Investigating the role of acute AgRP neuronal manipulation on energy balance

描述（申请人提供）：大脑通过调节食物摄入和能量消耗来维持热量平衡。为了理解这是如何发生的，不仅要确定体重调节神经回路，而且要确定这些神经元是如何从解剖学和化学上连接起来的。下丘脑弓状核中的一个神经元亚群共表达NPY和AgRP，这是一种促氧肽，当注射到大脑中时可以刺激强劲的摄食。此外，NPY和AgRP mRNA水平在饥饿条件下以及瘦素信号缺乏的肥胖动物中增加，强烈暗示这些神经元参与稳态控制。尽管有这些初步的观察结果，这些基因的基因缺失对体重调节的影响很小。最近的证据表明GABA的重要作用，它是由这些神经元共同释放的。然而，根据操纵这些神经元的策略，不同的表型被分配给这些神经元，这导致了该领域的十字路口。到目前为止，还没有直接的方法来精确控制神经元功能，并测量活的、自由活动的动物的行为反应。本文提出的DREADD技术将用于空间和时间上刺激/抑制AgRP神经元，确定其在维持体重稳态中的行为作用和功能相关性。

DESCRIPTION (provided by applicant): The brain maintains caloric balance by regulating food intake and energy expenditure. To understand how this occurs, it is imperative not only to identify the body- weight regulating neural circuits, but how these neurons are connected, both anatomically and chemically. A subpopulation of neurons in the arcuate nucleus of the hypothalamus coexpress NPY and AgRP, orexigenic peptides that stimulate robust feeding when injected into the brain. Furthermore, NPY and AgRP mRNA levels increase under starvation conditions, as well as in obese animals deficient in leptin signaling, strongly implicating these neurons in homeostatic control. Despite these initial observations, genetic deletion of these genes has minimal effects on body weight regulation. Recent evidence suggests an important role for GABA, which is co-released from these neurons. However, various phenotypes have been assigned to these neurons depending on the strategy used to manipulate them, leading to a crossroads in the field. Until now, there has been no direct way to acutely control neuronal function and measure the behavioral responses in live, free-moving animals. The DREADD technology proposed here will be used to spatially and temporally stimulate/inhibit the AgRP neurons, determining their behavioral role and functional relevance in maintaining body weight homeostasis. PUBLIC HEALTH RELEVANCE: With the bleak outlook that 75% of Americans will be overweight or obese in 10 years, it is essential to find efficient means to fight this unabated epidemic. Knowledge of the powerful and complex neural systems conferring the basic drive to eat and expend energy is a prerequisite for designing effective therapies. This proposal aims to forge a more complete understanding of one of these key hypothalamic circuits regulating body weight homeostasis, the AgRP neurons of the arcuate nucleus.