The role of Nucleus Accumbens and Calcium-Permeable AMPA Receptors in the Pathophysiology of Huntington's Disease

伏核和钙渗透性 AMPA 受体在亨廷顿病病理生理学中的作用

• 批准号: 9789701
• 负责人: Yao-Ying Ma
• 金额: $ 19.69万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789701
• 关键词: AMPA Receptors; Acids; Adolescent; Adult; Affect; Animal Genetics; Animal Model; Anxiety; Area; Attenuated; Behavioral; CAG repeat; Calcium; Cell physiology; Cells; Cerebral cortex; Chorea; Code; Cognitive; Communication; Corpus striatum structure; Dendritic Spines; Disease Progression; Dopamine D1 Receptor; Dopamine D2 Receptor; Dystonia; Electrophysiology (science); Fluorescent Dyes; Functional disorder; Genes; Genetic; Glutamates; Goals; Histopathology; Huntington Disease; In Vitro; Inherited; Ion Channel; Juvenile-Onset Huntington Disease; Lead; Measures; Medial; Mediating; Membrane; Mental Depression; Methods; Modeling; Moods; Morphology; Motivation; Motor; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Nucleus Accumbens; Outcome; Pathologic; Pathway interactions; Patients; Perception; Permeability; Pharmacology; Phenotype; Play; Prefrontal Cortex; Preparation; Property; Quality of life; Reinforcement Schedule; Research; Rodent Model; Role; Self Administration; Signal Transduction; Slice; Stains; Sucrose; Sum; Symptoms; Synapses; Testing; Vertebral column; Work; behavior measurement; density; emotion regulation; excitotoxicity; hippocampal pyramidal neuron; improved; indexing; insight; motor control; mouse model; neglect; novel therapeutics; optogenetics; patch clamp; postsynaptic; psychiatric symptom; receptor; reward processing; synaptic function; tool; voltage

Abstract Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by an anomalous expansion of CAG repeats in the HTT gene. Psychiatric symptoms in HD, including apathy, depression, mood swings and irritability, accompany and often precede the onset of motor abnormalities, but are poorly understood and insufficiently treated. The major histopathology in HD patients is the loss of medium- sized spiny neurons (MSNs) in the striatum and pyramidal neurons in the cerebral cortex. Surprisingly, while the role of the dorsolateral striatum, a region involved in motor control, has been extensively studied in HD, the role of the nucleus accumbens (NAc), a region of the ventromedial striatum involved in the cognitive processing of reward perception, emotion regulation, and motivational salience, has been largely neglected. Thus, the first aim of this proposal will examine the progression of functional and morphological abnormalities in NAc MSNs in two mouse models of HD, the R6/2 (a model of juvenile HD) and the Q175 (a model of adult-onset HD). We hypothesize that MSNs in the NAc, particularly those expressing dopamine D2 receptors, will display early electrophysiological and morphological abnormalities. The NAc receives glutamatergic projections from the medial prefrontal cortex (mPFC), a region that plays a critical role in motivation and, when dysfunctional, can lead to psychiatric symptoms. Additionally, in pathological conditions, the mPFC-NAc synapses undergo aberrant plastic changes supported by the insertion of atypical Ca2+-permeable (CP)-AMPA receptors (AMPARs). Although CP-AMPARs mediate excitotoxicity and have been hypothesized to play a pivotal role in neurodegenerative disorders, this hypothesis has not been tested systematically in HD. Therefore, the second aim of this proposal will examine the role of CP-AMPARs at mPFC-NAc synapses in MSN dysfunction in the NAc. We hypothesize that the NAc MSNs, particularly those expressing D2 receptors, become progressively affected in HD and that reverting neuronal abnormalities occurring in the mPFC-NAc projections by disabling synaptic CP-AMPARs can restore NAc normal function and delay impending cell loss. To test these hypotheses, we will use the slice preparation to examine electrophysiological and morphological changes in D1/D2 receptor-expressing MSNs in the NAc. Furthermore, we will use optogenetic approaches to isolate and attempt to restore normal communication in the mPFC-NAc projection. Finally, the involvement of the NAc and CP- AMPARs in HD-associated psychiatric symptoms (e.g., motivation deficits) will be confirmed by behavioral measurements and neuropharmacological manipulations. Our findings will be crucial to alleviate the progression of psychiatric symptoms, thereby providing novel therapeutic tools in order to improve the quality of life of HD patients.

抽象的 亨廷顿氏病（HD）是由异常扩张引起的遗传神经退行性疾病 HTT基因中的CAG重复序列。高清的精神症状，包括冷漠，抑郁，情绪 摇摆和烦躁，涉及并经常在运动异常的发作之前，但很差 理解和不足以治疗。 HD患者的主要组织病理学是培养基的丧失 大脑皮质中的纹状体和锥体神经元中的大小棘神经元（MSN）。出奇， 虽然背纹纹状体的作用是参与运动控制的区域，但已广泛 研究了HD的研究，伏隔核（NAC）的作用是腹侧纹状体的区域 在奖励感知，情感调节和动机显着的认知处理中， 他在很大程度上被忽略了。这是该提案的第一个目的将检查功能的进展 NAC MSN中NAC MSN的形态异常，在HD的两个小鼠模型中，R6/2（一种模型 少年高清）和Q175（成人发作HD的模型）。我们假设NAC中的MSN， 特别是那些表达多巴胺D2受体的人，将显示早期的电生理学和 形态异常。 NAC从媒体前额叶接收谷氨酸能项目 皮层（MPFC），一个在动机中起关键作用的区域，当功能失调时，可以导致 精神病症状。此外，在病理条件下，MPFC-NAC突触经历 异常的塑料变化，由非典型Ca2+可渗透（CP）-AMPA受体插入支撑 （AMPARS）。 在神经退行性疾病中的作用，该假设尚未在HD中系统地检验。 因此，该提案的第二个目的将研究CP-Ampars在MPFC-NAC中的作用 NAC中MSN功能障碍的突触。我们假设NAC MSN，尤其是那些 表达D2受体，在HD中逐渐受到影响，并恢复神经元 通过禁用突触CP-Ampars，在MPFC-NAC预测中出现异常 NAC的正常功能和延迟即将出现的细胞丢失。为了检验这些假设，我们将使用切片 准备D1/D2受体的电生理和形态学变化的准备 NAC中的MSN。此外，我们将使用光遗传学方法来隔离和尝试恢复 MPFC-NAC投影中的正常通信。最后，NAC和CP-的参与 HD相关的精神病症状（例如，动机缺陷）的AMPAR将由 行为测量和神经药理操纵。我们的发现对 减轻精神病症状的进展，从而提供新颖的热工具以进行 改善高清患者的生活质量。