Neurohypophyseal regulation of midbrain dopamine systems.

中脑多巴胺系统的神经垂体调节。

• 批准号: 10176186
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176186
• 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.

大脑由神经元组成的复杂回路组成，这些神经元通过大脑产生的快速电信号进行交流。 兴奋性和抑制性神经传递的协调作用。覆盖在这个广泛的结构是一个多样化的 一组较慢的指导性化学信号传导，统称为神经调节， 快速传输和神经功能。这项提案汇集了分子遗传学工具， 操纵和询问神经调节神经元回路，成像和电生理学， 多巴胺能神经元的神经垂体调节。多巴胺是一种重要的调节剂， 脊椎动物的生活多巴胺失调，在退行性疾病中研究得最好，也与焦虑有关 和情绪障碍，以及神经发育疾病和成瘾。催产素，一种神经垂体 与社会情感和生殖行为有关激素和神经调节剂，与奖赏相互作用 系统间接，也直接调节多巴胺神经元的紧张性活动，作为我们的工作， 实验室最近证实。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调节，这两者都强调了中央 这些内源性肽在发育中的重要性，并将其确定为治疗靶点， 改善疾病状态。这项建议的目的是在我们初步数据的基础上， 了解神经垂体直接控制DA神经元功能的机制和背景。的 这一建议的主要前提是神经垂体肽在中脑中枢起作用 多巴胺能区域调节细胞活动，突触传递，以及可塑性，这 调节与性别无关，在早期发育中很重要。为了解决几个假设， 从这个前提出发，我们综合了解剖学、电生理学和行为学分析， 创新，从新的光片成像技术到启动子驱动的病毒， 多个调制系统的控制。进行拟议的实验将推进我们的概念 了解复杂的神经调节系统调节影响和奖励，它是相关的， 许多精神健康、神经发育和神经退行性疾病，其特征在于功能障碍 神经调节