This proposal investigates the influence of serotonin (5-HT) and its associated neurons in the hypothalamic paraventricular nuclei (PVN) on neuronal corticotropin releasing factor (CRF) mRNA expression and feeding behavior in rats. PVN CRF neurons are important mediators in the control of feeding behavior;e.g. exogenous application of CRF or stimulation of CRF neurons result in the inhibition of food intake. Similarly, drugs that stimulate synaptic 5-HT transmission in the brain are also well known to inhibit food intake. Anatomically, it is also known that 5-HT terminal projections are found on PVN CRF neurons;this suggests that 5HT agents may suppress appetite through heretofore uncharacterized actions on PVN CRF neurons. A potential functional link between 5-HT is further supported by data demonstrating the presence of mRNAs for 5-HT receptor subtypes linked to appetite regulation in PVN CRF cell bodies. Remarkably, despite the suggestion of a number of studies, there have been no definitive studies to date demonstrating that 5-HT-associated drugs may indeed suppress feeding by stimulating CRF mRNA production and CRF protein expression. In this proposal, we hypothesize that there exists a functional link between serotonin (5-HT) and neuropeptides, such as CRF and melanocyte stimulating hormone (alpha MSH) and their respective neurons residing within the PVN (5-HT, CRF) and the arcuate (ARC) hypothalamic nuclei (alpha MSH), respectfully.
Our Specific Aims are to (1) determine if 5-HT release regulates CRF or alpha MSH neurons in the PVN to suppress food intake;(2) Determine if 5-HT release indirectly regulates CRF neurons in the PVN via 1-MSH neurons residing in the arcuate and its associated neurons;and (3) determine downstream targets of hypothalamic CRF and its associated neurons. In our experimental design, we will utilize fenfluramine (FEN), a drug that strongly promotes 5HT synaptic transmission. Central and systemic FEN administration will be used to assess PVN CRF mRNA expression in rats pre-treated with 5-HT receptor antagonists specific to PVN CRF neurons that are appetite-linked (the 5HT-1B, 2A, &2C subtypes). FEN will also be used to test whether 5-HT affects PVN CRF mRNA expression indirectly;1-MSH release onto CRF neurons is stimulatory;hence, FEN could stimulate CRF neurons by increasing 1-MSH signaling. RNA interference will be used to eliminate CRF mRNA, to determine if FEN-initiated 5-HT influences appetite suppression by additional downstream mechanisms. These studies should provide new insight into the role of a poorly characterized 5HT-CRF synaptic connection in the control of food intake, and ultimately contribute to understanding if and how this connectivity is important to the regulation of overall energy balance, and the etiology of obesity, anorexia, and other appetite-related health problems. This proposal investigates the influence of serotonin (5-HT) and its associated neurons in the hypothalamic paraventricular nuclei (PVN) on neuronal corticotropin releasing factor (CRF) mRNA expression and feeding behavior in rats. These studies should provide new insight into the role of a poorly characterized 5HT-CRF synaptic connection in the control of food intake, and ultimately contribute to understanding if and how this connectivity is important to the regulation of overall energy balance, and the etiology of obesity, anorexia, and other appetite-related health problems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074734-05
Application #
8212339
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Hyde, James F
Project Start
2008-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$292,070
Indirect Cost
$96,050
Name
Marquette University
Department
Other Basic Sciences
Type
Schools of Allied Health Profes
DUNS #
046929621
City
Milwaukee
State
WI
Country
United States
Zip Code
53201
Resch, Jon M; Maunze, Brian; Phillips, Kailynn A et al. (2014) Inhibition of food intake by PACAP in the hypothalamic ventromedial nuclei is mediated by NMDA receptors. Physiol Behav 133:230-5
Resch, Jon M; Albano, Rebecca; Liu, XiaoQian et al. (2014) Augmented cystine-glutamate exchange by pituitary adenylate cyclase-activating polypeptide signaling via the VPAC1 receptor. Synapse :
Lutgen, Victoria; Resch, Jon; Qualmann, Krista et al. (2014) Behavioral assessment of acute inhibition of system xc (-) in rats. Psychopharmacology (Berl) 231:4637-47
Lutgen, Victoria; Qualmann, Krista; Resch, Jon et al. (2013) Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc? activity in the medial prefrontal cortex. Psychopharmacology (Berl) 226:531-40
Resch, Jon M; Boisvert, Joanne P; Hourigan, Allison E et al. (2011) Stimulation of the hypothalamic ventromedial nuclei by pituitary adenylate cyclase-activating polypeptide induces hypophagia and thermogenesis. Am J Physiol Regul Integr Comp Physiol 301:R1625-34
Boisvert, Joanne P; Boschuetz, Tyler J; Resch, Jon M et al. (2011) Serotonin mediated changes in corticotropin releasing factor mRNA expression and feeding behavior isolated to the hypothalamic paraventricular nuclei. Neurosci Lett 498:213-7