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.

项目摘要。 为了最大化生存机会，动物不仅必须有效地预测未来结果的价值，而且还必须 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 被认为依靠纹状体，细胞在其突触权重中存储价值表示。价值更新被认为 依赖于多巴胺对这些纹状体突触的调制，因为多巴胺细胞在形式中编码一个键更新信号 奖励预测错误（RPE；预期和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而研究的来源是由GABA能引起的 Pallidum。众所周知，Pallidum在奖励指导的行为中起着至关重要的作用。一个被称为“ arkypallidal”的亚群 细胞（与构成pallidum其余的典型的细胞相比 极度致密的轴突抗化，使该人群成为最大的已知外源性纹状体抑制来源。 尽管解剖学证据表明Arkypallidal细胞在调节纹状体值方面有好处 表示迄今为止，没有直接测试这些单元格是否携带价值更新所需的信号。无论 纹状体的重要输入如何参与价值更新以支持灵活行为尚不清楚。 重要的是，关于一般信号中的苍白细胞如何基本动机变量（例如值或 预测错误，更不用说它们在复杂的价值指导任务中的功能了。我们假设这是在Pallidum中 arkypallidal细胞独特地信号预测误差并在激励的多个维度上整合 支持价值更新和灵活行为的变量。在AIM 1中，我将在小鼠中明确测试是否以及如何 arkypallidal和典型细胞编码动机变量，包括奖励和惩罚价值，不确定性， 和支持价值更新的预测错误。初步数据表明，推定的arkypallidal细胞优先 与假定的原型细胞相比，更强烈，更快地向RPE的正分量发出信号。在AIM 2中，我会 测试非人类灵长类动物（NHP）中的苍白细胞如何编码并跨奖励属性集成以支持 多属性决策。 Pallidum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个不同属性的奖励选项之间进行选择时，信息。初步数据建议 苍白的细胞编码了受试者用来指导其选择的广泛属性。进一步的初步分析 建议推定的arkypallidal细胞优先编码奖励价值PE，并在更多决策报价中整合 属性比推定的原型细胞。随后的分析将检验假定的arkypallidal细胞的假设 计算反映受试者选项的总体价值估计值的PE信号，该值在多个选项属性上集成。 随后的实验旨在使用靶向细胞类型的方法来验证这些结果，以鉴定在 猴子执行这项多属性决策任务。这些目标将阐明知情人士的作用 然而，在价值引导的行为中，解剖学上显着的苍白 - 纹状体投影。他们还将桥接功能研究 BG跨物种的电路，从而使对BG有更广泛的了解来帮助指导人类健康。