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

项目总结。 为了使生存机会最大化，动物不仅必须能够有效地预测未来结果的价值，而且 也是为了从错误的预测中吸取教训。基底节(BG)对这两个过程都是至关重要的。价值预测是 被认为依赖于纹状体，在那里细胞将价值表示存储在它们的突触权重中。价值更新被认为是 依赖于多巴胺对这些纹状体突触的调制，因为多巴胺细胞以 奖励预测误差(RPE；预期和意外奖励结果之间的差异)。然而， 解剖学研究表明，纹状体调制的另一个强大而未被研究的来源来自GABA能 梅毒。众所周知，苍白球在奖赏引导行为中起着至关重要的作用。一个被称为‘arkypallidal’的亚群 细胞(与构成梅毒其余部分的典型细胞不同)专门投射到纹状体并形成块状， 非常密集的轴突分支，使这个群体成为已知的最大的纹状体抑制的外源性来源。 尽管解剖学证据表明Arkypallidal细胞处于调节纹状体价值的良好位置 然而，到目前为止，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。是否 而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，人们对苍白球细胞如何发出基本激励变量的信号知之甚少 预测误差，更不用说它们在复杂的价值导向任务中的作用了。我们假设在苍白球内， Arkypallidal细胞独特地发出预测错误的信号，并跨动机的多个维度进行整合 支持值更新和灵活行为的变量。在目标1中，我将在小鼠身上明确测试是否以及如何 阿拉伯联盟和原型细胞编码激励变量，包括奖惩价值、不确定性、 和支持值更新的预测误差。初步数据表明，假定的节育细胞优先 与假定的原型细胞相比，RPE的阳性成分信号更强、更快。在《目标2》中，我会 测试非人灵长类(NHP)中的苍白球细胞如何编码并跨奖励属性整合，以支持 多属性决策。苍白球对于寻求奖励的行为至关重要，但目前还不清楚它是如何发出信号的。 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的信息。初步数据显示 这些苍白球状细胞编码了受试者用来指导他们选择的一系列属性。进一步的初步分析 提示假设的Arkypallidal细胞优先编码奖赏价值PE，并整合更多的决策提供 比假定的原型细胞更具属性。随后的分析将检验假设的Arkypallial细胞 计算PE信号，反映受试者对期权的整体价值估计，集成在多个期权属性上。 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，以确定阿卡帕里德细胞在 猴子执行这个多属性决策任务。这些目标将阐明一个鲜为人知的 然而，在价值引导行为中，具有解剖学意义的苍白球-纹状体投影。他们还将为功能研究牵线搭桥 对不同物种的BG回路的研究，使我们能够对BG有更广泛的了解，以帮助指导人类健康。

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.