Searching for intracollicular neural substrate and neural pathways involved in paradoxical kinesia in rats

寻找与大鼠反常运动有关的丘内神经基质和神经通路

• 批准号: 436414341
• 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: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/436414341?language=en
• 关键词: Searching; intracollicular; neural; substrate; pathways

Previous results from our group strongly suggest that the inferior collicuus (IC) can modulate motor deficits representing an alternative target for deep brain stimulation (DBS) in patients with Parkinson’s disease and other motor dysfunctions. Based on these studies, we have suggested the IC as part of an alternative pathway that, when activated, induces motor improvement and thus paradoxical kinesia. However, the exact identity of this pathway, and how it is activated, is still unknown. The first goal of the present proposal is to investigate which IC projections are involved in this motor response and which intracollicular neural substrate is activated in order to trigger paradoxical kinesia. Specifically, combining electrophysiological and optogenetic techniques we will investigate descent projections from the IC to the mesencephalic locomotion region and ascending projections from the IC to the medial geniculate nucleus, which projects to both auditory cortex and prefrontal cortex. For that, we will inject CaMKIIa::ChR2 into the IC and use pulsed illumination with a 473-nm laser diode to activate excitatory neurons in the IC. We hypothesize that optogenetic inhibition of intracollicular glutamatergic neurons projecting to MLR will decrease catalepsy time induced by haloperidol in rats and therefore induce paradoxical kinesia, whereas optogenetic activation of these same neurons will increase haloperidol-induced catalepsy. The second goal of the present proposal is to refine intracollicular DBS parameters in order to induce paradoxical kinesia focusing on the IC as a potential target to treat movement disorders. For that, we will search for the best combination between frequency and current amplitude avoiding aversive side effects. Therefore, we will apply 30 Hz frequency combined with two different current intensity 400 or 600 μA. In order to assess the effect of these new DBS parameters on catalepsy and anxiety-related behavior, rats will be submitted to the bar test and to the elevated plus maze test under continuous intracollicular stimulation. Therefore, the present proposal will contribute to refine intracollicular BDS parameters in order to induce paradoxical kinesia, in addition, to establish the optogenetic technique in our lab, which will be of great value in the future allowing us to combine this technique with other behavioral tests currently in use in our group.

本课题组以前的研究结果有力地表明，下丘(IC)可以调节运动缺陷，是帕金森病和其他运动功能障碍患者进行脑深部刺激(DBS)的替代靶点。基于这些研究，我们认为IC是另一种途径的一部分，当被激活时，会导致运动改善，从而导致矛盾的运动。然而，这条通路的确切身份，以及它是如何被激活的，仍然是未知的。本方案的第一个目标是调查哪些IC投射参与了这种运动反应，以及为了触发矛盾运动，哪些神经细胞内的神经底物被激活。具体地说，结合电生理和光遗传学技术，我们将研究从IC到中脑运动区的下降投射和从IC到内侧膝状体的上行投射，内侧膝状体投射到听觉皮质和前额叶皮质。为此，我们将向IC中注入CaMKIIa：：ChR2，并使用473 nm激光二极管的脉冲照射来激活IC中的兴奋性神经元。我们假设投射到MLR的谷氨酸能神经元的光发生抑制可以减少氟哌啶醇引起的大鼠惊厥时间，从而引起反常运动，而这些神经元的光发生激活会增加氟哌啶醇引起的惊厥。本建议的第二个目标是改进小球内DBS参数，以诱导矛盾运动，重点关注IC作为治疗运动障碍的潜在靶点。为此，我们将寻求频率和电流幅度之间的最佳组合，以避免副作用。因此，我们将应用30赫兹的频率和两种不同的电流强度400或600μA。为了评估这些新的DBS参数对惊厥和焦虑相关行为的影响，我们将在持续的眼球内刺激下对大鼠进行条形试验和高架+迷宫试验。因此，本建议将有助于改进眼球内的BDS参数以诱导反常运动，此外，还将在我们的实验室建立光遗传学技术，这将在未来具有重要的价值，使我们能够将该技术与我们小组目前使用的其他行为测试相结合。