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。尽管多巴胺的重要性，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电路都很复杂。鸣禽可以提供一个有用的小动物模型，以提供对DA功能的见解，因为它们的语音学习行为，歌曲，是由一组离散的大脑区域，包括一个专门的基底神经节-皮层电路，完成中脑DA输入。这种“前脑前通路”（AFP）对发声学习和成人发声可塑性至关重要，并且像哺乳动物基底神经节回路一样，受环境调节。特别是，以前的工作从这个实验室已经揭示，社会背景有力地调节这种感觉运动回路：男性唱歌给女性（“定向唱歌”）显示出显着下降的速度和变化的AFP神经元放电，因此在歌曲的变化，相比鸟类单独唱歌（“无定向”歌曲）。这个建议假设，这种社会调制的神经和歌曲的可变性是一个结果的DA行动，它代表了一个听话的例子DA的一般功能，在门控和选择输入和增加信号噪声在大脑中响应重要的外部线索。这将在三个一般的方式进行测试。首先，在体内微透析将被用来询问是否DA被释放到AFP的雄性雀在响应“定向”的社会背景。然后，通过输注DA拮抗剂急性地或用PD模型中使用的神经毒素慢性地破坏体内AFP中的DA信号传导，以测试这是否改变1）AFP中定向和非定向放电之间的正常神经生理学差异，和2）歌曲产生。预测是，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多变的无定向活动和歌曲，然后再转变为让人联想到DA疾病的异常。实验在这个简单的系统，其高度可量化的活动和运动输出应该揭示一般的功能DA的调制行为和行为变异性，与完整的动物和学习以及神经精神疾病的影响。