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

招募小脑回路来调节认知、奖励和避免威胁

• 批准号: 10589435
• 负责人: Erik Sean Carlson
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589435
• 关键词: Address; Adult; Affect; Amygdaloid structure; Anatomy; Animals; Area; Association Learning; Attention; Behavior; Behavioral; Behavioral Assay; Brain region; Catecholamines; Cell Nucleus; Cerebellar Cortex; Cerebellar Diseases; Cerebellar Nuclei; Cerebellum; Clinical Markers; Cognition; Cognitive; Compensation; Complex; Cues; Dentate nucleus; Discrimination; Dopamine; Dopamine D1 Receptor; Electrophysiology (science); Emotional; Esthesia; Etiology; Experimental Animal Model; Fiber; Fright; Functional disorder; Glutamates; Goals; Grant; Heart; Hemispherectomy; Human; Impaired cognition; Impairment; Intervention; Language; Lateral; Learning; Light; Maps; Measures; Mediating; Mental Depression; Mental disorders; Midbrain structure; Modeling; Motor; Mus; Mutation; Neuroanatomy; Neurobehavioral Manifestations; Neurobiology; Neurons; Nucleus Accumbens; Operant Conditioning; Output; Parkinson Disease; Pathway interactions; Pattern; Performance; Photometry; Population; Post-Traumatic Stress Disorders; Precision therapeutics; Production; Psychological reinforcement; Psychoses; Recovery; Rewards; Rodent; Sensory; Severities; Shock; Short-Term Memory; Signal Transduction; Social Interaction; Source; Stimulus; Structure; Symptoms; Testing; Thalamic structure; Ventral Tegmental Area; Veterans; Viral; With laterality; Work; behavior measurement; cell type; cerebellar lesion; cognitive function; cognitive performance; cognitive task; conditioned fear; dopaminergic neuron; emotional functioning; emotional symptom; flexibility; improved; in vivo; incentive salience; insight; interest; memory recognition; mesolimbic system; motor deficit; neural; neurobehavioral; neuropsychiatric disorder; neuropsychiatric symptom; neuroregulation; nonhuman primate; novel; optogenetics; paired stimuli; pharmacologic; recruit; response; social; stem; stroke recovery; time interval; tool; vesicular glutamate transporter 2; virtual

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.

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）或啮齿类动物的侧核（LCN），在执行复杂的认知任务时被激活。 我们之前已经证明多巴胺 D1 受体和囊泡谷氨酸转运蛋白 2 (Vglut2) 标记 LCN 中不同的神经元群并调节与以下任务相关的认知表现 DCN 与精神病患者的认知功能有关。 痛苦，但实际上对其基本的解剖学和功能组织一无所知。 将为认知领域的精准治疗奠定基础，而我们在这个领域几乎没有什么选择 例如，患有精神疾病的退伍军人患有创伤后应激障碍（PTSD）和创伤性脑损伤（TBI），表现出神经解剖学和精神疾病。 小脑功能障碍的临床标志物与认知和创伤后应激障碍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传导也可能是导致 PTSD 中的功能障碍，我们的小组和其他人反复证明，小脑核具有 腹侧被盖区的输入，腹侧被盖区是中脑边缘多巴胺系统的核心大脑区域， 介导奖励和恐惧学习。 与预测错误的感觉和产生密切相关（奖励/威胁和感觉错误， 分别）对于认知和情感功能具有离散的小脑病变表现。 神经精神症状，包括抑郁、语言和社交互动减少、间隔受损 在没有运动缺陷的情况下，时间安排、工作记忆、空间认知和注意力受到干扰。 我们通过实验扰乱了小鼠 LCN 的儿茶酚胺能输入，我们发现 行为灵活性、反应抑制、社会认知记忆和联想恐惧学习 控制，但粗大运动、感觉、工具学习或感觉运动门控功能没有缺陷。 研究发现，精神疾病中认知功能异常的根源之一是电路故障 值得注意的是，在充分表征的 VTA 和小脑之间发现了小脑激活。 人类中风康复后的帕金森病和实验动物模型 半球切除术证明了小脑恢复的必要性是否是这些小脑机制。 在认知功能障碍的病因学中很活跃，或者是否可以通过干预来招募他们 众所周知，联想学习或强化学习后，VTA 多巴胺的恢复情况尚不清楚。 当条件刺激（CS+）出现时，信号转变为预测奖励或威胁的提示。 忽略奖励，VTA 中的多巴胺神经元显示出预测错误。 此项研究表明，小脑促进了这种类型的学习，并且 LCN 之间的电路功能障碍 VTA 可能是不同精神疾病的关键组成部分，我们将使用有针对性的小鼠。 Vglut2 突变与特定病毒、光遗传学、体内电生理学和纤维相结合 光度测定方法来表征和操纵投射到 VTA 的特定 LCN 神经元的活动。 利用这些尖端工具与经典行为分析相结合将提供对该回路的见解， 它有望成为神经调节、行为或药理学干预的目标 接近。