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Phasic Dopamine and Symptom Domains of Mental Illness

阶段性多巴胺和精神疾病的症状域

基本信息

批准号：
8883158
负责人：
LARRY S ZWEIFEL
金额：
$ 37.77万
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 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883158
关键词：
Action Potentials Address Affective Attention Behavior Behavioral Biological Assay Biological Models Biological Neural Networks Brain Calcium Confocal Microscopy Corpus striatum structure Coupled DNA Sequence Alteration Dimensions Disease Dissection Dominant-Negative Mutation Dopamine Dopamine D1 Receptor Electric Stimulation Elements Equilibrium Etiology Fiber Optics Gene Delivery Gene Targeting Generations Genes Genetic Genetic Techniques Goals Human Image Impairment Indium Ion Channel Learning Maps Mediating Memory Mental disorders Midbrain structure Monitor Motivation Mus Mutation N-terminal Neurons Neurotransmitters Nucleus Accumbens Optics Pathway interactions Patients Pattern Physiology Play Prefrontal Cortex Process Regulation Regulatory Element Research Role Schizophrenia Sensory Signal Transduction Structure Symptoms System Techniques Ventral Striatum Ventral Tegmental Area Viral Viral Vector approach behavior base behavioral response brain circuitry brain tissue calcium indicator calcium-activated potassium channel small-conductance combinatorial dopamine system dopaminergic neuron in vivo innovation mutant neural circuit optical imaging optogenetics public health relevance recombinase response selective expression sensory gating sensory input

项目摘要

DESCRIPTION (provided by applicant): Activity patterns in the brain establish the manner in which sensory information is perceived and salience is assigned. Disruptions of these patterns through genetic mutations are likely a major cause of mental illness. The midbrain dopamine system plays an essential role in salience assignment and mutations within several ion channels known to regulate action potential firing patterns by dopamine neurons have been identified, yet virtually nothing is known of the impact of these mutations on dopamine physiology, circuit function, and behavior. We have demonstrated that a mutation in the calcium activated, small conductance potassium channel, SK3, identified in a patient with schizophrenia alters dopamine neuron activity pattern regulation. Selective, expression of this dominant-negative human SK3 mutant in dopamine neurons of mice shifts balance between tonic and phasic activity of dopamine neurons towards a more phasic state. The resulting dysregulation of activity patterns in dopamine neurons leads to impairments in sensory and attention gating processes. The major challenge that lies ahead is discovering how alterations in tonic-to-phasic dopamine ratios impact cortical and striatal circuits important for gating sensory information and to further defin behavioral domains impacted by such disruptions. Here, I outline several innovate approaches that we will utilize to determine how imbalances in dopamine activity patterns impact corticostriatal connectivity and function. Utilizing combinatorial viral vector gene delivery, we wll optogentically isolate inputs from the prefrontal cortex to the nucleus accumbens region of the striatum and define how expression of the human SK3 mutation in dopamine neurons impacts the connectivity of these two structures using in vivo fiber-optic confocal microscopy and imaging of a genetically encoded calcium indicator. We will monitor activity- dependent process in the nucleus accumbens using fiber-optic confocal microscopy and define how alterations in tonic-to-phasic dopamine activity influences activity in direct and indirect pathway neurons of the striatum in freely behaving mice during an attention gating task. Finally, we will use viral-mediated circuit dissection to define the minimal network elements in the brain required for dopamine-dependent modulation of sensory and attention gating.

描述（由申请人提供）：大脑中的活动模式建立了感知感官信息和分配显着性的方式。基因突变对这些模式的破坏可能是精神疾病的主要原因。中脑多巴胺系统在显着性分配中发挥着重要作用，已知调节多巴胺神经元动作电位放电模式的多个离子通道内的突变已被识别，但实际上我们对这些突变对多巴胺生理学、回路功能和行为的影响一无所知。我们已经证明，在精神分裂症患者中发现的钙激活小电导钾通道 SK3 的突变会改变多巴胺神经元的活动模式调节。这种显性失活的人类 SK3 突变体在小鼠多巴胺神经元中的选择性表达，将多巴胺神经元的强直性和阶段性活动之间的平衡转变为更具阶段性的状态。由此产生的多巴胺神经元活动模式失调会导致感觉和注意力门控过程受损。未来的主要挑战是发现强直与相位多巴胺比率的变化如何影响皮质和纹状体回路，这些回路对于控制感觉信息很重要，并进一步定义受此类干扰影响的行为领域。在这里，我概述了几种创新方法，我们将利用这些方法来确定多巴胺活动模式的不平衡如何影响皮质纹状体的连接和功能。利用组合病毒载体基因传递，我们将光学分离从前额皮质到纹状体伏隔核区域的输入，并使用体内光纤共聚焦显微镜和基因编码的钙指示剂成像来定义多巴胺神经元中人类SK3突变的表达如何影响这两个结构的连接。我们将使用光纤共聚焦显微镜监测伏隔核中的活动依赖性过程，并定义强直到阶段性多巴胺活动的变化如何影响伏隔核直接和间接通路神经元的活动。在注意力门控任务中自由行为的小鼠的纹状体。最后，我们将使用病毒介导的回路解剖来定义大脑中多巴胺依赖性感觉和注意力门控调节所需的最小网络元件。