Combining optogenetics and electrophysiology to dissect accumbens microcircuits

描述（由申请人提供）：本提案旨在使用新开发的用于识别和控制自由移动动物中神经元的技术来测试关于动机神经组织的关键假设。适应不良的动机在一系列常见的和使人衰弱的人类疾病中起着核心作用，包括药物成瘾、强迫、抑郁和肥胖。对特定脑回路在动机子过程中的作用的准确描述将是对这些疾病理解的重大进展。损伤研究，药物操作和神经影像学都暗示了延髓核是动机信息处理的关键节点。然而，这种结构所进行的基本计算仍然不清楚。分析细胞功能的一个主要障碍是无法区分不同细胞成分的活性模式。特别是，不同的多巴胺神经元表达不同的多巴胺受体，并投射到不同的靶点。假设这些亚群具有可分离的功能角色，分别使能和抑制动机显着信号转化为行动。以前的研究中的神经编码在黑猩猩已经被迫考虑这些亚群在一起，但这个障碍现在可以克服使用电生理学和“光遗传学”技术在自由移动的小鼠的组合。 光敏阳离子通道通道视紫红质-2将选择性地在表达多巴胺D1或D2受体的神经元亚群中表达。这些细胞将使用微电极进行监测，并通过它们对激光短脉冲的反应进行区分。我们将测试这一假设，即增加发射奖励预测线索主要表达D1受体，而那些减少发射主要表达D2受体。我们还将比较D1和D2表达神经元对苯丙胺和D2拮抗剂依替氯必利的反应，以进一步研究特定多巴胺神经元的放电与精神兴奋之间的联系。 在拟议的R21期间，我们预计将完成我们的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。如果获得资助，在随后的阶段，我们将充分利用这些工具，逐步探索动机信息处理的基本机制，以及这在关键的人类疾病中是如何出错的。 公共卫生相关性：该项目旨在更好地了解动机背后的神经机制。该项目的成功可能有助于设计新的治疗方法，用于治疗以不适当或不充分的动机为特征的常见人类疾病，包括药物成瘾，抑郁症和肥胖症。

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.