Adults in the United States today are consuming ~500 kcal per day more compared to adults in 1980, a phenomenon underlying the fact that obesity prevalence in the U.S. has increased by 75% in the past 30 years. Both the size of an individual meal and the frequency of meal or snack initiation are heavily influenced by previous experience and by exposure to external food-associated stimuli (e.g., visual, olfactory) that can override biological satiation and satiety cues. Therefore, the development of effective pharmacological treatments for obesity requires a better understanding of the neurobiological systems that integrate previous experience with external and internal cues to control food intake. Novel pilot data presented in this proposal implicate the hippocampal formation (HPF), particularly its ventral subregion (HPFv), in this type of higher-order regulation of feeding behavior. HPFv neurons influence food intake, in part, by processing neuroendocrine signals that inform about energy status. Meal size, meal frequency, and overall food intake are increased when receptors for the gut-derived hormone ghrelin (GHS-1RA) are activated on HPFv neurons. On the other hand, average meal size and overall food intake are potently reduced following activation of HPFv receptors for GLP-1, a GI- and hindbrain-secreted satiation peptide. In addition to neuroendocrine signals, HPF neurons receive gastrointestinal (GI) visceral information from ascending vagus nerve-hindbrain neural pathways. Our pilot data show that HPFv neurons are activated by peripheral cholecystokinin (CCK), a satiation peptide that reduces meal size via vagus nerve signaling. Other pilot data show that subdiaphragmatic vagotomy impairs HPF-dependent spatial working memory. Collectively, these novel findings indicate that HPF neurons are impacted by various physiological cues that inform about energy status. Experiments will expand these findings using behavioral, neuroanatomical, genetic (RNA-interference), surgical, and other methodologies to determine whether, [Aim I] endogenous HPFv GHS-R1A or GLP-1R signaling increases or decreases (respectively) meal size, meal frequency, and overall energy balance, and [Aim II] whether ablated GI vagus afferent signaling negatively impacts HPF-dependent appetitive learning processes related to food procurement. Additional experiments [Aim III] utilize neuroanatomical analyses to characterize the bi- directional, multisynaptic communication between HPFv and hindbrain neurons. The functional relevance of these neural pathways to feeding behavior will be tested using newly-developed techniques for monosynaptic neural inhibition (designer receptors exclusively activated by designer drugs). Overall our approach utilizes multiple levels of analysis to explore our hypothesis that the HPF is a critical neural locus for integrating previous experience with external food cues and internal visceral cues to control higher-order aspects of feeding. Results from proposed experiments have strong potential to deepen understanding of the neurochemical and neuroanatomical systems controlling excessive feeding behavior.
Over 2/3 of adults in the USA are overweight or obese and there is currently a shortage of effective drug treatments for the excessive food intake that leads to obesity. Pharmaceutical developments for obesity treatment are aided by basic science research identifying specific brain chemical systems that reduce food intake. A novel approach is taken here; we believe that more progress can be made towards obesity treatment and reducing associated health care costs if basic research were to focus on understanding neural and biological mechanisms through learning, reward, and environmental food cues interact to cause excessive feeding and obesity.
|Reiner, David J; Leon, Rosa M; McGrath, Lauren E et al. (2018) Glucagon-Like Peptide-1 Receptor Signaling in the Lateral Dorsal Tegmental Nucleus Regulates Energy Balance. Neuropsychopharmacology 43:627-637|
|Lee, Shin J; Sanchez-Watts, Graciela; Krieger, Jean-Philippe et al. (2018) Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity. Mol Metab 11:33-46|
|López-Ferreras, L; Richard, J E; Noble, E E et al. (2018) Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight. Mol Psychiatry 23:1157-1168|
|Hsu, T M; Noble, E E; Liu, C M et al. (2018) A hippocampus to prefrontal cortex neural pathway inhibits food motivation through glucagon-like peptide-1 signaling. Mol Psychiatry 23:1555-1565|
|Woodward, N C; Haghani, A; Johnson, R G et al. (2018) Prenatal and early life exposure to air pollution induced hippocampal vascular leakage and impaired neurogenesis in association with behavioral deficits. Transl Psychiatry 8:261|
|Hsu, Ted M; Noble, Emily E; Reiner, David J et al. (2018) Hippocampus ghrelin receptor signaling promotes socially-mediated learned food preference. Neuropharmacology 131:487-496|
|Suarez, Andrea N; Hsu, Ted M; Liu, Clarissa M et al. (2018) Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Nat Commun 9:2181|
|Noble, Emily E; Hahn, Joel D; Konanur, Vaibhav R et al. (2018) Control of Feeding Behavior by Cerebral Ventricular Volume Transmission of Melanin-Concentrating Hormone. Cell Metab 28:55-68.e7|
|Liu, Clarissa M; Kanoski, Scott E (2018) Homeostatic and non-homeostatic controls of feeding behavior: Distinct vs. common neural systems. Physiol Behav 193:223-231|
|Kanoski, Scott E; Grill, Harvey J (2017) Hippocampus Contributions to Food Intake Control: Mnemonic, Neuroanatomical, and Endocrine Mechanisms. Biol Psychiatry 81:748-756|
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