Systems-level electrophysiology for addiction and reward research

描述(申请人提供)：上瘾与大脑奖赏回路中的多巴胺传递功能障碍密切相关。尽管进行了几十年的研究，但人们对这条通路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。这个项目的广泛目标是将一种新的系统级记录方法引入成瘾和奖励大脑电路研究的武器库。这项研究将论证系统水平和分子水平神经科学相结合的可行性，使用可植入的多电极来记录细胞外单个单位的活动和调节奖赏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，辨别成瘾等奖赏相关行为中招募的通路的全网络动态一直是一项挑战。为了解决这个问题，拟议的记录仪器将在大脑的多个位置部署包含高密度电极的硅轴。其他 多电极探头技术缺乏这个项目所需的通道数量和几何形状来记录来自深层和分布区域的大量神经元。这里提出的设备将使用纳米制造方法来制造，以促进在整个小鼠大脑中插入几个包含多个电极的轴的微创。与fMRI等传统功能扫描技术不同，这种植入式设备将提供单位和亚毫秒级的分辨率。通过光基因激活中脑中的多巴胺能神经元，模仿奖励刺激的行为，将实现对该途径活动的功能控制。为了测试解决这种多巴胺能神经元扰动的系统水平活动的能力，我们将实施两种记录策略。在第一种方法中，我们将在感兴趣的解剖体积上逐步扫描二维(2D)探头，有效地构建高分辨率的动作电位活动3D地图。在第二种方法中，我们将同时监测与成瘾相关的几个大脑区域的反应，以捕捉小鼠大脑中多个分布但相互关联的中枢中多达2000个神经元的活动。从长远来看，拟议的设备和实验方案将为了解集体动态现象在大脑中的作用提供一个新的窗口。此外，这项技术将对神经生理和行为研究的许多方面产生广泛影响，包括奖赏中介学习和帕金森氏症。

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.