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量和能量消耗来维持热量平衡。要了解这是如何发生的，不仅要确定体重调节神经回路，而且要从解剖学和化学角度确定这些神经元是如何连接的。下丘脑弓状核中的神经元亚群共同表达NPY和AgRP，当注射到大脑中时，这两种促食欲素能刺激强劲的摄食。此外，NPY和AgRP mRNA水平在饥饿条件下增加，以及在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体内平衡控制。尽管有这些初步观察，这些基因的基因缺失对体重调节的影响微乎其微。最近的证据表明，由这些神经元共同释放的GABA扮演着重要的角色。然而，根据操纵这些神经元的策略，这些神经元被分配了不同的表型，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地控制神经元功能，并测量活的、自由活动的动物的行为反应。本文提出的DREADD技术将被用来在空间和时间上刺激/抑制AgRP神经元，确定它们在维持体重动态平衡中的行为作用和功能相关性。 与公共卫生相关：由于前景黯淡，75%的美国人将在10年内超重或肥胖，找到有效的方法来抗击这一有增无减的流行病是至关重要的。对强大而复杂的神经系统的了解是设计有效疗法的先决条件，这些神经系统赋予了人们进食和消耗能量的基本动力。这项提议旨在对调节体重稳态的关键下丘脑回路之一--弓状核的AgRP神经元--形成更完整的理解。

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.