Combining optogenetics and electrophysiology to dissect accumbens microcircuits

描述(申请人提供)：这项建议是为了测试一个关于动机的神经组织的关键假说，使用新开发的技术来识别和控制自由运动的动物的神经元。不适应的动机在一系列常见的和令人衰弱的人类疾病中起着核心作用，包括吸毒成瘾、强迫、抑郁和肥胖。准确描述特定大脑回路在激励子过程中的作用将是对这些障碍理解的重大进步。损伤研究、药物操作和神经成像都表明伏隔核是动机信息处理的关键节点。然而，这个结构正在进行的基本计算仍然不清楚。伏隔功能分析的一个主要障碍是无法区分不同细胞成分的活动模式。特别是，不同组的伏隔核神经元表达不同的多巴胺受体，并投射到不同的靶点。这些亚群被假设具有可分离的功能角色，分别支持和抑制动机显著信号转化为行动。以前对伏隔神经编码的研究被迫将这些亚群放在一起考虑，但现在可以通过在自由活动的小鼠身上使用电生理和光遗传技术的组合来克服这个障碍。光敏感的阳离子通道视紫红质-2将选择性地表达在表达多巴胺D1或D2受体的伏隔神经元亚群中。这些细胞将使用微电极进行监测，并通过它们对短暂激光脉冲的反应来区分。我们将检验这一假设，即伏隔核核心神经元对奖赏预测线索的放电增加主要表达D1受体，而那些减少放电的核心神经元主要表达D2受体。我们还将比较表达D1和D2的神经元对苯丙胺和D2拮抗剂乙氯必利的反应，以进一步研究特定伏隔神经元的放电与精神运动激活之间的联系。在拟议的R21期间，我们希望完成我们研究计划的第一阶段，将光遗传学工具整合到行为电生理学中，同时测试关于边缘电路组织的简单但关键的假设。如果得到资助，在随后的阶段，我们将充分利用这些工具，逐步探索激励信息处理的基本机制，以及这一机制在关键的人类疾病中是如何出错的。 公共卫生相关性：该项目旨在更好地理解动机背后的神经机制。该项目的成功可能有助于为常见的人类疾病设计新的治疗方法，这些疾病的特点是动机不适当或不足，包括药物成瘾、抑郁和肥胖。

DESCRIPTION (provided by applicant): This proposal is to test a key hypothesis about the neural organization of motivation, using newly- developed techniques for the identification and control of neurons in freely-moving animals. Maladaptive motivation plays a central role in a range of common and debilitating human disorders, including drug addictions, compulsions, depression and obesity. An accurate description of the roles of particular brain circuits in motivational subprocesses would be a major advance towards the understanding of these disorders. Lesion studies, drug manipulations and neuroimaging have all implicated the nucleus accumbens as a critical node in motivational information processing. However, the fundamental calculations being performed by this structure remain unclear. A major obstacle to the analysis of accumbens function has been the inability to distinguish the activity patterns of distinct cellular components. In particular, separate sets of accumbens neurons express distinct dopamine receptors, and project to distinct targets. These subpopulations are hypothesized to have dissociable functional roles, respectively enabling and suppressing the translation of motivationally salient signals into action. Prior investigations of neural coding in accumbens have been forced to consider these subpopulations together, but this obstacle can now be overcome using a combination of electrophysiological and "optogenetic" techniques in freely moving mice. The light-sensitive cation channel channelrhodopsin-2 will be selectively expressed in subpopulations of accumbens neurons that express either dopamine D1, or D2, receptors. These cells will be monitored using microelectrodes, and distinguished via their response to brief pulses of laser light. We will test the hypothesis that accumbens core neurons that increase firing to reward-predictive cues predominantly express D1 receptors, while those that decrease firing predominantly express D2 receptors. We will also compare the response of D1- and D2- expressing neurons to amphetamine and to the D2 antagonist eticlopride, to further examine the connection between the firing of specific accumbens neurons and psychomotor activation. In the proposed R21 period we expect to complete the first phase of our research program integrating optogenetics tools into behavioral electrophysiology, while testing simple yet critical hypotheses about the organization of limbic circuits. If funded, in subsequent phases we would make full use of these tools to progressively explore fundamental mechanisms of motivational information processing, and how this goes awry in key human disorders. PUBLIC HEALTH RELEVANCE: This project aims for a better understanding of the neural mechanisms underlying motivation. Success in this project may assist the design of novel therapies for common human disorders that are characterized by inappropriate or inadequate motivation, including drug addiction, depression and obesity.