Functional architecture of striatal networks in cue-reward learning

提示奖励学习中纹状体网络的功能结构

• 批准号: 10586511
• 负责人: Benjamin Thomas Saunders
• 金额: $ 60.35万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586511
• 关键词: Anatomy; Animals; Architecture; Association Learning; Attention; Automobile Driving; Back; Behavior; Behavioral; Biosensor; Brain; Cells; Cognition; Communication; Complex; Consumption; Corpus striatum structure; Cues; Data; Development; Disease; Disinhibition; Dopamine; Dopaminergic Cell; Dorsal; Fiber; Glutamates; Goals; Head; Influentials; Learning; Measures; Methods; Midbrain structure; Modeling; Monitor; Motivation; Motor Cortex; Movement; Neurobiology; Neurons; Nucleus Accumbens; Output; Pathologic; Pathway interactions; Pattern; Photometry; Positioning Attribute; Process; Rat Transgene; Rattus; Recruitment Activity; Recurrence; Rewards; Role; Series; Signal Transduction; Site; Stimulus; Substantia nigra structure; Sucrose; Synapses; System; Testing; Thalamic structure; Time; Training; Transgenic Organisms; Ventral Striatum; Ventral Tegmental Area; body position; dopaminergic neuron; gamma-Aminobutyric Acid; in vivo; innovation; insight; learning engagement; learning progression; neural; neurobiological mechanism; optogenetics; recruit; sensor; transmission process

Project Summary The mesocorticostriatal network is central to adaptive reward processes, as well as diseases of dysfunctional learning, motivation, and cognition. As learning progresses, there is a transition from initial reliance on nucleus accumbens (NAC) to later recruitment of dorsolateral striatum (DLS), which drives a shift from goal-directed behavior to more automatic behaviors characterized by rapid, stimulus-driven movement sequences. This transition is thought to involve a network of recurrent loops, including dense dopaminergic (DA) input from the ventral tegmental area (VTA)/substantia nigra (SNC) and glutamatergic input from cortex. Critically, however, the contributions of these loops have not been directly tested, and the circuit mechanisms driving this fundamental neurobiological adaptation remain undefined. In the proposed studies, we will use several innovative approaches to investigate how different loop systems within the mesocorticostriatal network communicate in vivo to organize conditioned behavior, and transition from ventral to dorsal striatal control, across learning. One influential anatomical framework, the mesostriatal “spiral” hypothesis, suggests that during learning, information flows serially across a subcortical loop, from the VTA to nucleus accumbens to SNC, to dorsolateral striatum. Despite broad acceptance in the field, support for the striatal spiral has not been demonstrated in vivo. Instead, emerging evidence suggests an alternative hypothesis: that cue-reward learning engages progressive recruitment of the dorsal striatum via nigro-thalamo-cortical circuits, rather than the classic striatal spiral mechanism. In Aim 1 we will combine fiber photometry recordings of somatic DA neuron activity in TH-cre rats with simultaneous recordings of a DA biosensor in the striatum, to characterize the spatial and temporal pattern of information flow through four nodes in the striatal DA system during cue-reward (i.e., Pavlovian) learning, testing predictions from the spiral framework. In Aim 2, we will use trans-synaptic targeting, optogenetics, and photometry to test the ascending spiral framework in vivo, determining if NAC direct pathway neurons disinhibit SNC DA neurons. We will use D1-cre rats to investigate the function of direct pathway output neurons in the NAC and DLS at different stages of learning. Finally, In Aim 3 we will combine photometry recordings of corticostriatal and thalamostriatal circuits with optogenetic manipulation of DA neurons in TH-cre rats, to assess the ability of nucleus accumbens DA signaling to engage the nigro-thalamo- cortical loop. We will then optogenetically manipulate input-defined nigral neurons projecting to the thalamus to determine the functional role of the nigro-thalamo-cortical loop in learning. These studies will resolve longstanding questions about the circuit mechanisms of information flow across striatal input-output circuits, establishing a normative framework for the in vivo functional architecture of the mesocorticostriatal network.

项目摘要 中皮层纹状体网络对于自适应奖励过程和疾病至关重要 功能失调的学习，动机和认知。随着学习的进行，从初始 依赖伏隔核（NAC）后来募集背外侧纹状体（DLS），这驱动了移动 从目标指导的行为到以快速，刺激驱动的运动为特征的更自动行为 序列。人们认为这种过渡涉及一个经常性循环网络，包括密集的多巴胺能 （DA）来自腹侧对盖区域（VTA）/黑质NIGRA（SNC）的输入和皮质的谷氨酸能输入。 然而，至关重要的是，这些回路的贡献尚未直接测试，并且电路机制 驱动这种基本的神经生物学适应仍然不确定。在拟议的研究中，我们将使用 几种创新的方法来研究中皮层网络中的不同循环系统如何 在体内沟通以组织条件行为，并从腹侧纹状体对照过渡， 跨学习。一种有影响力的解剖框架，即纹状体“螺旋”假设，表明 在学习过程中，信息在皮层下环上串行流动，从VTA到伏核的核 SNC，向背外侧纹状体。尽管在该领域接受广泛接受，但对纹状体螺旋的支持尚未 在体内展示。相反，新兴的证据提出了另一种假设：提示奖励学习 通过Nigro-Thalamo-cortical电路逐步招募背纹状体 经典的纹状体螺旋机制。在AIM 1中，我们将结合体细胞DA神经元的光纤光度计记录 在Th-cre大鼠中具有简单记录DA生物传感器的活性，以表征 提示回报期间，信息流过纹状体DA系统中的四个节点的空间和临时模式 （即Pavlovian）学习，从螺旋框架中测试预测。在AIM 2中，我们将使用反式突触 靶向，光遗传学和光度法测试体内上升的螺旋框架，确定NAC是否是NAC 直接途径神经元抑制SNC DA神经元。我们将使用D1-Cre大鼠研究直接的功能 途径在不同学习阶段的NAC和DLS中输出神经元。最后，在目标3中，我们将结合 与DA的光遗传操作 Th-cre大鼠中的神经元，以评估伏隔核DA信号传导的能力 皮质环。然后，我们将在光学上操纵输入定义的nit神经元，这些神经元投射到丘脑 确定Nigro-Thalamo-cortical循环在学习中的功能作用。这些研究将解决 关于跨纹状体输入输出电路的信息流的电路机理的长期问题， 为中皮质纹状体网络的体内功能架构建立正常框架。