Autonomic Regulation of Food Intake and Metabolism

描述（由申请人提供）：需要平衡控制食物摄入和能量消耗，以保持体重在正常范围内，并避免肥胖的发展，肥胖已达到流行病的程度，并与代价高昂的次要健康问题有关。尾侧脑干中的神经回路被认为在控制食物摄入和能量平衡中起关键作用，因为它们从消化道接收信息并组织口咽和自主神经反应所需的运动模式。该建议的基本假设是，下丘脑中的其他关键回路，携带较长期的代谢和认知信息，调节主要与短期反射作用有关的尾侧脑干回路，以实现整体的稳态调节。

DESCRIPTION (provided by applicant): A balanced control of food intake and energy expenditure is required to keep body weight in the normal range and to avoid development of obesity, which has reached epidemic proportions and is associated with costly secondary health problems. Neural circuits in the caudal brainstem are thought to play a key role in the control of food intake and energy balance, as they receive information from the alimentary canal and organize the necessary motor patterns for oropharyngeal and autonomic responses. The basic assumption of this proposal is that other key circuits in the hypothalamus, carrying longer-term metabolic and cognitive information, modulate caudal brainstem circuits concerned primarily with short-term reflex action, to achieve overall homeostatic regulation. Preliminary work by us and others has shown that (1) hypothalamic neurons expressing the "feeding peptides" melanocyte-stimulating hormone (a-MSH) and to a lesser extent agouti-related protein (AgRP), project to neurons in the caudal brainstem that receive gut signals and highly express melanocortin MC4- receptors, and (2) alpha-MSH and AgRP and their stable analogs applied directly to the caudal brainstem modulate food intake and meal size, as well as electrophysiological properties and intracellular signaling in neurons of the solitary nucleus and vagal motor nucleus. Now we propose to investigate the neurophysiological mechanisms by which alpha-MSH and AgRP modulate basic brainstem processes of ingestive control. In three specific aims we will focus on (1) the effects of the two peptides on meal structure and satiety mechanisms, (2) the connectivity and neurochemistry of the descending a-MSH and AgRP projections and the recipient neurons in the dorsal vagal complex, and (3) the neurophysiological and molecular mechanisms underlying the integration of visceral vagal and hypothalamic signals leading to changes in satiation and food intake. Our multidimensional approach using state-of-the-art behavioral, anatomical, as well as in vivo and in vitro electrophysiological and molecular techniques will provide crucial information about regulation of energy balance and will help develop therapies to prevent or combat obesity.