The goal of the project is to study brainstem control of food intake. The proposed experiments make use of the chronic decerebrate rat (CD), a model developed by the PI and his colleagues to isolate caudal brainstem circuits for feeding. The experiments are organized around three specific aims. These are: 1) to explore mechanisms of short-term intake control in intact and CD rats by identifying the peripheral sources and integration of signals that control meal size; 2) to characterize the transition between short-term and long-term intake control in CD rats; and 3) to evaluate caudal brainstem mediation of monoaminergic effects on feeding by combining intraventricular infusions with decerebration. Previous work on the CD rat has tended to emphasize the similarities between this preparation and intact rats. For example, CD rats adjust meal size in response to post ingestive stimuli and show ingestive responses to insulin, CCK, and several other pharmacological agents that are similar to those of intact rats. Gastric emptying of sugar solutions and sympathoadrenal responses to 2-deoxyglucose also appear normal. The proposed experiments build on the recent observation of the PI that CD rats show deficits in response to the omission of meals. CD rats appear to respond to removal of food from the gut but not to metabolic correlates of deprivation. These findings suggest that long- term control of feeding may depend on forebrain mechanisms. This and several other hypotheses compatible with the current data will be tested. To investigate mechanisms of short-term intake, central manipulations that bias the pattern of gastric postgastric and postabsorptive feedback will be used. Comparison of the responses of intact and CD rats to pyloric occlusion, the withdrawal of gastric contents, oral and intragastric preloads, and hepatic and systemic infusions of glucose and antimetabolites such as 2 -deoxyglucose (2 DG ) and 2, 5-anhydro-D- mannitol (2AM) will be used to evaluate the hypothesis that the caudal brainstem contains the neural substrate sufficient to control meal size. By comparing recovery profiles after ingestion in intact and CD rats, the hypothesis that both intact and CD rats increase their intake potential as the g.i. tract empties but that only normal rats will increase intake in a time - dependent manner to changes in metabolic/systemic variables. The response of intact and CD rats will be compared on a range of physiological variables including gastric emptying, plasma fuels, hepatic glycogen, insulin,and glucagon. Finally, to examine the caudal brainstem mediation of monoaminergic effects on feeding, lateral and 4th ventricular infusions of quince role, and d-fenfluramine will be compared in intact rats. Systemic administration and the ventricular infusion will be compared in normal and CD rats. In addition to evaluating the relative contribution of caudal brainstem and forebrain mechanisms, these studies will address the question of whether caudal brainstem circuits are recognized in CD rats. Exaggerated responses to the drugs would be evidence of reorganization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK021397-21
Application #
2668288
Study Section
Biopsychology Study Section (BPO)
Program Officer
Yanovski, Susan Z
Project Start
1983-07-01
Project End
1999-02-28
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gerth, Ashlynn I; Alhadeff, Amber L; Grill, Harvey J et al. (2017) Regional influence of cocaine on evoked dopamine release in the nucleus accumbens core: A role for the caudal brainstem. Brain Res 1655:252-260
Kanoski, Scott E; Grill, Harvey J (2017) Hippocampus Contributions to Food Intake Control: Mnemonic, Neuroanatomical, and Endocrine Mechanisms. Biol Psychiatry 81:748-756
Ong, Zhi Yi; Liu, Jing-Jing; Pang, Zhiping P et al. (2017) Paraventricular Thalamic Control of Food Intake and Reward: Role of Glucagon-Like Peptide-1 Receptor Signaling. Neuropsychopharmacology 42:2387-2397
Alhadeff, Amber L; Holland, Ruby A; Zheng, Huiyuan et al. (2017) Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss. J Neurosci 37:362-370
Ong, Zhi Yi; Bongiorno, Diana M; Hernando, Mary Ann et al. (2017) Effects of Endogenous Oxytocin Receptor Signaling in Nucleus Tractus Solitarius on Satiation-Mediated Feeding and Thermogenic Control in Male Rats. Endocrinology 158:2826-2836
Alhadeff, Amber L; Golub, Danielle; Hayes, Matthew R et al. (2015) Peptide YY signaling in the lateral parabrachial nucleus increases food intake through the Y1 receptor. Am J Physiol Endocrinol Metab 309:E759-66
Kanoski, S E; Ong, Z Y; Fortin, S M et al. (2015) Liraglutide, leptin and their combined effects on feeding: additive intake reduction through common intracellular signalling mechanisms. Diabetes Obes Metab 17:285-93
Swick, Jennifer C; Alhadeff, Amber L; Grill, Harvey J et al. (2015) Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist-Induced Hypophagia. Neuropsychopharmacology 40:2001-14
Müller, T D; Nogueiras, R; Andermann, M L et al. (2015) Ghrelin. Mol Metab 4:437-60
Ong, Zhi Yi; Alhadeff, Amber L; Grill, Harvey J (2015) Medial nucleus tractus solitarius oxytocin receptor signaling and food intake control: the role of gastrointestinal satiation signal processing. Am J Physiol Regul Integr Comp Physiol 308:R800-6

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