The neuroendocrine stress response is a double-edged sword. Activation of glucocorticoid secretion is clearly essential for adaptation to stressful environmental or physiologic stimuli. However, stress or disease-induced glucocorticoid hypersecretion has serious deleterious consequences on metabolism, cardiovascular tone, immunity and behavior. Thus, it is critical for the organism to carefully limit the strength and duration of neuroendocrine stress activation. In recent years, it has become apparent that a sizable proportion of such stress regulation is mediated by the hippocampal formation of the brain. Integrity of the hippocampus is essential for appropriate inhibition of the stress response. Further, neuroendocrine disturbances are accompanied by hippocampal pathology in numerous stress-related disease processes, including major depression. On the basis of the available data, we have developed the hypothesis that the hippocampus serves to protect the organism from the deleterious consequences of stress by interpreting the significance of incoming stimuli with respect to previous experiences.
The aims of the present proposal are designed to test this general hypothesis, and to identify specific neurocircuitry subserving translation of hippocampal information processing into inhibition of neuroendocrine stress responses.
Specific Aim l tests the hypothesis that the hippocampus preferentially affects neuroendocrine responses to cognitive stimuli (novelty, conditioning) but not systemic challenge (respiratory distress, immune stimulation).
Specific Aim 2 is designed to delineate neurocircuitry subserving hippocampal neuroendocrine modulation, focusing on the hypothesis that activation of the hippocampus by cognitive (but not systemic stress) is translated into inhibition of the stress axis by way of intermediary cell groups proximal to hypothalamic stress-integrative neurons.
Specific Aim 3 builds on this circuit analysis by testing the hypothesis that excitatory neurotransmission in subcortical targets of hippocampal outflow leads to inhibition of hypothalamic stress outflow. Together, these studies are expected to define the raphe of the hippocampus in stress processing, and indicate that dysfunction of this structure is a likely mitigating factor in depressive disorder and stress-related disease processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH049698-10
Application #
6363651
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1992-09-15
Project End
2002-05-14
Budget Start
2001-03-01
Budget End
2002-05-14
Support Year
10
Fiscal Year
2001
Total Cost
$264,558
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Smith, Brittany L; Morano, Rachel L; Ulrich-Lai, Yvonne M et al. (2018) Adolescent environmental enrichment prevents behavioral and physiological sequelae of adolescent chronic stress in female (but not male) rats. Stress 21:464-473
Herman, James P (2018) Regulation of Hypothalamo-Pituitary-Adrenocortical Responses to Stressors by the Nucleus of the Solitary Tract/Dorsal Vagal Complex. Cell Mol Neurobiol 38:25-35
Smith, Brittany L; Lyons, Carey E; Correa, Fernanda Guilhaume et al. (2017) Behavioral and physiological consequences of enrichment loss in rats. Psychoneuroendocrinology 77:37-46
Myers, Brent; McKlveen, Jessica M; Morano, Rachel et al. (2017) Vesicular Glutamate Transporter 1 Knockdown in Infralimbic Prefrontal Cortex Augments Neuroendocrine Responses to Chronic Stress in Male Rats. Endocrinology 158:3579-3591
Myers, Brent; Scheimann, Jessie R; Franco-Villanueva, Ana et al. (2017) Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses. Neurosci Biobehav Rev 74:366-375
Wulsin, Aynara C; Solomon, Matia B; Privitera, Michael D et al. (2016) Hypothalamic-pituitary-adrenocortical axis dysfunction in epilepsy. Physiol Behav 166:22-31
Smith, Brittany L; Schmeltzer, Sarah N; Packard, Benjamin A et al. (2016) Divergent effects of repeated restraint versus chronic variable stress on prefrontal cortical immune status after LPS injection. Brain Behav Immun 57:263-270
Wulsin, Aynara C; Wick-Carlson, Dayna; Packard, Benjamin A et al. (2016) Adolescent chronic stress causes hypothalamo-pituitary-adrenocortical hypo-responsiveness and depression-like behavior in adult female rats. Psychoneuroendocrinology 65:109-17
Ulrich-Lai, Yvonne M; Christiansen, Anne M; Wang, Xia et al. (2016) Statistical modeling implicates neuroanatomical circuit mediating stress relief by 'comfort' food. Brain Struct Funct 221:3141-56
McKlveen, Jessica M; Morano, Rachel L; Fitzgerald, Maureen et al. (2016) Chronic Stress Increases Prefrontal Inhibition: A Mechanism for Stress-Induced Prefrontal Dysfunction. Biol Psychiatry 80:754-764

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