Cerebellar Modulation of Innate Defensive Behaviors

先天防御行为的小脑调节

• 批准号: 10703716
• 负责人: Christopher Edward Vaaga
• 金额: $ 24.9万
• 依托单位: COLORADO STATE 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703716
• 关键词: Amygdaloid structure; Animals; Behavior; Behavior monitoring; Behavioral; Biological Assay; Brain region; Cerebellar Nuclei; Cerebellum; Complex; Conditioned Stimulus; Coupled; Dedications; Detection; Dopamine; Environment; Fiber; Foundations; Freezing; Fright; Goals; Heterogeneity; Impairment; Interneurons; Learning; Lesion; Medial; Midbrain structure; Monitor; Motor Neurons; 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; induced pluripotent stem cell; 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.

与生俱来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与生俱来的，但它们表现出惊人的灵活性，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，小脑可能提供了中脑导水管周围灰质内传入调节影响的一个来源。我们发现，小脑传入中脑导水管周围灰腹外侧区(VlPAG)内的冻结相关回路主要激活局部多巴胺能中间神经元，从而改变突触诱发的抑制和兴奋对冻结前运动神经元的相对强度。更具体地说，小脑的激活增加了IPSC的幅度，降低了EPSC的幅度，这被预测为提高了尖峰阈值，改变了输入-输出关系，改变了冰冻的运动前神经元的综合特性。这些结果支持了一种假设，即小脑通过激活局部vlPAG多巴胺神经元来调节先天防御行为的表达。为了验证这一假说，将使用体内行为和系统水平的方法相结合的方法来操纵小脑输入，并记录天生冻结行为期间的小脑活动，以确定产生的小脑信号的性质，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，我将类似地使用光纤光度法和光遗传致动器来记录和操纵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两种恐惧记忆的形成(就像小脑可塑性的破坏一样)，我将检验小脑联合可塑性通过调节vlPAG多巴胺活动而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有助于后天防御行为提供了一个框架。