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

项目摘要。 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， 从错误的预测中学习。基底神经节（BG）对这两个过程都至关重要。价值预测是 据认为依赖于纹状体，在那里细胞在它们的突触权重中存储值表示。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，因为多巴胺细胞编码一种关键的更新信号， 奖励预测错误（RPE，即预期和意外奖励结果之间的差异）。然而，在这方面， 解剖学研究表明，纹状体调制的另一个强有力但未充分研究的来源来自GABA能 苍白球Pallidum在奖励导向行为中起着至关重要的作用。一个被称为“arkypallidal”的亚种群 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， 非常密集的轴突分支，使这一人口的最大已知的外源性来源的纹状体抑制。 尽管解剖学证据表明隐球细胞处于调节纹状体价值的良好位置， 虽然这些细胞具有代表性，但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。是否 纹状体的这一重要输入如何参与价值更新以支持灵活行为仍不清楚。 重要的是，人们对苍白球细胞如何发出基本的激励变量信号知之甚少，如价值或 预测错误，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， 隐球细胞独特地发出预测错误的信号，并整合动机的多个维度。 变量来支持值更新和灵活的行为。在目标1中，我将明确地在小鼠中测试是否以及如何 原型细胞编码激励变量，包括奖励和惩罚值，不确定性， 以及支持值更新的预测误差。初步的数据表明，假定的arkypallidal细胞优先 与假定的原型细胞相比，更强和更快地发出RPE阳性成分的信号。在目标2中，我将 测试非人类灵长类动物（NHP）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Pallidum对奖赏寻求行为至关重要，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，初步数据表明 苍白球细胞编码了一系列属性，受试者用这些属性来指导他们的选择。进一步的初步分析 这表明假定隐球细胞优先编码奖励值PE，并整合更多的决策提供 比假定的原型细胞的属性。随后的分析将检验假定的隐珠细胞 计算反映受试者对多个选项属性的整体价值估计的PE信号。 随后的实验旨在使用细胞类型靶向方法来验证这些结果，以在细胞中鉴定arkypallidal细胞。 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 但在价值导向行为中具有解剖学意义的苍白球-纹状体投射。他们还将桥梁功能研究 跨物种的BG电路，允许对BG的更普遍的理解，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.