MULTI-OSCILLATOR SIGNALS IN CIRCADIAN ENERGY REGULATION

描述（改编自应用程序） 下丘脑腹内侧核（VMN）是昼夜节律的基础 调节能量平衡。VMN的病变产生高胰岛素血症和 进食的昼夜节律幅度显著降低， 下丘脑-垂体-肾上腺功能、体温和运动 活动这些影响的结合最终导致肥胖。 此外，这些昼夜节律可以从光的线索， 视交叉上核（SCN;主生物钟）提供食物线索 的VMN。当食物摄入量为 仅限于在光照阶段的很短时间内（大鼠是夜行性的 在黑暗时期进食）和VMN中的活动完好无损时。病变 阻止了这种节律的转变。然而，这些机制和/或 VMN对体重和昼夜节律产生影响的回路 节奏大多是未知的。本提案提出的假设是： 1)VMN放大调节神经元c-Fos节律SCN振荡输出 在已知控制能量平衡的大脑区域中;以及，2）差异 限制摄食时VMN中表达的基因参与调控 的昼夜能量平衡。假手术和SCN之间的比较 将使损伤的大鼠确定脑中的昼夜c-Fos节律 都被废除了VMN中差异表达基因的鉴定 由于VMN为 这是通过限制进食来控制昼夜节律所必需的。 抑制性消减杂交将用于分离和鉴定 VMN中差异表达的基因，这可能导致识别 用于调节昼夜节律和能量平衡的信号。畸变 能量平衡的昼夜节律调节可能与病理学有关， 肥胖、饮食和情感障碍如抑郁症。这些实验 和技术有助于长期的研究目标，以调查如何 神经系统整合昼夜节律，由几个 振荡器，这样一个系统的优点将提供，和代谢 破坏这样一个系统的后果。调查这些问题， 生理学、内分泌学和分子学的观点将有助于 将机制与功能结合起来。三年博士后培训， UCSF已经提供了强大的技术和研究技能， 积极塑造了SuJean Choi博士的研究事业发展。的 继续在UCSF和玛丽F.达尔曼 将提供一个多学科的研究方法，并提供重要的 在学术环境中从事研究事业的优势。

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.