MULTI-OSCILLATOR SIGNALS IN CIRCADIAN ENERGY REGULATION

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DESCRIPTION (adapted from the application) The hypothalamic ventromedial nuclei (VMN) are fundamental to the circadian regulation of energy balance. Lesions of the VMN produce hyperinsulinema and a marked reduction in the amplitudes of circadian rhythms of feeding, hypothalamic-pituitary-adrenal function, body temperature, and locomotor activity. The combination of these effects ultimately leads to obesity. Moreover, these circadian rhythms can be shifted from light cues provided by the suprachiasmatic nuclei (SCN; master biological clock) to food cues provided by the VMN. Entrainment of rhythms to food intake occurs when food intake is restricted to a very short period during the light phase (rats are nocturnal and eat during the dark period) and when activity in the VMN is intact. Lesions of the VMN prevent this shift in rhythms. However, the mechanisms and/or circuitry by which the VMN exert these effects on body weight and circadian rhythms are mostly unknown. The hypotheses presented in this proposal are that: 1) the VMN amplify SCN oscillatory outputs that regulate neuronal c-Fos rhythms in brain regions known to control energy balance; and, 2) differentially expressed genes in the VMN during restricted feeding participate in regulation of circadian energy balance by the VMN. Comparisons between sham and SCN lesioned rats will be made to determine if diurnal c-Fos rhythms in the brain are abolished. Identification of differentially expressed genes in the VMN between restrict fed and ad libitum fed rats will be made since VMN are necessary for the entrainment of circadian rhythms by restricted feeding. Suppression subtractive hybridization will be used to isolate and identify differentially expressed genes in the VMN, which may lead to identification of signals used to regulate circadian rhythms and energy balance. Aberrations in circadian regulation of energy balance may be linked to pathologies such as obesity, eating , and affective disorders such as depression. These experiments and techniques contribute to long-term research goals to investigate how the nervous system integrates circadian rhythms that are regulated by several oscillators, the advantages of such a system would provide, and the metabolic consequences of disruption of such a system. Investigating these questions from physiological, endocrinological, and molecular perspectives will help to integrate mechanisms with function. Three years of post-doctoral training at UCSF have already provided strong technical and research skills that have positively shaped the development of a research career for Dr SuJean Choi. The continuation of research at UCSF and in the laboratory of Dr. Mary F. Dallman would provide a multidisciplined approached to research and offer significant advantages for pursuing a research career in an academic setting.