Stress response is important for survival. However, prolonged exposure to stressors produces detrimental effects, increasing the susceptibility for anxiety disorders, depression, eating disorders and obesity. A common feature of these illnesses is the perturbation of the hypothalamic-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) plays a pivotal role in the mediation of stress responses, particularly HPA activation. Recently, anatomical and functional evidence indicates that the central melanocortin system, a critical regulator of energy balance, interacts with the stress system and modulates HPA activity through CRH. This system consists of two opposite signaling components, the endogenous agonist alpha-MSH and the endogenous antagonist AgRP. The goal of this project is to study the role of the melanocortin system in stress responsiveness, focusing on HPA activation. First, we plan to identify the regulatory effects of acute and chronic stress on alpha-MSH, AgRP and their common receptor MC4R by measuring their transcriptional and translational responses in two key structures within stress circuits (the paraventricular nucleus of the hypothalamus and amygdala) using in situ hybridization, receptor autoradiography and radioimmunoassay;Second, we will determine the impact of the melanocortin system on the HPA response to acute and chronic stress using pharmacologic and molecular means to alter activation status or the expression level of MC4R. Given that studies on this system have been primarily focused on the regulation of feeding and body weight in recent years, the proposed studies in this project will not only shed light on biological functions of melanocortin signaling in stress, but also provide new insights into the interface between stress and eating disorders/obesity.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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Desmond, Nancy L
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
United States
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Liu, Jing; Garza, Jacob C; Li, Wei et al. (2013) Melanocortin-4 receptor in the medial amygdala regulates emotional stress-induced anxiety-like behaviour, anorexia and corticosterone secretion. Int J Neuropsychopharmacol 16:105-20
Guo, Ming; Huang, Tung-Yi; Garza, Jacob C et al. (2013) Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours. Int J Neuropsychopharmacol 16:857-67
Guo, Ming; Lu, Yuan; Garza, Jacob C et al. (2012) Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression. Transl Psychiatry 2:e83
Garza, J C; Guo, M; Zhang, W et al. (2012) Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3?/?-catenin signaling. Mol Psychiatry 17:790-808
Liu, J; Perez, S M; Zhang, W et al. (2011) Selective deletion of the leptin receptor in dopamine neurons produces anxiogenic-like behavior and increases dopaminergic activity in amygdala. Mol Psychiatry 16:1024-38
Yu, Tao; Guo, Ming; Garza, Jacob et al. (2011) Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction. Int J Neuropsychopharmacol 14:303-17
Zhang, Di; Guo, Ming; Zhang, Wei et al. (2011) Adiponectin stimulates proliferation of adult hippocampal neural stem/progenitor cells through activation of p38 mitogen-activated protein kinase (p38MAPK)/glycogen synthase kinase 3? (GSK-3?)/?-catenin signaling cascade. J Biol Chem 286:44913-20
Ryu, K-Y; Fujiki, N; Kazantzis, M et al. (2010) Loss of polyubiquitin gene Ubb leads to metabolic and sleep abnormalities in mice. Neuropathol Appl Neurobiol 36:285-99
Liu, Jing; Garza, Jacob C; Bronner, Jamaur et al. (2010) Acute administration of leptin produces anxiolytic-like effects: a comparison with fluoxetine. Psychopharmacology (Berl) 207:535-45
Stunkard, A; Lu, X-Y (2010) Rapid changes in night eating: considering mechanisms. Eat Weight Disord 15:e2-8

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