Gut-brain axis in Parkinson's disease

项目摘要 最近的研究表明，特发性帕金森病（PD），第二个最常见的 在美国，神经退行性疾病可能起源于胃肠道（GI）。从那里，它通过 迷走神经到达脑干，随后到达黑质部的多巴胺能神经元 （SNPC）.事实上，胃肠道症状，如胃轻瘫和便秘是前驱发作的， 警局最近，我们发现了一条连接SNpc和背侧运动神经元的黑质-迷走神经通路， 迷走神经核（DMV），并且在SNpc刺激时，增加结肠运动性。黑质-迷走神经通路是 在PD的实验模型中受损，使得SNpc刺激在较小程度上增加运动性。我们 还产生了一种新的环境帕金森氏症啮齿动物模型，其中口服灌胃大鼠， 亚阈值剂量的除草剂百草枯（P）与凝集素（L）结合，凝集素是一种糖结合蛋白， 通常在人类饮食中，诱导左旋多巴反应性帕金森症。这样的P+L处理也会导致 在胃肠道以及DMV和SNpc中产生病理性α-突触核蛋白， 多巴胺能SNpc神经元变性（~50%）。我们的初步数据表明，P+L处理也 减慢胃-盲肠运输，减弱结肠对SNpc兴奋的反应，改变结肠 对脑干多巴胺给药的反应。与此同时，DMV神经元变得过度活跃， 补偿结肠蠕动的下降。 根据我们的初步研究，表明黑迷走神经的化学阻滞 通路阻止PD的发展，我们提出了以下新的假设：“α-突触核蛋白病- 相关的胃肠道运动功能低下诱导黑质-迷走神经通路的适应不良可塑性， 的PD”。我们进一步假设，纠正这种适应不良的神经可塑性将阻止帕金森症。到 为了研究这一新假说，我们将结合体内化学发生学和电生理学， 解剖学和行为学方法在啮齿动物中研究神经通路在 帕金森病相关的胃肠道功能障碍和PD的病因。

Project Summary Recent studies have shown that idiopathic Parkinson’s disease (PD), the second most common neurodegenerative disorder in the US, may originate in the gastrointestinal (GI) tract. From there it spreads via the vagus nerve to the brainstem and, subsequently, to the dopaminergic neurons of the substantia nigra pars compacta (SNpc). Indeed, GI symptoms such as gastroparesis and constipation are prodromal to the onset of PD. Recently, we discovered a nigro-vagal pathway that connects the SNpc to neurons of the dorsal motor nucleus of the vagus (DMV) and, upon SNpc stimulation, increases colonic motility. The nigro-vagal pathway is impaired in an experimental model of PD such that SNpc stimulation increases motility to a lesser extent. We have also generated a novel rodent model of environmental Parkinsonism, in which oral gavage of rats with subthreshold doses of the herbicide, paraquat (P), in combination with lectins (L), a sugar binding protein found commonly in the human diet, induces levodopa-responsive Parkinsonism. Such P+L treatment also induces generation of pathological α-synuclein in the GI tract, as well as in the DMV and SNpc, with significant degeneration (~50%) of dopaminergic SNpc neurons. Our preliminary data indicate that P+L treatment also slowed gastro-cecal transit, attenuated the colonic response to excitation of the SNpc and altered the colonic response to brainstem dopamine administration. At the same time, DMV neurons become hyperactive to compensate for the decreased colonic motility. Based on our preliminary studies, that demonstrate that chemogenetic blockade of the nigro-vagal pathway prevents the development of PD, we propose the following novel hypothesis: “α-synucleinopathy- associated GI hypomotility induces maladaptive plasticity in the nigro-vagal pathway, favoring the progression of PD”. We further hypothesize that correction of this maladaptive neuroplasticity will forestall parkinsonism. To investigate this novel hypothesis, we will use a combination of in vivo chemogenetic and electrophysiological, anatomical and behavioral approaches in rodents to investigate the role of the neural pathways affected in parkinsonian-related GI dysfunctions and in the etiology of PD.