Scientific Report 2006

Molecular and Integrative Neurosciences

Neurobiology of Feeding and Stress

E.P. Zorrilla, L. Steardo,* K. Inoue,** A. Tabarin,*** K. Rice,**** S. Iwasaki,** A. Chen,***** E. Fekete, Y. Zhao, V. Sabino, P. Cottone, M. Brennan, M. Mattock, Y. Grant

* University of Palermo, Palermo, Italy
** Osaka City University Medical School, Osaka, Japan
> *** Université Victor Ségalen Bordeaux 2, Hôpital du Haut-Lévêque, Pessac, France
**** National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
***** Weizmann Institute of Science, Rehovot, Israel

We study motivated behavior, with emphasis on brain reward and stress neurocircuits that control food intake. Understanding food intake requires understanding how the brain organizes units of ingestive behavior, or the “feeding microstructure.” This past year we pioneered a new way to study feeding microstructure in rats; the method is based on the recognition that eating and drinking are behaviorally integrated. We developed further tools to study dynamic changes in the rate and regularity of eating within a meal. We generalized the methods so we could study control of food intake in mutant transgenic mice. Studies with these models will help define the biological bases for specific dysfunctional feeding patterns of obesity and eating disorders and target therapies for these abnormalities appropriately.

For example, we showed that type 2 urocortins produced a leptinlike facilitation of satiety, acting through hypothalamic receptors for corticotropin-releasing factor 2. Studies with female mice deficient in urocortin 2 further revealed a regulatory role for this urocortin in the expression of vasopressin in hypothalamic magnocellular neurons associated with a phenotype of altered circadian regulation of stress hormones by the hypothalamic-pituitary-adrenal axis, homeostasis of body fluids, and resistance to depressive-like behavior.

We also study ghrelin, a 28-residue stomach hormone hypothesized to signal “energy insufficiency” to the brain. Ghrelin may hinder consolidation of weight loss through its anabolic properties. In collaboration with K.D. Janda, Department of Chemistry, we found that n-octanoylation and the N-terminal third residue in the amino acid sequence of ghrelin are critical for the ability of the hormone to induce feeding. Accordingly, active immunization with haptens that included the N-terminal residues of ghrelin slowed the accrual of body weight and fat in rats in proportion to the acquired capacity of the rats’ plasma to bind ghrelin. We now are using passive immunization with transfer of antibodies (whole immunoglobulin G or single-chain variable fragments) to the acylated ghrelin N terminus (residues 1–10).

Finally, we developed models of the hedonic (rather than homeostatic) control of food intake. Rats with intermittent, limited access to highly preferred foods will eat large quantities of these foods when the foods are available, even when fed to satiation before given access to the preferred foods. Conversely, with increasing experience with palatable foods, rats will reject less palatable rat chow for 5 days or longer, despite resulting weight loss. Thus, because of hedonic factors, rats in this model violate regulators of short-term homeostasis in both positive (“binge”) and negative (“finickiness”) directions. Despite taking in less energy (calories) overall than chow-maintained rats do, the rats in the model ultimately become heavier and fatter, have elevated levels of adipokines associated with metabolic complications of obesity, and appear anxious when their preferred food is not available. Treatment with opioid receptor antagonists reduced the finickiness and bingelike eating of rats given intermittent, limited access to highly preferred foods.

Publications

Chen, A., Zorrilla, E., Smith, S., Rousso, D., Levy, C., Vaughn, J., Donaldson, C., Roberts, A., Lee, K.-F., Vale, W. Urocortin 2-deficient mice exhibit gender-specific alterations in circadian hypothalamic-pituitary-adrenal axis and depressive-like behavior. J. Neurosci. 26:5500, 2006.

Chen, S.A., O’Dell, L.E., Hoefer, M.E., Greenwell, T.N., Zorrilla, E.P., Koob, G.F. Unlimited access to heroin self-administration: independent motivational markers of opiate dependence. Neuropsychopharmacology, in press.

Funk, C.K., Zorrilla, E.P., Lee, M.-J., Rice, K.C., Koob, G.F. CRF₁ antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biol. Psychiatry, in press.

Richardson, H.N., Zorrilla, E.P., Mandyam, C.D., Rivier, C.L. Exposure to repetitive versus varied stress during prenatal development generates two distinct anxiogenic and neuroendocrine profiles in adulthood. Endocrinology 147:2506, 2006.

Tabarin, A., Chaves, Y.D., Carmona, M.C., Catargi, B., Zorrilla, E.P., Roberts, A.J., Coscina, D.V., Rousset, S., Redonnet, A., Parker, G.C., Inoue, K., Ricquier, D., Penicaud, L., Kieffer, B.L., Koob, G.F. Resistance to diet-induced obesity in μ-opioid receptor-deficient mice: evidence for a “thrifty gene.” Diabetes 54:3510, 2005.

Valdez, G.R., Zorrilla, E.P., Koob, G.F. Homeostasis within the corticotropin-releasing factor system via CRF₂ receptor activation: a novel approach for the treatment of anxiety and depression. Drug Dev. Res., in press.

Zorrilla, E.P., Koob, G.F. The roles of urocortins 1, 2 and 3 in the brain. In: Handbook of Stress and the Brain, Part 1: The Neurobiology of Stress. Steckler, T., Kalin, N.H., Reul, J.M.H.M. (Eds.). Elsevier Science, New York, 2005, p. 179. Techniques in the Behavioral and Neural Sciences; Vol. 15.