Learning-induced changes in hyperpolarization-activated currents

描述（由申请人提供）：小脑参与几种类型的学习，包括恐惧条件反射，创伤后应激障碍（PTSD）的动物模型。此外，小脑功能障碍在许多精神疾病中很常见，如抑郁症和焦虑症。神经系统疾病的病理生理学涉及兴奋性、节律性和信号传导的紊乱。动物模型暗示了超极化激活的环核苷酸调节（HCN）通道在学习和疾病发展中的作用。这些通道在决定神经元的内在膜特性方面至关重要，这些特性最终会影响神经元的活动和输出。该提案将调查 学习诱导的小脑中间神经元超极化激活电流（Ih）变化如何影响网络功能和行为。我们的初步研究表明，恐惧学习后，HCN通道下调，导致Ih幅度降低和输入电阻增加。本提案中的两个目标将产生不同但互补的发现，其目的是理解1）由于Ih在联想学习范式后的改变而引起的内在膜特性的变化，以及2）这些变化对小脑皮层网络活动的功能后果。总的来说，这个提议的预期结果将有助于我们理解恐惧记忆是如何编码的。此外，这些研究可以验证HCN通道作为与Ih变化相关的神经系统疾病（如癫痫和抑郁症）的潜在治疗靶点。

DESCRIPTION (provided by applicant): The cerebellum is involved in several types of learning including fear conditioning, an animal model of post- traumatic stress disorder (PTSD). Additionally, cerebellar dysfunction is common in a number of mental illnesses, such as depression and anxiety disorders. The pathophysiology of neurological diseases involves disturbances in excitability, rhythmicity, and signaling. Animal models have implicated a role for hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in both learning and disease development. These channels are crucial in determining a neuron's intrinsic membrane properties which can ultimately affect neuronal activity and output. This proposal will investigate how learning-induced changes in hyperpolarization-activated current (Ih) of cerebellar interneurons can impact network function and behavior. Our preliminary studies show that following fear learning, there is a downregulation of HCN channels which results in reduced Ih amplitude and an increase in input resistance. The two aims in this proposal will yield different, yet complimentary findings with regards to their objective of understanding 1) changes in intrinsic membrane properties due to alterations in Ih following an associative learning paradigm and 2) the functional consequences of these changes on network activity in the cerebellar cortex. Taken together, the anticipated results of this proposal will contribute to our understanding of how fear memories are encoded. Additionally, such studies may validate HCN channels as potential therapeutic targets for neurological disorders that are associated with changes in Ih, such as epilepsy and depression.