenal components of the system will be determined, measuring B receptors, hypothalamic secretogogues, ACTH and B. The sensitivity of these components will be compared to that in non-stressed rats. 2. Brain negative feedback sites for B will be determined in rats using a combined lesion and B-implantation approach with measurement of ACTH. 3. The function of neurotransmitters known to arise from nearby nuclei involved in energy metabolism and to innervate corticotropin- releasing factor cells in the paraventricular nuclei will be determined by microinjection and measurement of ACTH; small lesions in these nuclei will be made and the effects of these on feeding- or fasting-induced changes in ACS activity will be tested. 4. The role of glucose in enabling a homeostatic response of adrenalectomized rats to stress will be tested using infusions of glucose and blockage of gluconeogenesis. Regulation of function in the rat ACS closely resembles that in man. The results of these studies should provide new insights into the mechanisms which underlie ACS malfunction in people with chronic diseases, adrenal enzyme deficiencies, eating disorders and depression.
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0.958 |
1997 — 2002 |
Dallman, Mary F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brain Pituitary Adrenal Interrelationships @ University of California San Francisco
DESCRIPTION (Adapted from applicant's abstract): The long term goals of this project are to delineate changes in neural control of the HPA axis which occur with chronic stress and to determine how these changes affect physiology and behavior. Chronic stress causes facilitated behavioral, sympathetic (SNS) and HPA responses to new stressors. Delineation of the mechanism(s) underlying these changes will apply directly to understanding of the major societal problem of chronic stress disorders, e.g., depression, PTSD, etc. Moreover, chronic stress has been suggested to cause preferential abdominal obesity, associated with NIDDM, CAD and stroke. Three characteristics of facilitated acute responses in chronically stressed rats must be explained by the neural circuit that mediates them: facilitation occurs in the AM, not the PM; as steady-state corticosterone (B) increases in stressed rats so does facilitation; and, SNS and behavioral responses are also facilitated in chronically stressed rats. The number of c-fos staining (active) neurons increases in 4 brain sites after acute stress in chronically stressed cf. naive rats: in midline thalamus (which received major circadian input from the suprachiasmatic nuclei and projects to), the amygdala (which project to) both neuroendocrine cells of the parvocelular paraventricular (PVN) hypothalamus and to central SNS nuclei. Three aims test whether: (1) the thalamic paraventricular nucleus (PVTh) controls diurnal facilitation and sends this information preferentially to the amygdala; (2) the amygdala, specifically corticotropin releasing factor (CRF) cells, execute facilitated responses in the HPA axis and the SNS; and (3) these extrahypothalamic cell groups alter function in medial hypothalamic nuclei that regulate energy balance during chronic stress. Methods to be used include: c-fos mRNA to follow facilitation after acute stress in chronically stressed rats; lesions to block facilitation in specific neural sites; beta implants over amygdala to determine the effect of the steroid on CRF; selected neropeptides and receptors measured by semiquantitative mRNA analysis. Food intake, body weight, plasma hormones and temperature, plasma metabolites and the activity in white and brown fat depots will be measured for HPA and SNS responsitivity and determination of changes in energy balance. If the underlying hypotheses are correct, these experiments will provide evidence that the basis neural circuit that mediates facilitated stress responses in chronically stressed rats is part of the "conditioned fear response" circuit.
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0.958 |
2003 — 2006 |
Dallman, Mary F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Chronic Stress Intensifies Incentive Relativity @ University of California San Francisco
DESCRIPTION (provided by applicant): Because drug abuse implies that normally rewarding activities become devalued relative to supernormal drug rewards, an incentive relativity paradigm is proposed in which normally rewarding 4% sucrose solutions become excessively devalued following experience with "supernormal," 32% sucrose solutions. Incentive relativity develops in stages, including: representing the incentive object (pre-shift solution), strong habit formation, a potential for physical dependency on the substance, detection of the incentive shift and evaluation of the normally rewarding alternative, exaggerated appetitive responses related to the missing substance, the activation of a stress response when that substance is not found, and a gradual recovery process whereby the relatively unsatisfactory incentive (the post-shift solution) eventually becomes acceptable. We hypothesize that high corticosterone (B) mounts central stress networks that enhance learning, performance, and recovery from incentive relativity effects. We intend to manipulate chronic stress variables (e.g., deprivation, B, corticotropin-releasing factor (CRF), opioids) and measure behavioral and neuroendocrine variables relevant to the acquisition, performance and recovery processes in an incentive relativity paradigm. We will test 4 hypotheses: 1. incentive shifts modify stress circuitry mediating psychological stressors; 2. High B improves acquistion and performance of sucrose drinking prior to the shift, and drinking and instrumental performance after the shift; 3. High B (and/or food deprivation) intensifies incentive relativity effects on a maze; and, 4. CRF and opioid systems are critical central opponent modulators of chronic stress relevant to incentive relativity effects. Methods include: behavior, ad lib and restricted food intake, immunocytochemical labeling, and double-labeling of cells for immediate-early genes and CRF, GABA and opioid peptides, adrenalectomy with B replacement, infusions into the ventricle of CRF-, mu/delta-opioid receptor antagonists and kappa-opioid receptor antagonists, before and after the shift in sucrose solution. The results should reveal brain mechanisms involved in incentive relativity and responses engendered in a paradigm analogous to drug-taking behavior. Because drug addiction and stress-induced relapse to drug taking have major social and societal, psychological and economic costs, studies that reveal mechanisms associated with drug taking behavior are of direct relevance to human health and drug addiction.
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0.958 |