EDITORIAL FOCUS
The motivated hypothalamus

SMBD-Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2

	ARTICLE

TOP ARTICLE REFERENCES

FINAL PHYSIOLOGICAL REGULATION of eating resides in the hypothalamus. There signals from the periphery (e.g., leptin, insulin, glucose) activate and inhibit circuits that drive ingestive behavior. Thus leptin and insulin act on neurons in the arcuate nucleus. Leptin inhibits neurons that coexpress neuropeptide Y (NPY) and agouti-related peptide (AGRP) and also activates proopiomelanocortin (POMC) neurons whose transmitter is the POMC-derived -melanocyte stimulating hormone (-MSH). As expected, POMC neurons are anorexigenic (their activation reduces ingestive behaviors), whereas the NPY/AGRP neurons are orexigenic (2, 6). Most arcuate nucleus POMC neurons also express cocaine- and amphetamine-related transcript (CART). All these neurons project to other regions of the hypothalamus, including the paraventricular nucleus and, importantly, the lateral hypothalamic area, where further signal processing occurs (6). In the lateral hypothalamus are found populations of neurons expressing melanin concentrating hormone (MCH) and orexins A and B, all peptides that have been demonstrated to be orexigenic. These are pathways that respond to alterations in body energy stores (circulating glucose levels, body fat content) and are quite specific (e.g., 10).

It is an everyday observation that humans and other animals show distinct food preferences. Consumption of different foods is heavily influenced by such preferences (e.g., 9), indicating food intake can be motivated by factors, such as taste, other than body energy stores. The preferred foods are considered to provide "rewards" and to engage reward, or motivational, circuitry in the brain. Reward circuitry is localized to the limbic system and is well known to affect ingestive behavior (e.g., 3). More than two decades ago, Mogenson et al. (5) proposed that the nucleus accumbens is an important motor output site for the limbic system, a proposal that has been abundantly confirmed (e.g., 1, 8). There is direct and indirect, bidirectional communication between nucleus accumbens, in particular the shell region, and relevant regions of the hypothalamus. Inhibition of neurons in the accumbens shell by injection of the inhibitory neurotransmitter GABA results in strong activation of neurons in several areas, including the paraventricular nucleus of the hypothalamus and, particularly, the lateral hypothalamic area (4, 7).

The elegant and lucid study by Zheng et al. (11) in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology exemplifies regulatory and integrative physiology and extends the previous studies of the role of nucleus accumbens in food intake. The authors used double labeling to identify which neurons in hypothalamus exhibit altered activation state after injection of a GABA agonist (muscimol) into the accumbens shell. Activation states were assessed by c-Fos immunoreactivity, and neurons were identified by antibodies directed against specific transmitters. In the lateral hypothalamus, a higher fraction of orexin, but not MCH, neurons were double labeled after muscimol injection; in the arcuate nucleus, double labeling of CART neurons was reduced, whereas double labeling of NPY neurons was probably increased. Because muscimol injection induced Fos expression in many other hypothalamic neurons of unknown phenotype, the authors point out that this is only the first step in tracking the activation patterns that occur in response to motivated feeding.

	FOOTNOTES

Address for reprint requests and other correspondence: W. A. Cupples, SMBD-Jewish General Hospital, 3755 Cote-Ste-Catherine Rd., Montreal, Quebec, Canada H3T 1E2 (E-mail: will.cupples{at}mcgill.ca).

10.1152/ajpregu.00062.2003

	REFERENCES

TOP ARTICLE REFERENCES

1.   Baldo, BA, and Kelley AE. Amylin infusion into rat nucleus accumbens potently depresses motor activity and ingestive behavior. Am J Physiol Regul Integr Comp Physiol 281: R1232-R1242, 2001[Abstract/Free Full Text].

2.   Elmquist, JK, Elias CF, and Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22: 221-232, 1999[Web of Science][Medline].

3.   Figlewicz, DP. Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am J Physiol Regul Integr Comp Physiol 284: R882-R892, 2003[Abstract/Free Full Text].

4.   Kelley, AE. Functional specificity of ventral striatal compartments in appetitive behaviors. Ann NY Acad Sci 877: 71-90, 1999[Web of Science][Medline].

5.   Mogenson, GJ, Jones DL, and Yim CY. From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol 14: 69-97, 1980[Web of Science][Medline].

6.   Schwartz, MW, Woods SC, Porte D, Jr, Seeley RJ, and Baskin DG. Central nervous system control of food intake. Nature 404: 661-671, 2000[Medline].

7.   Stratford, TR, and Kelley AE. Evidence of a functional relationship between the nucleus accumbens shell and lateral hypothalamus subserving the control of feeding behavior. J Neurosci 19: 11040-11048, 1999[Abstract/Free Full Text].

8.   Swanson, CJ, Heath S, Stratford TR, and Kelley AE. Differential behavioral responses to dopaminergic stimulation of nucleus accumbens subregions in the rat. Pharmacol Biochem Behav 58: 933-945, 1997[Web of Science][Medline].

9.   Tordoff, MG. Obesity by choice: the powerful influence of nutrient availability on nutrient intake. Am J Physiol Regul Integr Comp Physiol 282: R1536-R1539, 2002[Abstract/Free Full Text].

10.   Zheng, H, Corkern MM, Crousillac SM, Patterson LM, Phifer CB, and Berthoud HR. Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP. Am J Physiol Regul Integr Comp Physiol 282: R1773-R1781, 2002[Abstract/Free Full Text].

11.   Zheng, H, Corkern M, Stoyanova I, Patterson LM, Tian R, and Berthoud HR. Appetite-inducing accumbens manipulation activates hypothalamic orexin neurons and inhibits POMC neurons. Am J Physiol Regul Integr Comp Physiol 284: R1436-R1444, 2003[Abstract/Free Full Text].