Dopaminergic modulation of neural circuits and behavior

描述(申请人提供)：中脑多巴胺(DA)神经元及其支配的皮质-基底神经节回路在正常运动行为和学习、动机和奖励以及包括药物成瘾和帕金森病(PD)在内的许多神经精神障碍中起着至关重要的作用。尽管DA很重要，但关于它的作用机制仍有许多有待发现，部分原因是在许多动物中研究的行为和回路的复杂性。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，即歌声，是由一组离散的大脑区域提供支持的，这些区域包括一个专门的基底节-皮质回路，以及中脑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，就像哺乳动物的基底节回路一样，受到环境的调节。特别是，这个实验室之前的工作已经揭示了社会环境对这种感觉运动回路的有效调节：与单独唱歌(非定向歌唱)相比，雄性对雌性歌唱(“定向歌唱”)显示出AFP神经元放电的速率和变异性显著降低，因此歌声的变异性也显著降低。这一建议假设，神经和歌曲变异性的这种社会调节是DA作用的结果，它代表了DA在门控和选择输入以及提高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容易处理的例子。这将通过三种一般方式进行测试。首先，体内微透析将被用来询问DA是否被释放到雄雀的AFP中，以回应“定向”的社会背景。然后，体内AFP中的DA信号将被干扰，无论是急性地，通过注入DA拮抗剂，还是长期地，与PD模型中使用的神经毒素一起，以测试这是否改变了1)AFP直接和非定向放电之间的正常神经生理学差异，以及2)歌曲的产生。预测是，DA的减少将改变社会环境中的刻板印象的活动和行为，首先转向更具变数的非定向活动和歌曲，然后超越，转向让人联想到DA疾病的异常。在这个简单的系统中进行的实验具有高度可量化的活动和运动输出，应该能大致揭示DA在调节行为和行为变异性方面的功能，这对完整的动物和学习以及神经精神疾病都有意义。

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.