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 亨廷顿舞蹈症 (HD) 是一种由异常扩张引起的遗传性神经退行性疾病 HD 中 HTT 基因的 CAG 重复序列，包括冷漠、抑郁、情绪低落。 摇摆和烦躁，伴随并经常先于运动异常的发生，但效果不佳 HD 患者的主要组织病理学是中度丢失。 令人惊讶的是，纹状体中的棘状神经元（MSN）和大脑皮层中的锥体神经元。 而背外侧纹状体（一个参与运动控制的区域）的作用主要是 在 HD 中研究了伏隔核 (NAc) 的作用，伏隔核是涉及腹内侧纹状体的一个区域 在奖赏感知、情绪调节和动机显着性的认知处理中， 因此，该提案的第一个目标将检查功能的进展。 两种 HD 小鼠模型 R6/2（HD 模型）中 NAc MSN 的形态学异常 青少年HD）和Q175（成人HD的模型）我们在NAc中追逐了MSN， 特别是那些表达多巴胺 D2 受体的细胞，将表现出早期的电生理和 NAc 接收来自内侧前额叶的谷氨酸能投射。 皮层（mPFC），一个在动机中发挥关键作用的区域，当功能失调时，可能会导致 此外，在病理条件下，mPFC-NAc 突触会出现精神症状。 由非典型 Ca2+ 渗透性 (CP)-AMPA 受体插入支持的异常塑性变化 (AMPAR) 虽然 CP-AMPAR 介导兴奋性毒性并已被利用发挥关键作用。 在神经退行性疾病中的作用，这一假设尚未在 HD 中得到系统测试。 因此，该提案的第二个目标将研究 CP-AMPAR 在 mPFC-NAc 中的作用 NAc 中 MSN 功能障碍的突触 我们认为 NAc MSN，特别是那些 NAc MSN 中的突触。 表达 D2 受体，在 HD 中逐渐受到影响，并且恢复神经元 通过禁用突触 CP-AMPAR 可以恢复 mPFC-NAc 投射中发生的异常 NAc 的正常功能和延迟即将发生的细胞丢失为了检验这些假设，我们将使用切片。 准备检查 D1/D2 受体表达的电生理学和形态学变化 此外，我们将使用光遗传学方法来分离并尝试恢复 NAc 中的 MSN。 mPFC-NAc 投影中的正常通信最后，NAc 和 CP- 的参与。 HD 相关精神症状（例如动机缺陷）中的 AMPAR 将通过 我们的研究结果对于行为测量和神经药理学操作至关重要。 减轻精神症状的进展，从而提供新的治疗工具 提高 HD 患者的生活质量。