Phasic dopamine and symptom domains of mental illness

项目摘要 大脑中的活动模式建立了感知感官信息的方式，并突出了 价位被分配。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更广泛的定义。中脑多巴胺系统发挥作用 在已知的几个离子通道内的显著和价态分配和突变中起重要作用 在神经发育中已发现多巴胺神经元调节动作电位的放电模式 这些突变对多巴胺生理、回路的影响几乎一无所知。 功能和行为。我们已经证明了不同基因的遗传失活与 精神疾病可以对多巴胺神经元的生理和表型结果产生不同的影响。 神经发育障碍，如自闭症和精神分裂症，表现为表型的马赛克 导致这些疾病光谱性质的结果。离子通道功能中断，或 通道病是疾病病因学的主要因素。在这些通道中，钾通道最为多样 它们是与通道病牵连最广的群体之一。多巴胺神经元表达一套 调节动作电位波形的电压和非电压敏感钾通道，突触 整合和神经递质释放。基于这些不同的功能，我们建议澄清 生理和表型结果与多巴胺中这些通道功能的丧失有关 神经元将提供重要的洞察，了解这些通道的破坏如何产生表型的马赛克。至 为此，我们开发了一种基于单一病毒载体的系统，用于快速诱变钾 并证明了不同通道的失活会产生两个重叠 和小鼠的非重叠表型。这里提出的实验将进一步阐明共同的和 不常见的表型结局和离子通道对不同多巴胺作用的影响 子系统。

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.