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

帕金森病（PD）是一种神经退行性疾病，其特征是黑质致密部（SNc）多巴胺能神经元的丧失。SNc神经元的缺失导致纹状体多巴胺（DA）缺乏，这是帕金森病主要症状的原因，如运动迟缓、静息性震颤、肌肉僵硬和姿势异常。关于运动迟缓，有人认为严重残疾的病人仍然能够产生突然和短暂的活动，这通常是对情绪或身体压力的反应。为了解释这种被称为矛盾运动症的现象，有人认为PD患者有完整的运动程序，但在没有外部触发的情况下难以实现。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。这一观察结果表明，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运动。在听觉刺激中，下丘在情绪刺激激活的感觉运动门控中起着重要的作用，是影响矛盾运动的重要结构。因此，IC可能在矛盾运动期间被招募。在本研究中，我们假设以抑制频率的电刺激或微量注射谷氨酸能拮抗剂进入IC可能会减轻由暂时性（氟哌啶醇）或慢性（6-OHDA或MPTP）基底核DA缺陷引起的神经和运动功能障碍。具体来说，我们将测试这样一个假设，即适当调节另一种和感觉运动相关的途径可以进入运动程序，允许不动动物运动，而IC是这一途径的一部分。在动物身上验证我们的假设，显示暂时和慢性DA缺陷引起的运动障碍，将有助于验证一种新的矛盾运动动物模型。与行为分析并行，我们的目标是评估纹状体内神经活动，更具体地说，峰值和爆发活动的频率。在这里，我们将确定损伤诱导操作（氟哌啶酮或神经毒素）是否会导致纹状体中电活动的预期变化（减少尖峰率和爆发活动），以及我们的实验治疗方法（IC内的电或神经化学抑制）是否可以在神经和行为上重建正常活动。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，该系统可以直接比较不同治疗方法及其在清醒、自由活动的啮齿动物中的行为和神经结果。

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.