Developing tools for understanding neuromodulation of hypothalamic func

描述(由申请人提供)：下丘脑通过脑下垂体起作用，对机体适应动态平衡的挑战很重要。这些系统的功能障碍损害了健康，增加了成瘾行为，是复发的常见原因。因此，阐明分子细胞机制对于了解、预防或治疗包括药物滥用在内的各种相关疾病至关重要。下丘脑促肾上腺皮质激素释放因子(CRF)和垂体阿片黑素皮质素原(POMC)神经元在进化上在脊椎动物中是保守的。它们通过调节循环中的神经肽和糖皮质激素来控制机体对厌恶刺激的反应。然而，CRF和POMC神经元如何受到外部环境和内部神经状态的调节仍然知之甚少。涉及神经调节系统，但由于大多数神经调节系统的多效性作用，很难理解它们在CRF-POMC调节中的细胞类型和基因特异性方式的作用。多巴胺(DA)是一种经典的神经递质，最为人所知的是它在传递奖赏信号方面的作用。在包括人类、狗、大鼠、小鼠和鱼在内的各种物种中，多巴胺在下丘脑-垂体调节中也发挥着关键但知之甚少的作用。最近，我们发现多巴胺(DA)通过D1和D2受体调节斑马鱼幼体CRF-POMC的功能。这项研究将利用透明和高度可及的斑马鱼幼体系统和先进的分子遗传技术来了解多巴胺调节CRF-POMC功能的机制。本研究将揭示DA神经元如何与CRF和POMC神经元相互作用以调节其功能的新的分子和细胞机制。这些发现将为在生物体生存和福祉的背景下对这些重要神经系统的发展、功能和进化提供新的见解。同样重要的是，这项提议将建立广泛适用的工具，从基因上解剖复杂行为中的神经调节系统。

DESCRIPTION (provided by applicant): The hypothalamus acting through the pituitary is important for organismal adaptation to homeostatic challenges. Dysfunction in these systems impairs health, increases addictive behaviors and is a common cause of relapse. Elucidating the molecular cellular mechanisms is therefore critical for understanding, preventing, or treating a variety of associated disorders including substance abuse. The hypothalamic corticotrophin-releasing factor (CRF) and pituitary pro-opiomelanocortin (POMC) neurons are evolutionarily conserved across vertebrates. They control organismal responses to aversive stimuli through regulating circulating neuropeptides and glucocorticoids. However, it remains poorly understood how CRF and POMC neurons are regulated by both external environment and internal neural states. Neuromodulatory systems are involved, but because of the pleiotropic action of most neuromodulatory systems, it has been difficult to understand their role in CRF-POMC regulation in cell type- and gene-specific manners. Dopamine (DA) is a classical neurotransmitter that is best known for its role in signaling reward. Dopamine also plays a critical but poorly understood role in hypothalamic-pituitary regulation in a variety of species including humans, dogs, rats, mice, and fish. Recently, we have uncovered that dopamine (DA) regulates CRF-POMC function in larval zebrafish through both D1 and D2 receptors. This study will employ the transparent and highly accessible larval zebrafish system and advanced molecular genetic technologies to understand the mechanisms by which dopamine regulates CRF-POMC function. This study will unveil new molecular and cellular mechanisms on how DA neurons interact with CRF and POMC neurons to regulate their function. The findings will provide new insights into the development function and evolution of these important neural systems in the context of organismal survival and wellbeing. Equally importantly, this proposal will establish broadly applicable tools for genetically dissecting neuromodulatory systems in complex behaviors.