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 中皮质纹状体网络是适应性奖赏过程的中心，也是 学习、动机和认知功能失调。随着学习的进行，从最初的 依赖伏核(NAC)到后来重新招募背外侧纹状体(DLS)，从而推动了一种转变 从以目标为导向的行为到以快速、刺激驱动的运动为特征的更自动的行为 序列。这种转变被认为涉及一个循环循环的网络，包括密集的多巴胺能 (Da)腹侧被盖区(VTA)/黑质(SNC)传入和皮质谷氨酸能传入。 然而，关键的是，这些环路的贡献还没有得到直接测试，并且电路机制 推动这种基本的神经生物学适应仍然是未知数。在拟议的研究中，我们将使用 几种创新的方法来研究中皮质纹状体网络内不同的环路系统 在体内交流以组织条件性行为，并从腹侧纹状体控制过渡到背侧纹状体控制， 跨越学习。一个有影响力的解剖学框架，即中纹状体“螺旋”假说，表明 在学习过程中，信息连续地穿过皮质下环路，从VTA到伏隔核，再到 SNC，至背外侧纹状体。尽管在现场得到了广泛的接受，但对纹状体螺旋的支持并没有 在活体内得到证实。相反，新出现的证据提出了另一种假说：提示-奖赏学习 通过黑质-丘脑-皮质回路进行背侧纹状体渐进性招募，而不是 经典的纹路螺旋机构。在目标1中，我们将结合体细胞DA神经元的纤维光度记录 用纹状体DA生物传感器同步记录TH-cre大鼠的活动来表征 线索-奖赏过程中纹状体DA系统四个节点信息流的时空模式 (例如，巴甫洛夫式的)学习，测试来自螺旋框架的预测。在目标2中，我们将使用跨突触 靶向、光遗传学和光度学来测试体内的上升螺旋框架，确定NAC 直接通路神经元对黑质多巴胺神经元的抑制作用减弱。我们将使用d1-cre大鼠来研究DIRECT的功能。 在学习的不同阶段，通路输出神经元在NAC和DLS。最后，在目标3中，我们将结合 多巴胺光遗传操作对皮质纹状体和丘脑纹状体环路的光度记录 在TH-cre大鼠的神经元上，评估伏核DA信号与黑质-丘脑的联系能力。 皮质环路。然后，我们将通过光遗传学操作投射到丘脑的输入定义的黑质神经元，以 确定黑质-丘脑-皮质环在学习中的功能作用。这些研究将解决 关于纹状体输入输出回路中信息流的回路机制的长期存在的问题， 为中皮质纹状体网络的体内功能架构建立一个标准化框架。