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觉信息的方式和显著性， 价被分配。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定义更广泛。中脑多巴胺系统 在已知的几种离子通道内的显着性和价分配和突变中起重要作用， 多巴胺神经元调节动作电位放电模式已经在神经发育中被确定 疾病，但几乎没有什么是已知的影响，这些突变对多巴胺生理，电路 功能和行为。我们已经证明，与癌症相关的不同基因的遗传失活， 精神疾病可以对多巴胺神经元生理学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是由一个马赛克的表型 导致这些疾病的光谱性质的结果。离子通道功能中断，或 通道病变是疾病病因学的主要因素。其中，钾离子通道是最多样化的 组，是最广泛的牵连在通道病。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性钾通道，突触 整合和神经递质释放。基于这些不同的功能，我们建议阐明 生理和表型结果与这些通道的功能丧失有关， 神经元将提供重要的洞察这些通道的中断如何产生马赛克的表型。到 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 通道，并证明了不同通道的失活产生重叠 和非重叠表型。这里提出的实验将进一步阐明常见的和 不常见的表型结果和离子通道对不同多巴胺功能的影响 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.