Distributed Neural Activity Patterns Underlying Practice-Based Learning

项目概要/摘要 为了生存，动物必须通过一种特殊的方式来学习感觉线索和运动动作之间的适当联系。 试错的过程我们希望这种学习能够加强大脑中 代表感觉线索的神经元和启动运动动作的神经元。强化的突触可能 可以是这些神经元群体之间的直接突触连接，或者经由这些神经元群体之间的中间系统， 神经元，即，一个“可塑性大脑回路”或“通路”。突触可塑性在许多不同的大脑中被观察到 区域，并且机制被适度地理解。然而，我们一直在努力确定 特别是，可塑性脑回路是通过以下方式学习的感觉线索-运动动作关联的基础： 反复试验的过程这部分是由于许多大脑区域经历了可塑性变化 在学习过程中，由于学习的经验招募了各种不同的认知过程，包括 感觉检测、运动控制、反馈、工作记忆和强化学习--认知过程 它们都涉及不同的大脑区域和分布式网络。在我的博士后期间，我开发了一种方法， 将这些认知功能分配给不同的大脑回路，以进行小鼠的试错学习。的 方法涉及一种创新的行为范式和光遗传学工具， 准确小鼠学会了将视觉皮层的光遗传学激活（线索）与前肢接触联系起来， 抓食物颗粒（运动动作）。作为我博士后工作的结果，我现在知道大脑中的哪些神经元 编码这个线索，并需要启动这个运动动作。因此我现在可以确定 可塑性的大脑回路，是这个线索和这个动作之间的习得性联系的基础。在此，我提议 研究线索编码神经元和启动运动神经元之间的大脑回路 动作，而小鼠在体内学习线索-动作关联。我会研究线索的神经活动流程- 视觉皮层中的编码神经元到上级丘中的神经元，这些神经元是启动 运动动作在目标1中，我将确定学习过程中视觉皮层线索活动的变化。在目标2中，我将 确定上级丘的活动在学习过程中的变化。在目标3中，我将确定 该通路的输出足以在学习之后触发运动动作。因此，这项工作直接谈到 大脑倡议的一个关键目标是“证明大脑活动和行为之间的因果关系”。我会学 在该技术专家Sabatini博士的指导下，对Aim 1进行了体内双光子成像。目标2 和3将在独立阶段使用体内电生理学进行， 经验丰富。这些实验将有助于确定从视觉皮层到上级的通路 储存习得的联想记忆的丘。寻找习得的感觉线索-运动的神经基础 行动协会将是必不可少的，以治疗特定的有害协会，如发生在创伤后应激障碍，强迫症， 自闭症和焦虑症，而一般不会破坏感觉或运动行为。

PROJECT SUMMARY / ABSTRACT To survive, animals must learn appropriate associations between sensory cues and motor actions through a process of trial and error. We expect that this learning will strengthen the synaptic connections between neurons representing the sensory cue and neurons initiating the motor action. The strengthened synapses may be direct synaptic connections between these neuronal populations or via systems intermediate between these neurons, i.e., a “plastic brain circuit” or “pathway.” Synaptic plasticity has been observed in many different brain areas, and the mechanisms are moderately well understood. However, we have struggled to identify which plastic brain circuit underlies, specifically, the sensory cue-to-motor action association that is learned through the process of trial and error. This is due, in part, to the fact that many brain areas undergo plastic changes during learning, as the experience of learning recruits a variety of different cognitive processes, including sensory detection, motor control, feedback, working memory and reinforcement learning -- cognitive processes that all engage different brain areas and distributed networks. During my postdoc, I developed an approach to assign these cognitive functions to different brain circuits for a case of trial and error learning in mice. The approach involved an innovative behavior paradigm and optogenetic tools that are spatially and temporally precise. Mice learned to associate the optogenetic activation of visual cortex (cue) with a forelimb reach to grab a food pellet (motor action). As a result of my postdoc work, I now know which neurons in the brain encode this cue and which are required to initiate this motor action. Therefore I am now equipped to identify the plastic brain circuit underlying the learned association between this cue and this action. Here I propose to study the brain circuit between the cue-encoding neurons and the neurons necessary to initiate the motor action, in vivo while mice learn the cue-action association. I will study the flow of neural activity from the cue- encoding neurons in the visual cortex to the neurons in the superior colliculus that are necessary to initiate the motor action. In Aim 1, I will identify changes in the cued activity in visual cortex over learning. In Aim 2, I will determine how activity in the superior colliculus changes over learning. In Aim 3, I will determine whether the output of this pathway is sufficient to trigger the motor action after learning. Hence this work speaks directly to a key goal of the Brain Initiative, to “demonstrate causal links between brain activity and behavior.” I will learn in vivo two-photon imaging for Aim 1 under the guidance of Dr. Sabatini, an expert at this technique. Aims 2 and 3 will be conducted in the independent phase using in vivo electrophysiology, a technique with which I have extensive experience. These experiments will help to identify a pathway from visual cortex to superior colliculus that stores a learned, associative memory. Finding the neural basis of learned, sensory cue-motor action associations will be essential to treat specific harmful associations, such as occur in PTSD, OCD, autism and anxiety, without generally disrupting sensory or motor behavior.