Cerebellar Modulation of Innate Defensive Behaviors

先天防御行为的小脑调节

• 批准号: 10380141
• 负责人: Christopher Edward Vaaga
• 金额: $ 12.43万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380141
• 关键词: Amygdaloid structure; Animals; Behavior; Behavior monitoring; Behavioral; Biological Assay; Brain region; Cerebellar Nuclei; Cerebellum; Complex; Conditioned Stimulus; Coupled; Detection; Dopamine; Environment; Fiber; Foundations; Freezing; Fright; Goals; Heterogeneity; Impairment; Interneurons; Learning; Lesion; Medial; Midbrain structure; Monitor; Movement; Mus; Muscle; Nature; Neurons; Optics; Output; Pattern; Photometry; Play; Predatory Behavior; Property; Role; Signal Transduction; Source; Synapses; System; Techniques; Testing; Wild Type Mouse; Work; behavior change; behavioral outcome; behavioral response; conditioned fear; dopaminergic neuron; experimental study; fear memory; flexibility; habituation; in vivo; midbrain central gray substance; neural circuit; optogenetics; response; sex

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.

天生的防御行为通过允许动物检测和应对环境中的威胁（如捕食者）来促进生存。虽然这些防御行为是天生的，但它们表现出了显著的灵活性，并受到强大的习惯化的影响，这表明防御行为背后的电路受到调节控制。我们最近的工作表明，小脑可能提供了一个来源的传入调制的影响内的导水管周围灰质。我们发现，小脑传入的冷冻相关的电路在腹外侧水管周围灰质（vlPAG）主要激活当地的多巴胺能中间神经元，随后改变突触诱发的抑制和兴奋冷冻运动前神经元的相对强度。更具体地说，小脑激活增加IPSC振幅和降低EPSC振幅，这被预测为增加尖峰阈值和改变输入-输出关系，改变冷冻运动前神经元的整合特性。这些结果激发了测试小脑通过激活局部vlPAG多巴胺神经元来调节先天防御行为的表达的假设。为了验证这一假设，在体内的行为和系统水平的方法相结合，将被用来操纵小脑输入和记录小脑活动在先天冻结行为，以确定小脑产生的信号的性质，以及它们对冻结行为的表达所产生的影响。为了研究vlPAG多巴胺神经元在调节先天性冻结行为中的作用，我将使用纤维光度学和光遗传学致动器类似地记录和操纵vlPAG多巴胺神经元活动。最后，因为选择性病变的vlPAG多巴胺神经元破坏小鼠的恐惧记忆的形成（如破坏小脑可塑性），我将测试的假设，小脑的关联可塑性有助于通过调节vlPAG多巴胺活性的恐惧记忆的形成。总之，这些实验提供了一个框架，了解小脑如何调节先天冻结和更广泛的小脑可塑性如何有助于学习防御行为。