Circuit and neurotransmitter mechanisms underlying neural and behavioral variabil

神经和行为变异背后的电路和神经递质机制

• 批准号: 7500143
• 负责人: STEPHEN G LISBERGER
• 金额: $ 17.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500143
• 关键词: Address; Adolescent; Adult; Affect; Age; Anterior; Area; Arousal; Attention; Basal Ganglia; Behavior; Behavioral; Birds; Brain; Cell Nucleus; Cells; Condition; Cues; Development; Disease; Dopamine; Exhibits; Female; Fire - disasters; Goals; Grant; Human; Learning; Left; Life; Measures; Midbrain structure; Modeling; Motor; Motor Pathways; Nervous system structure; Neural Pathways; Neuromodulator; Neurons; Neuropharmacology; Neurophysiology - biologic function; Neurotoxins; Neurotransmitters; Norepinephrine; Outcome; Output; Pathway interactions; Pattern; Pharmacology; Production; Prosencephalon; Psychological reinforcement; Reading; Role; Signal Transduction; Social Environment; Songbirds; Source; Speech; Stereotyping; Study models; System; Testing; Thalamic structure; Travel; Vertebrates; insight; juvenile animal; motor learning; neural circuit; neuropsychiatry; relating to nervous system; research study; response; social; tool; zebra finch

In songbirds, a discrete neural circuit is devoted to the learning and production of a stereotyped vocal motor behavior, song, providing a useful model for studying brain mechanisms of behavior, with strong relevance to human speech learning. In particular, a specialized 'cortical'-basal ganglia circuit known as the anterior forebrain pathway (AFP) is crucial for song learning and plasticity throughout life. Recent evidence from our lab and others has revealed that the AFP provides a source of variability potentially important for learning to the motor circuit. In addition, we have found that the outflow nucleus of the AFP, 'LMAN', switches from bursty, highly variable firing when birds sing alone, to more reproducible firing when birds sing to a female, suggesting that social cues could be important in the control of variability. The two social states of LMAN activity are associated with high and low variability song, respectively. Here we propose to further investigate the function of AFP variability by examining and then manipulating the circuit and neurotransmitter mechanisms that give rise to it. We will record chronically from cells in the basal ganglia inputs to LMAN as well as from LMAN neurons, to study where the social context-dependent variability of firing emerges and how it travels across this circuit. We will also measure how correlated LMAN firing is across neurons, to assess how variability may be 'read out' to the motor pathways, and how it relates to behavior (Aim 1). We will then alter the levels of the neuromodulators norepinephrine (NE) and dopamine (DA) both in adults (Aim 2) and in juveniles in late sensorimotor learning (Aim 3), and examine the effects on AFP activity and on song, to test the hypothesis that these neurotransmitters regulate neural and consequently behavioral variability. The song system provides a tractable model for studying the mechanisms by which social and other environmental cues act on the nervous system and ultimately affect behavioral output, both normally and in disease. Understanding these mechanisms has the potential to provide insights into the many neuropsychiatric disorders that have their locus in cortical-basal ganglia circuits.

在鸣禽中，一个离散的神经回路专门用于学习和产生刻板印象的发声运动。 为研究行为的大脑机制提供了一个有用的模型，与 人类的语音学习。具体地说，一个被称为前额叶的特殊的‘皮质’-基底神经节回路 前脑通路(AFP)对歌曲学习和一生的可塑性至关重要。最近的证据来自我们的 Lab和其他人揭示了AFP提供了一个变异性的来源，对学习 马达电路。此外，我们还发现，AFP的流出核LMAN从 当鸟儿独自歌唱时，爆发式的、高度可变的射击，到鸟儿向雌性歌唱时更具重复性的射击， 这表明社交线索在控制变异性方面可能很重要。LMAN的两种社会状态 活动分别与高变异性和低变异性歌曲有关。在这里，我们建议进一步调查 甲胎蛋白可变性通过检测和操纵电路和神经递质的作用 产生它的机制。我们将从基底节细胞向LMAN的输入记录为 以及来自LMAN神经元的，以研究放电的社会背景相关变异性出现在哪里，以及 它是如何穿过这条赛道的。我们还将测量LMAN放电在神经元之间的相关性，以 评估变异性如何“读出”到运动通路，以及它与行为的关系(目标1)。我们 然后会改变成人神经调节剂去甲肾上腺素(NE)和多巴胺(DA)的水平(AIM 2)和感觉运动学习后期的青少年(目标3)，并检查对AFP活性和 为了验证这些神经递质调节神经并因此调节行为的假设 可变性。歌唱系统提供了一个易于处理的模型，用于研究社会和 其他环境线索作用于神经系统，并最终影响行为输出，两者都是正常的 在疾病中。了解这些机制有可能提供对许多 以皮质-基底节环路为中心的神经精神障碍。