Phasic Dopamine and Symptom Domains of Mental Illness

 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突出度的方式。通过基因突变破坏这些模式可能是导致精神疾病的一个主要原因。中脑多巴胺系统在突显分配中起着至关重要的作用，已发现几个已知调节多巴胺神经元动作电位放电模式的离子通道内的突变，但这些突变对多巴胺生理、电路功能和行为的影响几乎一无所知。我们已经证明，在精神分裂症患者中发现的钙激活的小电导钾通道SK3突变改变了多巴胺神经元的活动模式调节。选择性地，在小鼠的多巴胺神经元中表达这种显性负性人类SK3突变体，使多巴胺神经元的紧张性和相性活动之间的平衡向更多的相性状态转变。由此导致的多巴胺神经元活动模式的失调会导致感觉和注意力门控过程的损害。摆在我们面前的主要挑战是，如何发现强直相多巴胺比率的变化如何影响皮层和纹状体回路，这些回路对于选通感觉信息和进一步定义受此类干扰影响的行为领域至关重要。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失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，我们将从前额叶皮质到纹状体伏隔核区域的光遗传分离输入，并使用体内光纤共聚焦显微镜和遗传编码的钙指示剂成像来确定人类SK3突变在多巴胺神经元中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依赖活动的过程，并确定紧张期到相期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。 在注意力集中任务中表现自由的小鼠的纹状体。最后，我们将使用病毒介导的电路解剖来确定大脑中依赖多巴胺的感觉和注意力门控调制所需的最小网络元素。

 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.