Social and Environmental Influences on Response Inhibition

项目摘要 反应抑制指的是抑制正在进行的运动动作的能力 需要的或适当的，是行政职能的基本特征，支持灵活和 目标导向型行为。功能障碍反应抑制是多种精神疾病的核心缺陷 障碍包括注意力缺陷多动障碍(ADHD)、精神分裂症、自闭症 谱系障碍，强迫症，创伤后应激障碍，双相情感障碍 精神紊乱和吸毒成瘾。涉及的神经底物和神经调节系统 反应抑制在人类受试者和啮齿动物模型中都有很好的特征；然而， 潜在的细胞和分子机制在很大程度上是未知的。为了解决这个问题，我们 研究了一个更简单的模型系统，发现果蝇表现出 反应抑制。这是第一次在无脊椎动物身上观察到的结果，并提供了一个极好的 模型阐明抑制性控制的神经生物学基础。的首要目标是 建议的研究是为了阐明神经、细胞和分子机制 果蝇的反应抑制。初步数据表明，多巴胺是一种重要的 反应抑制的神经调节剂。具有增强的多巴胺信号或具有 缺陷的多巴胺转运体表现出异常的反应抑制。值得注意的是，这 表型是通过同时暴露于环境和社会刺激而诱导的，但不是 只有一个因素。这项拟议的研究旨在识别多巴胺受体和 神经底物(目标1)、多巴胺神经元(目标1)和细胞内信号(目标3)对 反应抑制。这将为进一步描述全面的神经网络提供基线， 细胞和分子机制。这项拟议的研究具有创新性，具有巨大的潜力 提供对神经生物学和反应抑制进化的见解，并帮助填补 我们对与多种疾病相关的功能失调的抑制控制的理解存在知识差距 精神错乱。

Project Abstract Response inhibition refers to the ability to suppress ongoing motor actions that are no longer needed or appropriate and is a fundamental feature of executive function supporting flexible and goal-oriented behaviors. Dysfunctional response inhibition is a core deficit in a variety of mental disorders including attention deficit hyperactivity disorder (ADHD), schizophrenia, autism spectrum disorders, obsessive compulsive disorder, post traumatic stress disorder, bipolar disorder and drug addiction. The neural substrates and neuromodulatory systems involved in response inhibition are well characterized in human subjects and rodent models; however, the underlying cellular and molecular mechanisms are largely unknown. To address this, we investigated a simpler model system and found that Drosophila melanogaster manifests response inhibition. This is the first observation made in invertebrates and provides an excellent model to elucidate the neurobiological basis of inhibitory control. The overarching goal of the proposed study is to elucidate the neural, cellular and molecular mechanisms underlying response inhibition in Drosophila. The preliminary data point to dopamine as an important neuromodulator for response inhibition. The flies with enhanced dopamine signaling or with deficient dopamine transporter display abnormal response inhibition. Remarkably, this phenotype is induced by simultaneous exposure to environmental and social stimuli, but not to one factor alone. The proposed research is directed at identifying the dopamine receptor and neural substrate (Aim 1), dopamine neurons (Aim 1), and intracellular signals (Aim 3) crucial for response inhibition. This will provide a baseline to further delineate comprehensive neural, cellular and molecular mechanisms. The proposed study is innovative, has great potential to provide insights into neurobiology and evolution of response inhibition and help fill the knowledge gap in our understanding of dysfunctional inhibitory control associated with diverse mental disorders.