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
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 110).
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.
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., ODell, 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.