Dopaminergic modulation of neural circuits and behavior

神经回路和行为的多巴胺能调节

• 批准号: 7267031
• 负责人: Allison Jane Doupe
• 金额: $ 26.18万
• 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/7267031
• 关键词: Adult; Affect; Agonist; Animal Model; Animals; Anterior; Area; Baclofen; Basal Ganglia; Behavior; Behavioral; Bilateral; Birds; Brain; Brain region; Cannulas; Cell Nucleus; Chronic; Collaborations; Corpus striatum structure; Courtship; Critical Pathways; Cues; Detection; Disease; Disruption; Dopamine; Dopamine Antagonists; Dopamine Receptor; Dose; Drug Addiction; Electrodes; Extracellular Fluid; Female; Finches; Fire - disasters; High Pressure Liquid Chromatography; Implant; Infusion procedures; Injection of therapeutic agent; Learning; Lesion; Light; Link; Measures; Microdialysis; Midbrain structure; Modeling; Motivation; Motor; Motor Activity; Motor output; Neurons; Neurotoxins; Noise; Numbers; Output; Parkinson Disease; Pathway interactions; Physiology; Play; Production; Prosencephalon; Range; Rate; Research Personnel; Rewards; Role; Sampling; Signal Transduction; Social Environment; Songbirds; Speech; Stereotyping; Structure; Substantia nigra structure; Symptoms; System; Techniques; Testing; Ventral Tegmental Area; Work; brain behavior; dopaminergic neuron; in vivo; insight; male; neural circuit; neurophysiology; neuropsychiatry; neurotransmitter release; relating to nervous system; research study; response; social; transmission process; vocal learning; zebra finch

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）神经元和他们神经支配的皮质 - 基质神经节电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，包括吸毒和帕金森氏病（PD）。尽管DA的重要性很重要，但其作用机理的许多内容仍有待发现，部分原因是许多动物中研究的行为和电路的复杂性。鸣禽可以提供一个有用的小动物模型来提供有关DA功能的见解，因为它们的语音式学习行为，歌曲，由一组离散的大脑区域提供，其中包括专门的基底神经神经化皮层电路，并配有Midbrain DA输入。这种“前脑途径”（AFP）对于声音学习和成人声音可塑性至关重要，并且像哺乳动物的基底神经节电路一样，受到环境的调节。特别是，该实验室的先前工作表明，社交环境有效调节了这种感觉运动电路：男性向女性唱歌（“指向唱歌”）表明，与单独的鸟类歌唱相比，AFP神经元射击的速度和变异性明显降低，并因此在歌曲的变化中降低了。该提议假设神经和歌曲变异性的这种社会调节是DA动作的结果，并且它代表了DA在门控和选择输入中的一般功能的典型示例，并响应重要的外部线索而在大脑中增加信号到噪声。这将通过三种一般方式进行测试。首先，将使用体内微透析来询问DA是否响应“定向”的社会背景而释放到男性雀科的AFP中。然后，通过在PD模型中使用的神经毒素注入DA拮抗剂或长期以来，将DA信号传导在体内中断，以急性地注入DA拮抗剂，以测试该神经毒素，以测试该拮抗剂。预测是，DA中的减少将首先将社交环境中的刻板印象和行为转变为更可变的无向活动和歌曲，然后再转变为异常，使人联想到DA疾病。在这个简单系统中具有高度量化活性和电动机输出的实验，应一般阐明DA在调节行为和行为变异性中的功能，对完整动物和学习以及神经精神疾病都有影响。