Role of Variability in SPA in Susceptibility to Obesity

描述（由申请人提供）：肥胖的治疗仍然有限，成功率低。目前的治疗方法并没有考虑到个体肥胖易感性的已知差异，这可能是开发成功治疗方法的关键。肥胖的易感性和严重程度与自发身体活动（SPA）的个体差异有关。我们的长期目标是为个性化肥胖治疗的发展提供生物学基础。为了做到这一点，我们将使用一种新的肥胖易感性模型，即高活性（HA）和低活性（LA）大鼠。HA大鼠比LA大鼠具有肥胖抵抗性和更高的食欲素肽信号。食欲素是SPA和能量平衡的关键调节剂。我们的总体目标是在HA/LA大鼠模型中确定食欲素参与SPA的机制及其与肥胖易感性的相关性。关于食欲素的一个长期存在的假设是它们的功能专门化，该假设提出食欲素神经元在下丘脑外侧（LH）介导奖励，而在皮层周围区（PeF）和下丘脑背内侧（DMH）的神经元介导唤醒。目的1将确定哪个食欲素神经元亚群（LH或PeF/DMH）与HA/LA表型更相关。我们将在这些区域敲除和过度表达食欲素，以测试它们对SPA的必要性或充分性。接下来，我们将重点关注通过吻侧LH （rLH）信号传导食欲素。该途径介导SPA的增加，可能是HA表型表达的关键。目的2将确定rLH食欲素信号与HA/LA大鼠肥胖易感性的相关性。我们将确定肥胖如何影响HA/LA大鼠的orexin rLH信号，以及阻断rLH的orexin反应是否会增加HA大鼠的肥胖易感性。接下来，我们将研究rLH与伏隔核壳（NAcSh）的相互作用。NAcSh与食欲素神经元相互作用，影响摄食和SPA。抑制NAcSh - gaba能输出可增加LA大鼠rLH的SPA，而HA大鼠无此作用。目的3将研究NAcSh和rLH在HA/LA表型中的相互作用。我们将确定在HA大鼠中是否存在rLH和NAcSh食欲素信号的联合作用，操作NAcSh后HA/LA大鼠的摄食反应是否不同，并确定NAcSh和rLH食欲素反应神经元之间的神经解剖学联系。这些研究将填补食欲素神经回路介导HA和LA大鼠表型差异的知识空白，这将提高我们对个体肥胖易感性的大脑机制的理解，并增强肥胖的治疗方法。

DESCRIPTION (provided by applicant): Treatments for obesity remain limited and with low success. Current therapies do not account for known differences in individual obesity susceptibility, which might be key for developing successful treatments. Susceptibility and severity to obesity are linked to individual differences in spontaneous physical activity (SPA). Our long-term goal is to provide the biological basis for development of personalized obesity therapies. To do this, we will use a novel model of differential susceptibility to obesity, the hig activity (HA) and low activity (LA) rats. HA rats are obesity resistant and higher signaling by orexin peptides than LA rats. The orexins are key modulators of SPA and energy balance. Our overall goal is to define the mechanisms underlying orexin involvement in to SPA and their relevance to obesity susceptibility in the HA/LA rat model. A long-standing hypothesis about the orexins is their functional specialization, which proposes that orexin neurons in the lateral hypothalamus (LH) mediate reward, while neurons in the perifornical area (PeF) and dorsomedial hypothalamus (DMH) mediate arousal. Aim 1 will determine which orexin neuron subpopulations (LH or PeF/DMH) are more relevant for the HA/LA phenotype. We will knock- down and over-express orexins in these areas to test their necessity or sufficiency for SPA in. Next, we will focus on orexin signaling through rostral LH (rLH). This pathway mediates increases in SPA and may be key for expression of the HA phenotype. Aim 2 will determine the relevance of rLH orexin signaling to obesity susceptibility in HA/LA rats. We will determine how obesity affects orexin rLH signaling in HA/LA rats and if blocking orexin responses in rLH increases obesity susceptibility in HA rats. Next, we will study interactions between rLH and nucleus accumbens shell (NAcSh). NAcSh interacts with orexin neurons to affect feeding and SPA. Inhibition of NAcSh GABAergic efferents increases SPA caused by orexin injection in rLH in LA, but not in HA rats. Aim 3 will study NAcSh and rLH interactions in the HA/LA phenotype. We will determine if there is a combined effect of rLH and NAcSh orexin signaling in HA rats, whether feeding responses after manipulation of NAcSh are different between HA/LA rats and define the neuroanatomical connections between NAcSh and rLH orexin-responsive neurons. These studies will fill the gap in knowledge of orexin neural circuitry in mediating phenotypic differences between HA and LA rats, which will improve our understanding of brain mechanisms underlying individual obesity susceptibility and enhance therapeutic approaches to obesity.