Systems-level electrophysiology for addiction and reward research

描述（申请人提供）：成瘾与大脑奖赏回路中多巴胺传递功能障碍密切相关。尽管经过几十年的研究，人们对这一途径中的系统级现象如何编码信息以及这些信息如何调节行为知之甚少。该项目的总体目标是为成瘾和奖励脑回路研究引入一种新的系统级记录方法。本研究将展示系统水平与分子水平神经科学相结合的可行性，使用可植入的多电极记录细胞外单细胞活动和介导奖励的神经元亚群的选择性激活。由于多巴胺奖赏回路的高度相互联系和几何分布的性质，辨别奖赏相关行为（如成瘾）中招募的通路的网络范围动态一直具有挑战性。为了解决这个问题，该仪器将在大脑的多个位置部署含有高密度电极的硅轴。其他

DESCRIPTION (provided by applicant): Addiction is closely linked with dysfunction of dopamine transmission in the brain circuitry of reward. Despite many decades of work, little is known about how systems-level phenomena in this pathway encode information, and how this information regulates behavior. The broad objective of this project is to introduce a new systems-level recording methodology to the arsenal of addiction and reward brain circuitry research. This study will demonstrate the feasibility of combining systems-level with molecular-level neuroscience, using implantable multi-electrodes to record extracellular single-unit activity and selective activation of neuronal subpopulations that mediate reward. Due to the highly interconnected and geometrically distributed nature of dopamine reward circuitry, it has been challenging to discern the network-wide dynamics of pathways recruited in reward-related behaviors such as addiction. To address this problem, the proposed recording instrument will deploy silicon shafts containing high-density electrodes at multiple locations in the brain. Other multi- electrode probe technologies lack the number of channels and geometry to record large numbers of neurons from deep and distributed areas required for this project. The devices proposed here will be built using nanofabrication methods to facilitate minimally invasive insertion of several multi-electrode-containing shafts throughout the mouse brain. Unlike traditional functional scanning techniques such as fMRI, the implantable devices will offer single-unit and sub-millisecond resolution. Functional control of activity in the pathway will be achieved by optogenetically activating dopaminergic neurons in the midbrain, mimicking the action of a rewarding stimulus. To test the ability to resolve systems-level activity of this dopaminergic neuron perturbation, we will implement two recording strategies. In the first approach, we will progressively scan a two-dimensional (2D) probe across an anatomical volume of interest, effectively constructing a high-resolution 3D map of action potential activity. In the second approach, we will simultaneously monitor the response of several brain areas associated with addiction, to capture the activity of up to 2,000 neurons in parallel in several distributed, but interconnected hubs in the mouse brain. In the long term the proposed devices and experimental protocols will provide a new window into the role of collective dynamic phenomena in the brain. Moreover, this technique will have broad impact on many aspects of neurophysiological and behavioral research, including reward-mediated learning and Parkinson's disease.