Phasic dopamine and symptom domains of mental illness

阶段性多巴胺和精神疾病的症状领域

基本信息

批准号：
10560509
负责人：
LARRY S ZWEIFEL
金额：
$ 52.84万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-04 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10560509
关键词：
Action Potentials Acute Address Affective Behavior Behavioral Biological Models Brain Cell physiology Cells Clustered Regularly Interspaced Short Palindromic Repeats Code Coupled DNA Sequence Alteration Dimensions Disease Dopamine Electrophysiology (science)Elements Etiology Gene Silencing Generations Genes Genetic Genetic Techniques Goals Human Ion Channel Lead Learning Mediating Memory Mental disorders Methodology Midbrain structure Motivation Mutagenesis Mutation Nature Neurodevelopmental Disorder Neurons Neurotransmitters Outcome Pattern Phase Phenotype Physiological Physiology Play Potassium Channel Process Property Regulation Regulatory Element Rewards Role Schizophrenia Sensory Slice Symptoms Synapses System Ventral Tegmental Area Viral Viral Vector autism spectrum disorder aversive conditioning design dopamine system dopaminergic neuron experimental study in vivo information processing insight loss of function mosaic neural circuit neural network neurotransmitter release operation optogenetics patch clamp virtual voltage

项目摘要

Project Summary Activity patterns in the brain establish the manner in which sensory information is perceived and salience and valence are assigned. Disruptions of these patterns through genetic mutations are likely a major cause of neurodevelopmental disorders and mental illness more broadly defined. The midbrain dopamine system plays an essential role in salience and valence assignment and mutations within several ion channels known to regulate action potential firing patterns by dopamine neurons have been identified in neurodevelopmental disorders, yet virtually nothing is known of the impact of these mutations on dopamine physiology, circuit function, and behavior. We have demonstrated that genetic inactivation of different genes associated with mental illness can have differential effects on dopamine neuron physiology and phenotypic outcomes. Neurodevelopmental disorders such as autism and schizophrenia are represented by a mosaic of phenotypic outcomes that gives rise to the spectral nature of these disorders. Disruption of ion channel function, or channelopathies are a major factor in disorder etiology. Of these, potassium channels are the most diverse group and are among the most broadly implicated in channelopathies. Dopamine neurons express a suite of voltage and non-voltage sensitive potassium channels that regulate the action potential waveform, synaptic integration, and neurotransmitter release. Based on these diverse functions, we propose that elucidating the physiological and phenotypic outcomes associate with a loss of function of these channels in dopamine neurons will provide important insight into how disruption of these channels yields a mosaic of phenotypes. To this end, we have developed a single viral vector-based system for the rapid mutagenesis of potassium channels in dopamine neurons and demonstrated that inactivation of different channels yields both overlapping and non-overlapping phenotypes in mice. The experiments proposed here will further elucidate common and uncommon phenotypic outcomes and the impact of ion channels on the operation of distinct dopamine subsystems.

项目概要大脑中的活动模式确定了感知信息的方式以及显着性和化合价被指定。通过基因突变破坏这些模式可能是导致神经发育障碍和精神疾病的定义更广泛。中脑多巴胺系统发挥作用在已知的几个离子通道内的显着性和价态分配以及突变中起着重要作用在神经发育中已发现多巴胺神经元调节动作电位放电模式疾病，但实际上对这些突变对多巴胺生理学、回路的影响一无所知功能和行为。我们已经证明，不同基因的遗传失活与精神疾病可能对多巴胺神经元生理学和表型结果产生不同的影响。自闭症和精神分裂症等神经发育障碍表现为马赛克表型导致这些疾病的光谱性质的结果。离子通道功能中断，或通道病是疾病病因学的主要因素。其中，钾通道最为多样化组，是与通道病相关最广泛的群体之一。多巴胺神经元表达一系列调节动作电位波形、突触的电压和非电压敏感钾通道整合和神经递质释放。基于这些不同的功能，我们建议阐明生理和表型结果与多巴胺这些通道的功能丧失相关神经元将为了解这些通道的破坏如何产生马赛克表型提供重要的见解。到为此，我们开发了一种基于单一病毒载体的系统，用于钾的快速诱变多巴胺神经元中的通道，并证明不同通道的失活会产生重叠和小鼠中不重叠的表型。这里提出的实验将进一步阐明常见的和不常见的表型结果以及离子通道对不同多巴胺运作的影响子系统。