Investigating the role of a pallido-striatal projection in value-guided behavior

研究苍白球纹状体投射在价值引导行为中的作用

• 批准号: 10824704
• 负责人: Julia Pai
• 金额: $ 3.33万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-11-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10824704
• 关键词: Address; Anatomy; Animals; Association Learning; Axon; Basal Ganglia; Behavior; Brain; Calcium; Calcium Signaling; Cell Nucleus; Cell physiology; Cells; Characteristics; Cognitive; Complex; Corpus striatum structure; Data; Data Set; Decision Making; Dermal; Dimensions; Disease; Dopamine; Electrophysiology (science); FOXP2 gene; Fiber; Future; Globus Pallidus; Head; Health; Human; Investigation; Lasers; Learning; Link; Mediating; Methods; Monkeys; Motivation; Mus; Neurons; Neurophysiology - biologic function; Outcome; Photometry; Population; Positioning Attribute; Predictive Value; Primates; Process; Punishment; Reporting; Rest; Rewards; Rodent; Role; Signal Transduction; Source; Specificity; Subcellular Anatomy; Subgroup; Synapses; System; Testing; Training; Uncertainty; Update; Viral; Water; Weight; Work; awake; calcium indicator; cell type; combinatorial; design; experimental study; flexibility; motivated behavior; neural; nonhuman primate; novel; optogenetics

Project summary. To maximize chances of survival, animals must not only be able to effectively predict the values of future outcomes, but also to learn from erroneous predictions. The basal ganglia (BG) are crucial for both processes. Value prediction is thought to rely on striatum, where cells store value representations in their synaptic weights. Value updating is thought to rely on modulation of these striatal synapses by dopamine, since dopamine cells encode a key updating signal in the form of reward prediction errors (RPE; the difference between expected and unexpected reward outcomes). However, anatomical studies suggest that another strong yet understudied source of striatal modulation arises from the GABAergic pallidum. Pallidum is known to have a crucial role in reward-guided behaviors. A subpopulation known as `arkypallidal' cells (in contrast to `prototypical' cells comprising the rest of pallidum) project exclusively to striatum and form massive, extremely dense axonal arborizations, making this population the largest known exogenous source of striatal inhibition. Despite anatomical evidence suggesting that arkypallidal cells are well positioned to modulate striatal value representations, no study to date has directly tested if these cells carry the signals necessary for value updating. Whether and how this important input to striatum participates in value updating to support flexible behavior remains unclear. Importantly, little is known about how pallidal cells in general signal basic motivational variables such as value or prediction error, let alone their function in complex value-guided tasks. We hypothesize that within pallidum, arkypallidal cells uniquely signal prediction errors and integrate across multiple dimensions of motivational variables to support value updating and flexible behavior. In aim 1, I will explicitly test in mice whether and how arkypallidal and prototypical cells encode motivational variables including reward and punishment value, uncertainty, and prediction error in support of value updating. Preliminary data suggest that putative arkypallidal cells preferentially signal the positive component of RPE more strongly and quickly compared to putative prototypical cells. In aim 2, I will test how pallidal cells in the non-human primate (NHP) encode and integrate across reward attributes in support of multi-attribute decision-making. Pallidum is crucial for reward-seeking behaviors, but it is not clear how it signals information when subjects must choose between reward options with multiple varying attributes. Preliminary data suggest that pallidal cells encode a wide range of attributes that subjects use to guide their choices. Further preliminary analyses suggest that putative arkypallidal cells preferentially encode reward value PE, and integrate across more decision offer attributes than putative prototypical cells. Subsequent analyses will test the hypothesis that putative arkypallidal cells compute PE signals that reflect subjects' overall value estimates of options, integrated over multiple option attributes. Subsequent experiments aim to verify these results using cell type-targeted approaches to identify arkypallidal cells in monkeys performing this multi-attribute decision-making task. These aims will elucidate the role of a poorly understood yet anatomically significant pallido-striatal projection in value-guided behavior. They will also bridge functional studies of BG circuitry across species, allowing for a more generalized understanding of BG to help guide human health.

项目概要。 为了最大限度地提高生存机会，动物不仅必须能够有效地预测未来结果的价值，而且还必须能够有效地预测未来结果的价值。 还可以从错误的预测中学习。基底神经节（BG）对于这两个过程都至关重要。价值预测是 人们认为依赖于纹状体，其中细胞将值表示存储在突触权重中。价值更新被认为是 依赖于多巴胺对这些纹状体突触的调节，因为多巴胺细胞以以下形式编码关键的更新信号 奖励预测错误（RPE；预期奖励结果与意外奖励结果之间的差异）。然而， 解剖学研究表明，纹状体调节的另一个强大但尚未充分研究的来源来自 GABAergic 苍白球。众所周知，苍白球在奖励引导行为中发挥着至关重要的作用。一个被称为“arkypallidal”的亚群 细胞（与构成苍白球其余部分的“原型”细胞相反）专门投射到纹状体并形成块状， 极其密集的轴突树枝状结构，使该群体成为已知最大的纹状体抑制外源性来源。 尽管解剖学证据表明 arkypallidal 细胞处于调节纹状体值的良好位置 表示，迄今为止还没有研究直接测试这些细胞是否携带价值更新所需的信号。无论 纹状体的这一重要输入如何参与价值更新以支持灵活的行为仍不清楚。 重要的是，人们对苍白球细胞一般如何发出基本动机变量（例如价值或价值）的信号知之甚少。 预测误差，更不用说它们在复杂的价值引导任务中的功能了。我们假设在苍白球内， arkypallidal 细胞独特地发出预测错误信号，并在动机的多个维度上进行整合 变量支持值更新和灵活的行为。在目标 1 中，我将在小鼠中明确测试是否以及如何 arkypallidal 和原型细胞编码动机变量，包括奖励和惩罚值、不确定性、 和支持值更新的预测误差。初步数据表明，假定的 arkypallidal 细胞优先 与推定的原型细胞相比，RPE 的阳性成分发出的信号更强烈、更迅速。在目标2中，我会 测试非人类灵长类动物 (NHP) 中的苍白球细胞如何编码和整合奖励属性以支持 多属性决策。苍白球对于寻求奖励的行为至关重要，但尚不清楚它如何发出信号 当受试者必须在具有多种不同属性的奖励选项之间进行选择时的信息。初步数据表明 苍白球细胞编码了广泛的属性，受试者用这些属性来指导他们的选择。进一步初步分析 表明假定的 arkypallidal 细胞优先编码奖励值 PE，并整合更多决策提供 属性比假定的原型细胞。随后的分析将检验假定的 arkypallidal 细胞的假设 计算反映受试者对选项总体价值估计的 PE 信号，并综合多个选项属性。 随后的实验旨在使用针对细胞类型的方法来验证这些结果，以识别 arkypallidal 细胞 猴子执行这种多属性决策任务。这些目标将阐明一个鲜为人知的角色的作用 但在价值引导行为中具有解剖学意义的苍白球纹状体投射。他们还将架起功能研究的桥梁 跨物种的 BG 电路，可以更广泛地了解 BG，从而帮助指导人类健康。