Neurohypophyseal regulation of midbrain dopamine systems.

中脑多巴胺系统的神经垂体调节。

基本信息

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
项目类别：
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

项目摘要

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.

大脑由复杂的神经元电路组成，这些神经元通过由神经元产生的快速电信号进行通信。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之上的是多样化的一组较慢的指导性化学信号，统称为神经调节，它严格调节快速传输和神经元功能。该提案汇集了分子遗传学工具、专业知识操纵和询问神经调节神经元回路、成像和电生理学来破译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多，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影响和生殖行为有关的激素和神经调节剂，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强直活性，正如我们的工作实验室最近证明。神经垂体肽对多巴胺信号传导的控制代表了对基本适应性行为的强大调节，这两者都强调了中央这些内源性肽在发育中的重要性，并将它们确立为治疗靶点改善疾病状态。该提案的目的是基于我们的初步数据，以便更好地了解神经垂体直接控制 DA 神经元功能的机制和背景。这该提案的主要总体前提是神经垂体肽在中脑中发挥作用多巴胺能区域调节细胞活动、突触传递以及可塑性调节与性别无关，并且在早期发育中很重要。为了解决得出的几个假设在此前提下，我们综合了解剖学、电生理学和行为分析，并结合了技术从新的光片成像技术到启动子驱动的正交病毒的创新多个调制系统的控制。进行所提出的实验将推进我们的概念了解调节情感和奖励的复杂神经调节系统，它与许多以功能障碍为特征的心理健康、神经发育和神经退行性疾病神经调节。