Recruitment of Cerebellar Circuits to Modulate Cognition, Reward and Avoidance of Threat

对人类和非人类灵长类动物的研究已经确定了小脑齿状核的一个区域 (DCN)啮齿类动物的外侧核（LCN），在执行复杂的认知任务时被激活。 我们先前已经证明多巴胺D1受体和囊泡谷氨酸转运蛋白2（VEGF 2） 标记LCN中不同的神经元群体，并调节与以下相关任务的认知表现： 注意力和工作记忆。DCN与精神病患者的认知功能有关 疾病，但几乎没有人知道它的基本解剖和功能组织。解开这个 将为认知领域的精确治疗奠定基础，在这个领域，我们几乎没有选择。 有精神疾病的退伍军人。例如，患有创伤后应激障碍和创伤性脑损伤的退伍军人， 小脑功能障碍的临床标志物与认知和PTSD症状的严重程度相关。 腹侧被盖区（VTA）产生的异常多巴胺信号也可能是一个原因， 创伤后应激障碍的功能障碍，我们的小组和其他人一再表明，小脑核团具有 输入到腹侧被盖区，这是位于中脑边缘多巴胺系统中心的大脑区域， 调节奖励和恐惧学习。VTA和小脑回路（LCN和小脑后外侧皮质）是 强烈地牵涉到预测错误的感觉和产生（奖励/威胁和感觉错误， 分别用于认知和情感功能。患有离散性小脑病变的人类表现为 神经精神症状，包括抑郁、语言和社会互动减少、间隔受损 在没有运动缺陷的情况下，时间、工作记忆、空间认知和注意力的障碍。当 我们已经在实验上干扰了小鼠LCN的儿茶酚胺能输入，我们发现了 行为灵活性，反应抑制，社会认知记忆，以及相关的恐惧学习 控制，但没有缺陷的大运动，感觉，工具性学习，或感觉运动门控功能。我们 假设精神障碍中认知功能异常来源之一是错误的回路 VTA和小脑之间的联系值得注意的是，小脑激活见于 帕金森氏病，从人类中风中恢复后，和帕金森氏病的实验动物模型， 大脑半球切除术证明了小脑在恢复中的必要性。这些小脑机制 在认知功能障碍的病因学中是活跃的，或者他们是否可以通过干预招募， 恢复是未知的。众所周知，在联想或强化学习之后，腹侧被盖区多巴胺 信号转变为预测奖励或威胁的线索。当条件刺激（CS+）被呈现时， 如果忽略奖励，腹侧被盖区的多巴胺神经元就会显示出预测错误。最重要的假设是 小脑促进了这种类型的学习，而LCN之间的电路功能障碍， VTA可能是不同精神疾病的重要组成部分。我们将使用小鼠， 结合特异性病毒、光遗传学、体内电生理学和纤维 光度法来表征和操纵投射到腹侧被盖区的特定LCN神经元的活性。 利用这些尖端工具与经典的行为分析相结合，将提供对这一电路的深入了解， 它有望成为神经调节、行为或药理学干预的靶点 接近。

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 complex cognitive tasks. We have previously shown that the dopamine D1 receptor and the vesicular glutamate transporter-2 (Vglut2) mark different populations of neurons in the LCN and modulate cognitive performance on tasks related to attention and working memory. The DCN is implicated in cognitive function in humans with psychiatric illnesses, but virtually nothing is known about its basic anatomical and functional organization. Unraveling this will set the stage for precision therapeutics in the cognitive domain, an area where we have few options to offer Veterans with psychiatric disorders. Veterans with PTSD and TBI, for example, show neuroanatomical and clinical markers of cerebellar dysfunction which correlate with the severity of cognitive and PTSD symptoms. Aberrant dopamine signaling arising from the ventral tegmental area (VTA) is also a likely contributor to dysfunction in PTSD, and it has been repeatedly shown by our group and others that cerebellar nuclei have inputs to the ventral tegmental area, a brain region at the heart of the mesolimbic dopamine system which mediates reward and fear learning. VTA and cerebellar circuits (LCN and posterolateral cerebellar cortex) are strongly implicated in the sensation and production of prediction errors (reward/threat and sensory errors, respectively) for cognitive and emotional function. Humans with discrete cerebellar lesions manifest neuropsychiatric symptoms, including depression, reduced language and social interactions, impaired interval timing, disturbances of working memory, spatial cognition, and attention in the absence of motor deficits. When we have experimentally perturbed catecholaminergic inputs to the LCN in mice, we have found impairments in behavioral flexibility, response inhibition, social recognition memory, and associative fear learning relative to controls, but no deficits in gross motor, sensory, instrumental learning, or sensorimotor gating functions. We hypothesize that one source of aberrant cognitive function in psychiatric disorder stems from faulty circuitry between the well-characterized VTA and the understudied cerebellum. Notably, cerebellar activations seen in Parkinson’s Disease, after recovery from stroke in humans, and experimental animal models of hemispherectomy demonstrate the necessity of cerebellum in recovery. Whether these cerebellar mechanisms are active in the etiology of cognitive dysfunction, or whether they can be recruited by an intervention during recovery is unknown. It is well known that following associative or reinforcement learning, the VTA dopamine signal shifts to a cue which predicts a reward or threat. When conditioned stimuli (CS+) are presented and rewards are omitted, dopamine neurons in the VTA display prediction errors. The overarching hypothesis of this grant is that the cerebellum facilitates this type of learning, and that circuit dysfunction between the LCN and VTA may be a critical component of different psychiatric disorders. We will use mice with a targeted mutation of Vglut2 in combination with specific viral, optogenetic, in vivo electrophysiology and fiber photometry approaches to characterize and manipulate the activity of specific LCN Neurons projecting to VTA. Leveraging these cutting-edge tools paired with classical behavioral assays will offer insights into this circuit, which holds promise as a target of intervention with neuromodulatory, behavioral, or pharmacological approaches.