Developing tools for understanding neuromodulation of hypothalamic func

描述（由申请人提供）：下丘脑通过垂体起作用，对机体适应稳态挑战很重要。这些系统的功能障碍会损害健康，增加成瘾行为，并且是复发的常见原因。因此，阐明分子细胞机制对于理解、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）和垂体促肾上腺皮质激素（POMC）神经元在脊椎动物中具有进化保守性。它们通过调节循环神经肽和糖皮质激素来控制机体对厌恶刺激的反应。然而，对于CRF和POMC神经元是如何受到外部环境和内部神经状态的调节，人们仍然知之甚少。神经调节系统参与其中，但由于大多数神经调节系统的多效性作用，很难理解它们在细胞类型和基因特异性方式中对CRF-POMC调节的作用。多巴胺（DA）是一种经典的神经递质，以其在信号奖励中的作用而闻名。多巴胺在包括人类、狗、大鼠、小鼠和鱼类在内的各种物种的下丘脑-垂体调节中也起着关键但鲜为人知的作用。最近，我们发现多巴胺（DA）通过D1和D2受体调节斑马鱼幼虫的CRF-POMC功能。本研究将利用透明且易获取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。这些发现将为这些重要的神经系统在有机体生存和健康的背景下的发育功能和进化提供新的见解。同样重要的是，这一建议将建立广泛适用的工具，遗传解剖神经调节系统的复杂行为。

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.