Recruitment of Cerebellar Circuits with Balance Training for Cognitive Rehabilitation in a Mouse Model of Mild Traumatic Brain Injury

认知和平衡功能的下降与许多神经精神障碍有关，影响 退伍军人，包括创伤后应激障碍(PTSD)和创伤性脑损伤(TBI)。这两个函数都具有 重叠，以功能激活的形式，在人类小脑中。接触TBI尤其与以下方面有关 退伍军人会增加认知功能障碍、失衡和失衡以及痴呆症的风险。TBI是 伊拉克和阿富汗战争中的标志性损伤，增加了认知功能障碍和 痴呆症。在这些疾病中，这些症状缺乏治疗。创伤性脑损伤的负担 家庭和美国卫生系统是巨大的，因此新的干预措施非常有意义。治疗方法： 年轻人和老年人的平衡能力得到改善，认知症状也得到改善。对人类和非人类的研究 人类灵长类动物已识别出小脑齿状核(DCN)的一个区域，即外侧核 啮齿动物(LCN)，在执行复杂的空间和空间认知任务时被激活 顺序计划。与认知有关的人类小脑后外侧区域 功能、握力和步态速度重叠并投射到DCN。大脑中的这个轨迹尤其是 很有希望，因为有证据表明，小脑的衰老速度慢于大脑的其他部分，并显示出 中风和神经退行性疾病的代偿性激活。我们之前已经开始剖析 并确定了特定LCN回路在支持认知方面的作用 工作记忆、情景记忆、反应抑制、感觉辨别和社会功能 功能。我们还表明，这个区域直接连接到中脑结构，如腹侧。 被盖区，参与联想学习。在初步数据中，我们显示了一个特定的基于旋转棒的 平衡训练方案挽救了几种认知和情感症状，特别是在 轻度颅脑损伤小鼠模型中奖赏学习和对威胁刺激反应的联想学习 退伍军人精神创伤和创伤后应激障碍的相关性。在这项拨款提案中，我们将从行为上剖析具体的 运动与平衡在这个mTBI模型中的贡献，并确定它们对认知功能的影响。 换句话说，我们将量化反应抑制和冲动、空间导航记忆以及 不同平衡和运动干预对mTBI小鼠恐惧的潜伏期 运动对平衡训练的影响。这笔赠款还旨在确定基于扶轮扶轮的平衡 训练1)改变称为小胶质细胞的神经炎性细胞亚群，使它们更 神经保护而不是神经毒性，2)它可以在LCN中招募特定的认知小脑回路。至 要做到这一点，我们将使用免疫组织化学、蛋白质定量方法和单细胞RNA 来自LCN的小胶质细胞的测序。我们还将使用化学发生电路方法(抑制性和 兴奋性DREADDS)来增加或降低特定兴奋性输出细胞群体的兴奋性 在平衡训练中的小脑外侧(齿状)核。然后，我们将测试功能 上述反应抑制和冲动、空间导航测试中这些扰动的结果 记忆，以及恐惧的孵化。成功完成我们提出的目标将提供对 小鼠平衡训练的临床前模型，小脑中支持认知和平衡的回路 功能，并建立一个新的，精确的治疗框架，以帮助脑外伤患者或 伴有认知和平衡功能障碍的神经退行性疾病。

Declines in cognitive and balance function are associated with numerous neuropsychiatric disorders affecting Veterans, including post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). Both functions have overlap, in the form of functional activation, in the human cerebellum. TBI exposure is particularly relevant to Veterans and increases risk of cognitive dysfunction, disequilibrium and imbalance, and dementia. TBI is the signature injury of the wars in Iraq and Afghanistan and increases risk of both cognitive dysfunction and dementia. Across these disorders, these symptoms have a paucity of treatments. The burden of TBI on families and the US health system is enormous, so novel interventions are of great interest. Treatments that elicit improved balance in the young and elderly also improve cognitive symptoms. Studies in humans and non- human primates have identified a region of the dentate nucleus of the cerebellum (DCN), or lateral nucleus in rodents (LCN), which is activated during performance of cognitive tasks involving complex spatial and sequential planning. Posterior-lateral areas of the human cerebellum that are associated with cognitive function, grip strength, and gait speed overlap and project to the DCN. This locus in the brain is particularly promising, as there is evidence that the cerebellum ages more slowly than the rest of the brain and shows compensatory activation in stroke and neurodegenerative disease. We have previously begun to dissect the circuit components of this nucleus in mice and defined a role for specific LCN circuits in supporting cognitive functions in working memory, episodic memory, response inhibition, sensory discrimination, and social functions. We have also shown that this region directly wires to midbrain structures, such as the ventral tegmental area, involved in associative learning. In preliminary data, we show that a specific rotarod-based balance training protocol rescues several cognitive and affective symptoms, particularly with respect to associative learning in both reward learning and response to threat stimuli, in a mild TBI (mTBI) mouse model relevant to mTBI and PTSD in Veterans. In this grant proposal, we will behaviorally dissect specific contributions of exercise versus balance in this mTBI model and determine their effects on cognitive function. In other words, we will quantify levels of response inhibition and impulsivity, spatial navigation memory, and incubation of fear in mTBI mice treated with different balance and exercise interventions designed to isolate effects of balance training from exercise. This grant also aims to determine whether rotarod-based balance training 1) alter the subpopulations of neuroinflammatory cells called microglia so that they are more neuroprotective rather than neurotoxic, and 2) it can recruit a specific cognitive cerebellar circuit in the LCN. To accomplish this, we will use immunohistochemistry, protein quantification methods and single cell RNA Sequencing of microglia from the LCN. We will also use a chemogenetic circuit approach (inhibitory and excitatory DREADDs) to increase or decrease the excitability of a specific excitatory output population of cells in the lateral (dentate) nucleus of the cerebellum during balance training. Then, we will test the functional outcomes of these perturbations in the above tests of response inhibition and impulsivity, spatial navigation memory, and incubation of fear. Successful completion of our proposed aims will provide novel insight into a preclinical model of balance training in mice, circuits in the cerebellum that support cognitive and equilibrium functions, and establish a framework for novel, precision therapeutics to assist patients with TBI or neurodegenerative disease with cognitive and equilibrium dysfunction.