Developing tools for understanding neuromodulation of hypothalamic func

开发用于理解下丘脑功能神经调节的工具

• 批准号: 9284415
• 负责人: Su Guo
• 金额: $ 33.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284415
• 关键词: Addictive Behavior; Alpha Cell; Aversive Stimulus; Axon; Behavior; Brain; Canis familiaris; Cells; Complex; Corticotropin; Corticotropin-Releasing Hormone; Data; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Engineering; Environment; Evolution; Extracellular Domain; Fertilization; Fishes; Functional disorder; Gene Activation; Gene Silencing; Genes; Glucocorticoids; Health; Human; Hydrocortisone; Hypothalamic structure; Impaired health; Impairment; Label; Laboratories; Light; Maps; Measures; Mediating; Mental Depression; Methods; Microscopy; Molecular; Molecular Genetics; Mus; Neurons; Neuropeptides; Neurophysiology - biologic function; Neurosciences Research; Neurotransmitters; Nucleic Acid Regulatory Sequences; Outcome; Phenotype; Pituitary Gland; Play; Preventive measure; Pro-Opiomelanocortin; RNA Interference; Rattus; Regulation; Relapse; Reporter; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Rhodopsin; Role; Signal Transduction; Substance abuse problem; Synapses; System; Technology; Testing; Transgenic Organisms; Transmembrane Domain; Tyrosine 3-Monooxygenase; Vertebrates; Zebrafish; addiction; cell type; dopaminergic neuron; effective therapy; genetic technology; immunoreactivity; improved; in vivo; insight; melanocyte; neuroregulation; overexpression; prevent; public health relevance; receptor; relating to nervous system; response; small hairpin RNA; spatiotemporal; stress related disorder; tool

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.

描述（由申请人提供）：下丘脑通过垂体起作用，对于生物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、预防或治疗包括物质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）和垂体前阿黑皮素（POMC）神经元在脊椎动物中是进化保守的。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，它仍然知之甚少CRF和POMC神经元是如何调节外部环境和内部神经状态。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，很难理解它们在细胞类型和基因特异性方式的CRF-POMC调节中的作用。 多巴胺（DA）是一种经典的神经递质，其在奖赏信号中的作用最为人所知。多巴胺在包括人类、狗、大鼠、小鼠和鱼类在内的多种物种的下丘脑-垂体调节中也起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受体调节斑马鱼幼鱼CRF-POMC功能。本研究将采用透明且高度可及的斑马鱼幼鱼系统和先进的分子遗传学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神经系统在生物体生存和健康背景下的发育功能和进化提供新的见解。同样重要的是，这项建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。