Influence of the inferior colliculus on motor deficits of parkinsonian rodents: behavioral and electrophysiological studies

下丘对帕金森病啮齿动物运动缺陷的影响：行为和电生理学研究

• 批准号: 308581546
• 负责人: Professorin Dr. Liana Melo-Thomas, Ph.D.
• 金额: --
• 依托单位: Abteilung Verhaltensneurowissenschaft
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/308581546?language=en
• 关键词: Influence; inferior; colliculus; motor; deficits

The disease of Parkinson (PD) is a neurodegenerative disorder which is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Loss of SNc neurons leads to striatal dopamine (DA) deficiency, which is responsible for the major PD symptoms such as bradykinesia, resting tremor, muscle rigidity, and postural abnormalities. In respect to bradykinesia it has been suggested that severely disabled patients remain able to produce a sudden and brief period of mobility typically seen in response to emotional or physical stress. To explain this phenomenon, called paradoxical kinesia, it has been suggested that patients with PD have intact motor programs but have difficulty accessing them without an external trigger. However, external sensory (auditory or visual) stimulation may be able to activate these motor programs. This observation suggests that structures responsible for the integration of emotional, sensory and motor information must be activated to produce paradoxical kinesia. Regarding to auditory stimulation the inferior colliculus (IC) raises as an important structure that may influence paradoxical kinesia since it plays a role in sensorimotor gating activated by emotional stimuli. Therefore it is possible that the IC can be recruited during paradoxical kinesia. In the present proposal we hypothesize that electrical stimulation in an inhibitory frequency or microinjection of glutamatergic antagonists into the IC may reduce neural and motor dysfunctions as induced by temporary (haloperidol) or chronic (6-OHDA or MPTP) DA deficits in the basal nuclei. Specifically, we will test the hypothesis that appropriate modulation of an alternative and sensory-motor related pathway can access motor programs allowing akinetic animals to move, and that the IC is part of this pathway. Testing our hypothesis in animals showing motor impairments induced by temporary and chronic DA deficits will contribute to validate a new animal model of paradoxical kinesia. In parallel to behavioural analysis, we aim to assess intrastriatal neural activity, more specifically the frequency of spikes and burst activity. Here, we will determine whether the impairment-inducing manipulations (haloperidol or neurotoxin) lead to the expected changes in electrical activity in the striatum (reduced spike rate and burst activity) and whether our experimental therapeutic approaches (electrical or neurochemical inhibition within the IC) can re-establish normal activity both, neuronally and behaviorally. Importantly, all experiments will be performed using a new, bidirectional telemetric recording/stimulation system (BTSR) which allows direct comparisons between treatments, and their behavioral and neural outcomes in awake, freely-moving rodents.

帕金森病(PD)是一种以黑质致密部(SNC)多巴胺能神经元丢失为特征的神经退行性疾病。黑质神经元的缺失导致纹状体多巴胺(DA)缺乏，导致帕金森病的主要症状，如运动迟缓、静止性震颤、肌肉僵硬和姿势异常。关于运动迟缓，有人提出，严重残疾的患者仍然能够产生一段突然而短暂的活动期，这通常是对情绪或身体压力的反应。为了解释这种现象，称为矛盾运动，有人认为帕金森病患者有完整的运动程序，但在没有外部触发的情况下很难获得它们。然而，外部感觉(听觉或视觉)刺激可能能够激活这些运动程序。这一观察表明，负责整合情绪、感觉和运动信息的结构必须被激活，才能产生矛盾的运动。关于听觉刺激，下丘(IC)在情绪刺激激活的感觉运动门控中起着重要作用，是影响矛盾运动的重要结构。因此，IC有可能在反常运动过程中被招募。在本研究中，我们假设，抑制频率的电刺激或向IC内微量注射谷氨酸能拮抗剂，可以减轻基底核暂时(氟哌啶醇)或慢性(6-OHDA或MPTP)DA缺乏所引起的神经和运动功能障碍。具体地说，我们将测试这样一种假设，即适当调节另一条与感觉-运动相关的途径可以获得允许无运动动物运动的运动程序，并且IC是这条途径的一部分。在表现出暂时性和慢性DA缺陷引起的运动障碍的动物身上测试我们的假设，将有助于验证一种新的矛盾运动的动物模型。在行为分析的同时，我们的目标是评估纹状体内的神经活动，更具体地说是尖峰和爆发活动的频率。在这里，我们将确定损伤诱导手法(氟哌啶醇或神经毒素)是否导致纹状体电活动的预期变化(减少尖峰频率和爆发活动)，以及我们的实验性治疗方法(IC内的电或神经化学抑制)是否可以重建神经和行为的正常活动。重要的是，所有实验都将使用一种新的双向遥测记录/刺激系统(BTSR)进行，该系统允许在清醒、自由活动的啮齿动物中直接比较治疗方法及其行为和神经结果。