Mechanisms for internally and externally guided sensorimotor learning

腹侧被盖区(VTA)的神经元在运动学习和神经系统疾病中起着关键作用。 影响VTA神经元或其靶点的基底神经节(BG)严重扰乱行为。值得注意的是，有很多 我们对VTA如何在运动学习中发挥作用的理解依赖于使用 外部奖励或惩罚，涉及相对缓慢和简单的行为，如按杠杆或 在舔。相比之下，我们的许多最复杂和最有价值的行为，如演讲和音乐 表达，可以在没有外部强化的情况下学习，这表明他们的学习是内部的 加强了。此外，内部强化的行为，如演讲或音乐能力，需要高度复杂 和快速运动序列，在青少年敏感期更容易获得。VTA如何 与BG相互作用，调节复杂形式的内部和外部强化的听觉运动 学习仍然是未知的。在这里，我们建议确定VTA和BG如何相互作用来调解不同的 使用一种新的交叉遗传方法组合的听觉-运动学习形式选择性地 消融VTA神经元、微透析、钙成像和VTA终末和BG的光遗传操作 神经元与快速和时间上精确的行为操作相结合。这些方法将是 用来测试这样的假设，即VTA作为评估听觉反馈和 指导性地改变BG运动前活动，进而驱动内部和外部强化的听觉- 运动学习。解决VTA-BG电路如何调节这些形式的学习是 了解运动可塑性在健康和疾病中的作用。事实上，言语病理是各种疾病的典型代表。 这会影响VTA-BG电路，而破坏BG中多巴胺介导的信号的突变也会损害 声乐学习。因此，这项拟议的研究可以阐明 实现复杂的内部和外部强化行为学习，同时揭示功能障碍 在这些回路中干扰了交流行为的学习和执行。

Neurons in the ventral tegmental area (VTA) play a key role in motor learning, and neurological diseases that affect VTA neurons or their targets in the basal ganglia (BG) severely disrupt behavior. Notably, much of our understanding of how the VTA functions in motor learning has relied on paradigms that employ external reward or punishment and involve relatively slow and simple behaviors, such as lever pressing or licking. In contrast, many of our most complex and valued behaviors, such as speech and musical expression, can be learned without external reinforcement, suggesting that their learning is internally reinforced. Further, internally reinforced behaviors such as speech or musicianship require highly complex and rapid motor sequences and are more readily acquired during juvenile sensitive periods. How the VTA interacts with the BG to mediate complex forms of internally and externally reinforced auditory-motor learning remains unknown. Here we propose to identify how the VTA and BG interact to mediate different forms of auditory-motor learning using a novel combination of intersectional genetic methods to selectively ablate VTA neurons, microdialysis, calcium imaging and optogenetic manipulation of VTA terminals and BG neurons combined with rapid and temporally precise behavioral manipulations. These approaches will be used to test the hypothesis that the VTA functions as a “critic” that evaluates auditory feedback and instructively modifies BG premotor activity, which in turn drives internally and externally reinforced auditory- motor learning. Resolving how VTA-BG circuits mediate these forms of learning are critical issues for understanding motor plasticity in health and disease. In fact, speech pathologies typify various diseases that affect VTA-BG circuitry, while mutations that disrupt dopamine-mediated signaling in the BG also impair vocal learning. Therefore, the proposed research can shed light on the neural circuit mechanisms that enable complex internally and externally reinforced behavioral learning while also revealing how dysfunction in these circuits interferes with the learning and execution of communicative behaviors.