Astrocytic function in DBS for essential tremor

 描述（由申请人提供）：已知DBS对帕金森病和特发性震颤等疾病非常有效，但其机制尚不清楚。它在运动障碍方面的治疗成功使其被认为是一组迅速扩大的神经和精神疾病，从强迫症到抑郁症和记忆丧失。扩大DBS应用的压力使我们更好地理解其潜在机制以及研究其治疗作用的所有潜在分子和生理过程变得更加重要。到目前为止，基础科学研究的重点是DBS驱动的神经元变化及其在DBS电极导线周围的投射。而且，虽然星形胶质细胞的生理作用，在大脑中最众多的细胞类型，已被广泛研究，很少有人注意到他们的功能作用，在治疗DBS。我们知道星形胶质细胞在神经传递、化学稳态、突触可塑性和血流控制中起重要作用。我们还知道，它们对高频刺激（HFS）（与治疗性DBS相似的条件）的反应是通过改变神经元网络活动的重要调节因子，诱导谷氨酸、ATP和腺苷的释放。因此，星形胶质细胞在DBS中的作用值得研究。我们的主要假设是星形胶质细胞对DBS的治疗效果做出了局部和远端贡献。不打算作为DBS期间神经元调制理论的替代，而是一种关键的改进，这种应用可以被视为加深我们对这些变化的理解，并更准确地反映其复杂性。这项研究的总体计划是表征体内HFS驱动的星形胶质细胞激活对局部腺苷释放、远端神经回路激活和震颤减少的影响。选择震颤作为易于测量且已知DBS可成功治疗的代表性疾病。目的1，将通过在DBS期间和选择性星形胶质细胞激活期间使用光遗传学方法检查局部腺苷释放、电生理学和神经网络激活效应来表征腹外侧（VL）丘脑（震颤的临床有效DBS靶点）的HFS驱动的星形胶质细胞功能，受试者组根据选择性细胞类型（神经元与星形胶质细胞）激活而变化。目的2将使用猪震颤-震颤模型来表征感染了光遗传学载体的受试者中HFS驱动的星形胶质细胞或神经元活化对震颤的不同影响。为了进一步验证调查结果， 将在一组猪中研究DBS期间对震颤的影响，其中使用可抑制星形胶质细胞神经胶质递质释放的shRNA选择性阻断SNARE蛋白活性。最终，尚未确定的DBS相关功能的星形胶质细胞的表征应该会影响DBS治疗，为靶点选择，闭环刺激装置的开发以及现在和未来DBS治疗的神经和精神疾病的其他个性化干预提供关键信息。

 DESCRIPTION (provided by applicant): DBS is known to be highly effective for conditions such as Parkinson's disease and essential tremor, but its mechanisms are not well understood. Its therapeutic success in movement disorders has led to its consideration for a rapidly expanding set of neurologic and psychiatric conditions from obsessive compulsive disorder to depression and memory loss. The pressure to expand DBS applications makes it all the more critical that we improve understanding of its underlying mechanisms and that all potential molecular and physiologic processes that bear on its therapeutic action be investigated. To date, basic science research has focused on DBS-driven changes in neurons and their projections around the DBS lead. And, while the physiological actions of astrocytes, the most numerous cell type in the brain, have been extensively investigated, little attention has been paid to their functional role in therapeutic DBS. We know that astrocytes play a significant role i neurotransmission, chemical homeostasis, synaptic plasticity, and control of blood flow. We also know that they respond to high frequency stimulation (HFS), conditions similar to those of therapeutic DBS, by altering important regulators of neuronal network activity, inducing the release of glutamate, ATP, and adenosine. Thus, the role of astrocytes in DBS warrants investigation. Our main hypothesis is that astrocytes make local and distal contributions to the therapeutic effects of DBS. Not intended as an alternative to theories of neuronal modulation during DBS, but rather a critical refinement, this application can be seen as deepening our understanding of those changes and more accurately reflecting their complexity. The overall plan for this investigation is to characterize the effects of in vivo HFS-driven astrocyte activatin on local adenosine release, on distal neural circuitry activation, and on tremor reduction. Tremor was chosen as a representative disorder that is easy to measure and known to be successfully treated by DBS. Aim 1, will characterize HFS-driven astrocytic function at the ventrolateral (VL) thalamus, a clinically effective DBS target for tremor, by examining local adenosine release, electrophysiology, and neural network activation effects during DBS and during selective astrocytic activation using an optogenetic approach in subject groups that vary according to selective cell type (neuronal versus astrocytic) activation. Aim 2 will use a swine harmaline- tremor model to characterize the differential effects on tremor of HFS-driven astrocytic or neuronal activation in subjects infected with optogenetic vectors. To further validate the findings the effects on tremor during DBS will be investigated in a group of pigs with selectively blockage of SNARE protein activity using shRNA, which can inhibit astrocytic gliotransmitter release. Ultimately, characterization of the as yet unidentified DBS-related functions of astrocytes should impact DBS therapy, providing key information for target selection, the development of closed-loop stimulation devices and other individualized interventions for neurologic and psychiatric conditions that are treated by DBS, now and in the future.