Cerebellar Modulation of Innate Defensive Behaviors

天生的防御行为通过让动物探测到环境中的威胁并做出反应来促进生存，比如捕食者。虽然是天生的，但这些防御行为表现出显著的灵活性，并受到强大的习惯化的影响，这表明防御行为背后的回路受到调节控制。我们最近的工作表明，小脑可能提供了输水管周围灰质内传入调节影响的一个来源。我们发现，小脑向腹侧导水管周围灰质（vlPAG）的冷冻相关回路的传入主要激活局部多巴胺能中间神经元，这随后改变了突触诱发的对冷冻前运动神经元的抑制和兴奋的相对强度。更具体地说，小脑的激活增加了IPSC的振幅，降低了EPSC的振幅，这被预测会增加尖峰阈值，改变输入输出关系，改变冻结前运动神经元的整合特性。这些结果激发了小脑通过激活局部vlPAG多巴胺神经元来调节先天防御行为表达的假设的验证。为了验证这一假设，研究人员将结合体内行为和系统水平的方法来操纵小脑输入，并记录先天冻结行为期间小脑的活动，以确定小脑信号产生的性质，以及它们对冻结行为表达的影响。为了研究vlPAG多巴胺神经元在调节先天冻结行为中的作用，我将使用纤维光度法和光遗传致动器记录和操纵vlPAG多巴胺神经元的活动。最后，由于vlPAG多巴胺神经元的选择性损伤破坏了小鼠恐惧记忆的形成（小脑可塑性的破坏也是如此），我将测试小脑联想可塑性通过调节vlPAG多巴胺活性来促进恐惧记忆形成的假设。总之，这些实验为理解小脑如何调节先天冻结以及更广泛地说，小脑可塑性如何促进习得性防御行为提供了一个框架。

Innate defensive behaviors promote survival by allowing animals to detect and respond to threats within their environment, such as predators. Although innate, these defensive behaviors show a remarkable amount of flexibility and are subject to robust habituation, suggesting that the circuitry underlying defensive behaviors is subject to modulatory control. Our recent work suggests that the cerebellum may provide one source of afferent modulatory influence within the periaqueductal gray. We find that cerebellar afferents to the freezing-related circuitry in ventrolateral periaqueductal gray (vlPAG) predominantly activate local dopaminergic interneurons, which subsequently alter the relative strength of synaptically evoked inhibition and excitation onto freezing premotor neurons. More specifically, cerebellar activation increases IPSC amplitudes and decreases EPSC amplitudes, which is predicted to increase spike threshold and alter the input-output relationship, altering the integrative properties of freezing premotor neurons. These results motivate testing the hypothesis that the cerebellum modulates the expression of innate defensive behaviors through activation of local vlPAG dopamine neurons. To test this hypothesis, a combination of in vivo behavioral and systems-level approaches will be used to manipulate cerebellar input and record cerebellar activity during innate freezing behaviors to determine the nature of the cerebellar signals produced, and their resulting effects on expression of freezing behavior. To study the role of vlPAG dopamine neurons in modulating innate freezing behaviors, I will similarly record and manipulate vlPAG dopamine neuron activity using fiber photometry and optogenetic actuators. Finally, because selective lesions of vlPAG dopamine neurons disrupt both fear memory formation in mice (as do disruptions in cerebellar plasticity), I will test the hypothesis that cerebellar associative plasticity contributes to fear memory formation by modulating vlPAG dopamine activity. Together, these experiments provide a framework for understanding how the cerebellum modulates both innate freezing and more broadly how cerebellar plasticity contributes to learned defensive behaviors.