Phasic Dopamine and Symptom Domains of Mental Illness

阶段性多巴胺和精神疾病的症状域

• 批准号: 9197337
• 负责人: LARRY S ZWEIFEL
• 金额: $ 31.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/9197337
• 关键词: Accelerometer; 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; DNA cassette; Definity; Dimensions; Disease; Dissection; Dominant-Negative Mutation; Dopamine; Dopamine D1 Receptor; Electric Stimulation; Elements; Enterobacteria phage P1 Cre recombinase; Equilibrium; Etiology; Fiber Optics; Gene Delivery; Gene Targeting; Generations; Genes; Genetic; Genetic Techniques; Goals; Human; Image; Impairment; Ion Channel; Learning; Maps; Mediating; Memory; Mental disorders; Midbrain structure; Motivation; Mus; Mutation; N-terminal; Neurons; Neurotransmitters; Nucleus Accumbens; Optics; Pathway interactions; Patients; Pattern; Phase; Physiology; Play; Potassium Channel; 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; microscopic imaging; mutant; neural circuit; optical imaging; optogenetics; public health relevance; response; selective expression; sensory gating; sensory input; virtual

 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著性的方式。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著性分配中起着至关重要的作用，并且已知通过多巴胺神经元调节动作电位放电模式的几个离子通道内的突变已经被确定，但几乎没有人知道这些突变对多巴胺生理学，电路功能和行为的影响。我们已经证明，突变的钙激活，小电导钾通道，SK3，在精神分裂症患者中发现改变多巴胺神经元活动模式的调节。这种显性负性人SK3突变体在小鼠多巴胺神经元中的选择性表达使多巴胺神经元的紧张性和阶段性活性之间的平衡向更阶段性的状态转变。多巴胺神经元活动模式的失调导致感觉和注意力门控过程的损伤。摆在面前的主要挑战是发现紧张性与相位性多巴胺比率的改变如何影响皮层和纹状体回路，这些回路对于门控感觉信息至关重要，并进一步定义受这种干扰影响的行为领域。在这里，我概述了几种创新的方法，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递送，我们将光遗传学地分离从前额叶皮层到纹状体的纹状体核区域的输入，并使用体内光纤共聚焦显微镜和遗传编码的钙指示剂的成像来定义多巴胺神经元中的人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来监测丘脑核中的活动依赖性过程，并确定紧张性到相位性多巴胺活动的改变如何影响丘脑直接和间接通路神经元的活动。 纹状体在自由行为的小鼠在注意门控任务。最后，我们将使用病毒介导的电路解剖来定义大脑中多巴胺依赖的感觉和注意门控调制所需的最小网络元素。