Dopaminergic modulation of neural circuits and behavior

描述（由申请人提供）：中脑多巴胺（DA）神经元及其支配的皮质-基底神经节回路在正常的运动行为和学习、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））中发挥着重要作用。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身上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，因为它们的类似语言的习得行为——唱歌，是由一组离散的大脑区域控制的，这些区域包括一个专门的基底神经节-皮层回路，以及中脑的DA输入。这种“前前脑通路”（AFP）对声乐学习和成人声乐可塑性至关重要，就像哺乳动物的基底神经节回路一样，受环境调节。特别是，该实验室之前的研究表明，社会环境可以有效地调节这种感觉运动回路：与单独鸣叫的鸟类（“无定向鸣叫”）相比，雄性向雌性鸣叫（“定向鸣叫”）的甲胎蛋白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明显降低。该建议假设，这种神经和歌曲可变性的社会调节是DA作用的结果，并且它代表了DA在门控和选择输入以及响应重要外部线索增加大脑信号噪声方面的一般功能的一个可处理的例子。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信号将被破坏，要么是通过注射DA拮抗剂急性地破坏，要么是慢性地破坏PD模型中使用的一种神经毒素，以测试这是否会改变1)AFP中定向和非定向发射之间的正常神经生理差异，以及2)歌曲产生。预测是，DA的减少将使社会环境中的刻板活动和行为首先转变为更可变的无定向活动和歌曲，然后再转变为使人联想到DA疾病的异常。在这个具有高度可量化的活动和运动输出的简单系统中进行的实验，应该会对DA在调节行为和行为变异性方面的功能有一般的了解，这对完整的动物和学习以及神经精神疾病都有影响。

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.