Obesity is a major public health concern, especially in the United States, as currently over two-thirds of the US population is considered overweight or obese. The lack of safe and effective obesity treatments highlights the urgency of developing effective anti-obesity drug therapies. Since obesity is driven, in part, by excess caloric intake o palatable foods, research must focus on defining the neural circuits involved in the control of such food intake. Leptin is among the most critical anorectic signals involved in the control of energy balance, and signaling through its receptor (LepRb) in certain hindbrain, midbrain, and forebrain nuclei reduces food intake and food-motivated behaviors. Leptin receptor signaling in the nucleus tractus solitarius (NTS) of the caudal brainstem is necessary for the control of food intake, body weight, and processing of vagally-derived GI satiation signals, and recently it has also been implicated in the regulation of food-motivated and appetitive behaviors. The main goal of this proposal is to test the novel hypothesis that a population of neurons in the NTS integrates leptin and GI-derived satiation signals and projects directly to midbrain and forebrain reward- related structures that contribute to the control of food-motivated and appetitive (food-seeking) behaviors.
Specific Aim I investigates the anatomical connectivity of NTS neurons that respond to both leptin and gastric stimulation with three reward-related nuclei [ventral tegmental area (VTA), nucleus accumbens (NAc) shell, and lateral hypothalamus (LH)]. Triple immunohistochemistry for leptin-induced pSTAT3 (a well-established marker of LepRb signaling), GI-stimulation-induced cFos, and neuronal tracers (Fluorogold and Retrobeads) will be used to identify neurons that integrate these anorectic signals and project to one or more reward-related nuclei. The experiment proposed in Specific Aim II examines the hypothesis that effects of NTS leptin signaling on food intake and reward-related feeding behavior may involve changes in the transcription of energy-balance relevant genes in the VTA, NAc shell, and/or LH, and that these changes may be potentiated by GI-derived satiation signals. This experiment will utilize qPCR to examine a deductively-chosen set of genes whose protein products influence reward-related feeding and food-motivated behaviors. Research proposed in this application has the potential to deepen the understanding of the anatomical and molecular mechanisms that mediate the control of palatable food intake.

Public Health Relevance

The dramatic increase in overweight and obesity in the US is causing devastating public health issues. As increased food intake is a main cause for obesity, effective drug therapies must be developed through basic research investigating the neural control of feeding behavior. The proposed work is relevant to anti-obesity drug development as experiments are designed to elucidate the role of the hindbrain nucleus tractus solitarius (NTS) in the integration of energy-balance relevant signals and subsequent connectivity to and manipulation of reward-related brain nuclei. Understanding the details of neural circuits involved in food intake control is likely to provide new insight into mechanisms of action and potential targets for the treatment of obesity.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F06-T (20))
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He, Janet
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University of Pennsylvania
Schools of Arts and Sciences
United States
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Sarkar, Ambalika; Chachra, Parul; Kennedy, Pamela et al. (2014) Hippocampal HDAC4 contributes to postnatal fluoxetine-evoked depression-like behavior. Neuropsychopharmacology 39:2221-32
Alhadeff, Amber L; Grill, Harvey J (2014) Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding. Am J Physiol Regul Integr Comp Physiol 307:R465-70