Dopaminergic modulation of neural circuits and behavior

神经回路和行为的多巴胺能调节

• 批准号: 7088485
• 负责人: Allison Jane Doupe
• 金额: $ 26.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088485
• 关键词: basal ganglia; behavioral /social science research tag; cues; developmental psychology; dopamine; high performance liquid chromatography; inhibitor /antagonist; mesencephalon; microdialysis; motivation; muscle relaxants; neural plasticity; neural transmission; neuroendocrine system; neurotoxins; reinforcer; songbirds; tegmentum; verbal learning; vocalization

DESCRIPTION (provided by applicant): Midbrain dopamine (DA) neurons and the cortico-basal ganglia circuits they innervate are critically involved in normal motor behavior and learning, in motivation and reward, and in numerous neuropsychiatric disorders, including drug addictions and Parkinson's disease (PD). Despite the importance of DA, much about its mechanism of action remains to be discovered, in part because of the complexity both of the behaviors and of the circuits studied in many animals. Songbirds can provide a useful small animal model for providing insights into DA function, because their speech-like learned behavior, the song, is subserved by a discrete set of brain regions that include a specialized basal ganglia-cortical circuit, complete with midbrain DA inputs. This 'anterior forebrain pathway' (AFP) is critical for vocal learning and adult vocal plasticity, and like mammalian basal ganglia circuits, is modulated by context. In particular, prior work from this lab has revealed that social context potently modulates this sensorimotor circuit: males singing to females ('directed singing') show a marked decrease in the rate and variability of AFP neuronal firing and consequently in the variability of song, compared to birds singing alone ('undirected' song). This proposal hypothesizes that this social modulation of neural and song variability is a result of DA action, and that it represents a tractable example of DA's general function in gating and selecting inputs and increasing signal-to-noise in the brain in response to important external cues. This will be tested in three general ways. First, in vivo microdialysis will be used to ask whether DA is released into the AFP of male finches in response to the 'directed' social context. Then DA signaling will be disrupted in the AFP in vivo, either acutely, by infusing DA antagonists, or chronically, with a neurotoxin used in models of PD, to test whether this alters 1) the normal neurophysiological differences between directed and undirected firing in the AFP, and 2) song production. The prediction is that decreases in DA will transform the stereotyped activity and behavior in the social setting first towards the more variable undirected activity and song, and then beyond, towards abnormalities reminiscent of DA diseases. Experiments in this simple system with its highly quantifiable activity and motor output should shed general light on the function of DA in the modulation of behavior and behavioral variability, with implications both for intact animals and learning as well as for neuropsychiatric diseases.

描述（由申请人提供）：中脑多巴胺（DA）神经元及其支配的皮质基底神经节回路与正常运动行为和学习、动机和奖励以及许多神经精神疾病（包括药物成瘾和帕金森病（PD））密切相关。尽管 DA 很重要，但其作用机制仍有待发现，部分原因是在许多动物中研究的行为和回路都很复杂。鸣禽可以提供一个有用的小动物模型来深入了解 DA 功能，因为它们类似言语的学习行为（即鸣叫）受到一组离散的大脑区域的支持，这些区域包括专门的基底神经节-皮质回路，并配有中脑 DA 输入。这种“前前脑通路”（AFP）对于声音学习和成人声音可塑性至关重要，并且像哺乳动物基底神经节回路一样，受到环境的调节。特别是，该实验室之前的工作表明，社会环境有效地调节了这种感觉运动回路：与单独唱歌（“非定向”歌曲）的鸟类相比，雄性向雌性唱歌（“定向唱歌”）显示 AFP 神经元放电的速率和变异性显着下降，从而导致歌曲的变异性显着下降。该提议假设，神经和歌曲变异性的这种社会调节是 DA 作用的结果，并且它代表了 DA 在门控和选择输入以及增加大脑中的信噪比以响应重要的外部线索方面的一般功能的一个易于处理的例子。这将以三种一般方式进行测试。首先，体内微透析将用于询问 DA 是否被释放到雄性雀的 AFP 中以响应“定向”的社会环境。然后，体内 AFP 中的 DA 信号传导将被破坏，要么通过注入 DA 拮抗剂来急性破坏，要么通过 PD 模型中使用的神经毒素长期破坏，以测试这是否会改变 1) AFP 中定向和非定向放电之间的正常神经生理学差异，以及 2) 歌曲产生。据预测，DA 的减少将首先将社会环境中的刻板活动和行为转变为更加多变的无定向活动和歌曲，然后进一步转变为让人想起 DA 疾病的异常。在这个简单系统中进行的实验及其高度可量化的活动和运动输出应该能够全面阐明 DA 在行为调节和行为变异中的功能，对完整动物和学习以及神经精神疾病都有影响。