Neurohypophyseal regulation of midbrain dopamine systems.

中脑多巴胺系统的神经垂体调节。

• 批准号: 10412959
• 负责人: YEVGENIA KOZOROVITSKIY
• 金额: $ 39.5万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-13 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412959
• 关键词: Adaptive Behaviors; Address; Affect; Amines; Anatomy; Anxiety; Anxiety Disorders; Basal Ganglia; Basic Science; Behavior; Behavioral; Behavioral Assay; Biological; Brain; Cells; Chemicals; Clinical; Complex; Data; Degenerative Disorder; Development; Diffuse; Discipline of Nursing; Disease; Dopamine; Electrophysiology (science); Endocannabinoids; Female; Fiber; Future; G-Protein-Coupled Receptors; Goals; Health; Human; Hypothalamic structure; Image; Imaging technology; In Situ Hybridization; Instruction; Knowledge; Laboratories; Learning; Life; Light; Mental Depression; Mental Health; Microscopy; Midbrain structure; Modeling; Molecular; Molecular Genetics; Mood Disorders; Motor; Neonatal; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuromodulator; Neurons; Neurosciences; Newborn Infant; Optics; Oxytocin; Oxytocin Receptor; Pattern; Peptides; Perinatal; Pharmacogenetics; Physiology; Pilot Projects; Posterior Pituitary Hormones; Receptor Activation; Regulation; Reproductive Behavior; Research; Rewards; Signal Transduction; Structure; Substantia nigra structure; Synapses; Synaptic Transmission; System; Techniques; Therapeutic; Tissues; Vasopressins; Ventral Tegmental Area; Vertebrates; Viral; Virus; Work; Workplace; addiction; autism spectrum disorder; base; dopamine system; dopaminergic neuron; experimental study; genetic manipulation; imaging modality; information processing; innovation; male; neural circuit; neuronal circuitry; neuroregulation; neurotransmission; optogenetics; paraventricular nucleus; pars compacta; peptide hormone; postnatal; promoter; receptor; response; sex; social; therapeutic target; tool; transmission process

The brain is composed of intricate circuits of neurons communicating via fast electrical signals created by the coordinated actions of excitatory and inhibitory neurotransmission. Overlaid on this broad structure is a diverse set of slower instructive chemical signaling, referred to collectively as neuromodulation, which critically regulate fast transmission and neuronal function. This proposal brings together molecular-genetic tools, expertise in manipulating and interrogating neuromodulatory neuronal circuits, imaging and electrophysiology to decipher neurohypophyseal regulation of dopaminergic neurons. Dopamine is an essential modulator, required for vertebrate life. Dopamine dysregulation, best studied in degenerative disease, is also associated with anxiety and mood disorders, as well as neurodevelopmental diseases and addiction. Oxytocin, a neurohypophyseal hormone and neuromodulator implicated in social affect and reproductive behaviors, interacts with reward systems indirectly, and also by directly regulating the tonic activity of dopamine neurons, as work from our laboratory has recently demonstrated. The control of dopamine signaling by neurohypophyseal peptides represents a powerful regulation of essential adaptive behaviors, which both emphasizes the central importance of these endogenous peptides in development and establishes them as therapeutic targets for ameliorating disease states. The objective for this proposal is to build on our preliminary data in order to better understand the mechanisms and context of direct neurohypophyseal control over DA neuron function. The major overall premise of this proposal is that neurohypophyseal peptides act centrally in midbrain dopaminergic regions regulating cellular activity, synaptic transmission, as well as plasticity, and that this regulation is sex-independent and important in early development. To address several hypotheses deriving from this premise, we synthesize anatomical, electrophysiological, and behavioral assays, with technical innovations ranging from new light-sheet imaging technologies to promoter-driven viruses for orthogonal control of multiple modulatory systems. Carrying out the proposed experiments would advance our conceptual understanding of the complex neuromodulatory systems regulating affect and reward, and it is relevant to numerous mental health, neurodevelopmental and neurodegenerative disorders characterized by dysfunctional neuromodulation.

大脑由错综复杂的神经元电路组成，这些神经元通过快速电信号进行交流，这些电信号是由 兴奋性和抑制性神经传递的协调作用。覆盖在这个宽阔的结构上的是一个多样化的 一组较慢的指导性化学信号，统称为神经调节，它关键地调节 传输速度快，神经功能强。这项提议将分子遗传学工具、专业知识 操纵和询问神经调制神经元电路、成像和电生理学以破译 神经垂体对多巴胺能神经元的调节。多巴胺是一种重要的调节剂，需要 脊椎动物的生活。多巴胺失调是对退行性疾病最好的研究，也与焦虑有关。 以及情绪障碍，以及神经发育疾病和成瘾。催产素，一种神经垂体素 荷尔蒙和神经调节剂与社会情感和生殖行为有关，与奖励相互作用 系统间接地，也通过直接调节多巴胺神经元的紧张性活动，正如我们的工作 实验室最近展示了。神经垂体肽对多巴胺信号的调控 代表了对基本适应行为的强大规则，这既强调了中央 这些内源性多肽在发育中的重要性，并将它们确立为治疗的靶点 改善疾病状态。这项建议的目标是以我们的初步数据为基础，以便更好地 了解神经垂体对DA神经元功能的直接控制的机制和背景。这个 这一提议的主要总体前提是神经垂体肽在中脑起中枢作用 调节细胞活动、突触传递以及可塑性的多巴胺能区，而这 监管是不分性别的，在早期发育阶段很重要。为了解决几个假设， 从这一前提出发，我们综合了解剖学、电生理学和行为分析，以及技术 从新的光片成像技术到启动子驱动的病毒等创新 多路调制系统的控制。实施拟议的实验将推进我们的概念 了解调节情绪和奖赏的复杂神经调节系统，它与 以功能障碍为特征的许多精神健康、神经发育和神经退行性疾病 神经调节。