A Novel Role for Local Striatal Interneuron Regulation of Goal-Directed Action

摘要 目标导向行为缺陷是许多神经精神疾病的标志。背内侧表盘 纹状体(DMS)已成为目标定向行为的关键中介，是 感觉运动、动机和认知信息的整合。尽管如此，细胞机制 调解这些基本行为在很大程度上仍然不清楚。我们最近发现，低谷 DMS内的阈值尖峰中间神经元(LTSI)亚型是早期目标定向动作的关键调节因子。 通过对这种细胞在行为过程中的首次活体成像，我们发现了与奖赏相关的强健 随着动物学会了工具性反应任务，这种活动被下调了。通过后续神经 电路操作，我们证明了LTSI活动的减少可以在持续的情况下推动学习 活动减慢了学习的速度。在这个提案中，我们继续这些初步的研究，以探索细胞和神经 这些效应的电路机制。我们假设，下调LTSI的监管会增强 纹状体回路的反应性，这是在早期学习期间驱动行为的关键步骤。我们建议LTSI 下调通过两种协同机制增强纹状体增益：(1)纹状体局部多巴胺增加 (2)通过减少前馈抑制，增加皮质纹状体对SPN的输入。前期工作 LTSI抑制可促进纹状体DA释放，这可能是其潜在机制 推动增强型收购。我们将测试LTSI抑制是否增强了学习过程中的纹状体DA 多巴胺神经元终末和病毒表达的多巴胺感受器的钙成像。为了更好地理解 这种调制机制，我们将采用急性切片电化学方法进行光诱发 LTSI活动操纵过程中的多巴胺释放。最后，我们将使用DA的电路目标操作 投射到DMS的神经元以测试纹状体DA释放增强是否是增强学习的中介 伴随LTSI下调。现有文献和初步数据也表明，LTSI是 参与SPN树突的前馈控制--传入神经信号整合的关键部位。 首先，我们从解剖学和电生理学两个方面描述LTSI是如何整合到关键皮质中的--以及 丘脑纹状体回路。接下来，我们使用双光子显微镜来放大SPN树突和突触的水平 脊椎，以了解LTSI如何调节这些重要间隔中的钙信号。同时，我们 探索伴随学习而来的长期突触变化。最后，我们测试了LTSI介导的增益是否 特定纹状体回路中的变化是学习能力改变的原因。完成后，这些目标将提供 我们第一次瞥见纹状体LTSI是如何开启学习之门的，提高了我们对细胞机制的理解 调节目标导向的行为。

Summary Deficits in goal-directed behavior are the hallmark of many neuropsychiatric diseases. The dorsomedial striatum (DMS) has emerged as a key mediator of goal-directed actions, serving as a critical node for integration of sensorimotor, motivational, and cognitive information. Nevertheless, the cellular mechanisms mediating these fundamental behaviors remain largely unclear. We have recently discovered that the low threshold spiking interneuron (LTSI) subtype within the DMS is a key regulator of early goal-directed actions. Performing the first in vivo imaging of this cell type during behavior, we uncovered robust reward-related activity that was down-regulated as animals learned an instrumental response task. Via subsequent neural circuit manipulations, we demonstrated that this reduction in LTSI activity could drive learning, while sustained activity slowed learning. In this proposal, we follow up these initial studies to explore the cellular and neural circuit mechanisms of these effects. We hypothesize that downregulation of LTSIs enhances the responsiveness of striatal circuits, a key step in driving behavior during early learning. We suggest LTSI downmodulation enhances striatal gain via two synergistic mechanisms: (1) increased local striatal dopamine levels and (2) enhanced corticostriatal input to SPNs via reductions in feedforward inhibition. Preliminary work demonstrates that LTSI inhibition can enhance striatal DA release, which may be an underlying mechanism driving enhanced acquisition. We will test whether LTSI inhibition enhances striatal DA during learning via calcium imaging of DA neuron terminals and virally-expressed DA sensors. To better understand the mechanism of this modulation, we will employ acute slice electrochemical measures of optically-evoked dopamine release during manipulation of LTSI activity. Finally, we will use circuit-targeted manipulations of DA neurons projecting to DMS to test whether enhanced striatal DA release is a mediator of the enhanced learning accompanying LTSI down regulation. Existing literature and preliminary data also suggest that LTSI are engaged in feed-forward control of SPN dendrites – a key site for the integration of incoming neural signals. First, we describe both anatomically and electrophysiologically, how LTSIs integrate within key cortico- and thalamostriatal circuits. Next we use 2-photon microscopy to zoom into the level of SPN dendrites and synaptic spines, to understand how LTSIs regulate calcium signaling in these important compartments. In parallel, we explore long-term synaptic changes that accompany learning. Finally, we test whether LTSI-mediated gain changes within specific striatal circuits accounts for altered learning. When completed, these aims will provide our first glimpse into how striatal LTSIs gate learning, improving our understanding of the cellular mechanisms modulating goal-directed behavior.