The long term goal of this proposal is to investigate the regulation of mood and motivation by hypothalamic feeding systems. Disruptions in appetite and body weight regulation are among the most important concerns to patients with mood disorders. Metabolic diseases including obesity, type II diabetes mellitus and heart disease are all much more common in patients with major depression, bipolar disorder, and post-traumatic stress disorder. Despite substantial clinical evidence that links mood disorders and feeding, very little is known about the underlying neurobiological mechanism that regulates these two systems. Recently we have demonstrated that restriction of calorie intake can produce dramatic anxiolytic-like and antidepressant-like responses in mice. Additionally, mice subjected to chronic social stress not only develop depressive symptoms, but also display increased food intake, increased adipose tissue, and elevated insulin and triglyceride levels. Preliminary analysis of these chronically stressed mice demonstrates central leptin resistance and decreased melanocortin signaling. Administration of a melanocortin agonist decreases body weight and food intake but worsens depressive symptoms. Based upon these preliminary data we propose a hypothesis that disruption of melanocortin signaling by chronic stress may help alleviate mood symptoms but at the cost of metabolic side effects. In order to test this hypothesis we have obtained two mouse lines. One line expresses green fluorescent protein under the control of the melanocortin receptor 4 promoter. The second line prevents expression of the melanocortin receptor 4 unless exposed to Cre-recombinase. With these two powerful tools we propose the following Specific Aims: 1. To determine if melanocortin receptor 4 neurons in the ventral striatum innervate the lateral hypothalamic area using our unique melanocortin receptor 4 -GFP mouse. 2. To determine if genetic blockade of melanocortin receptor 4 produces anxiolytic-like and antidepressant-like behaviors. 3. To determine if selective re-expression of melanocortin receptor 4 in the nucleus accumbens is sufficient to restore normal anxiety and depression responses in melanocortin receptor 4 null mice.

Public Health Relevance

Patients suffering from major depression, bipolar disorder, and post-traumatic stress disorder have much higher rates of obesity and related diseases such as diabetes and heart disease. The purpose of this research is to investigate the link between mood disorders and feeding and body weight regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH084058-06
Application #
8440839
Study Section
Special Emphasis Panel (ZRG1-PMDA-A (01))
Program Officer
Rosemond, Erica K
Project Start
2009-04-16
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
6
Fiscal Year
2013
Total Cost
$170,640
Indirect Cost
$12,640
Name
University of Iowa
Department
Psychiatry
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Mason, Brittany L; Lobo, Mary Kay; Parada, Luis F et al. (2013) Trk B signaling in dopamine 1 receptor neurons regulates food intake and body weight. Obesity (Silver Spring) :
Xu, Pin; Grueter, Brad A; Britt, Jeremiah K et al. (2013) Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice. Proc Natl Acad Sci U S A 110:10759-64
Kumar, Jaswinder; Chuang, Jen-Chieh; Na, Elisa S et al. (2013) Differential effects of chronic social stress and fluoxetine on meal patterns in mice. Appetite 64:81-8
Cui, H; Lutter, M (2013) The expression of MC4Rs in D1R neurons regulates food intake and locomotor sensitization to cocaine. Genes Brain Behav 12:658-65
Cui, Huxing; Mason, Brittany L; Lee, Charlotte et al. (2012) Melanocortin 4 receptor signaling in dopamine 1 receptor neurons is required for procedural memory learning. Physiol Behav 106:201-10
Vialou, Vincent; Cui, Huxing; Perello, Mario et al. (2011) A role for ?FosB in calorie restriction-induced metabolic changes. Biol Psychiatry 70:204-7
Chuang, Jen-Chieh; Perello, Mario; Sakata, Ichiro et al. (2011) Ghrelin mediates stress-induced food-reward behavior in mice. J Clin Invest 121:2684-92
Scott, Michael M; Marcus, Jacob N; Pettersen, Ami et al. (2011) Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behav Brain Res 222:289-94
Chuang, Jen-Chieh; Cui, Huxing; Mason, Brittany L et al. (2010) Chronic social defeat stress disrupts regulation of lipid synthesis. J Lipid Res 51:1344-53
Perello, Mario; Chuang, Jen-Chieh; Scott, Michael M et al. (2010) Translational neuroscience approaches to hyperphagia. J Neurosci 30:11549-54

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