Gut-brain axis in Parkinson's disease

帕金森病的肠脑轴

• 批准号: 10672043
• 负责人: Kirsteen Nairn Browning
• 金额: $ 59.71万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672043
• 关键词: Address; Affect; Anatomy; Animal Model; Animals; Area; Attenuated; Behavioral; Bilateral; Binding Proteins; Brain Stem; Breath Tests; Cecum; Cell Nucleus; Characteristics; Confocal Microscopy; Constipation; Data; Development; Diet; Disease; Dopamine; Dose; Electrophysiology (science); Enteral; Enteric Nervous System; Etiology; Exhibits; Experimental Models; Functional disorder; Gastrointestinal Motility; Gastrointestinal Transit; Gastrointestinal tract structure; Gastroparesis; Generations; Herbicides; Human; Human Resources; Hyperactivity; Idiopathic Parkinson Disease; Impairment; Intervention; Intestines; Lead; Lectin; Levodopa; Lewy Bodies; Microinjections; Midbrain structure; Modeling; Motor; Nerve Degeneration; Neural Pathways; Neuraxis; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neurotoxins; Oral; Paraquat; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathway interactions; Patients; Positioning Attribute; Rattus; Regulation; Rodent; Rodent Model; Role; Slice; Source; Squalamine; Stomach; Substantia nigra structure; Testing; Therapeutic Intervention; Time; Vagus nerve structure; alpha synuclein; base; biomarker discovery; cell motility; dietary; dopaminergic neuron; dorsal motor nucleus; gastrointestinal; gastrointestinal symptom; gut-brain axis; in vivo; inorganic phosphate; motor behavior; motor deficit; nigrostriatal degeneration; non-motor symptom; novel; novel therapeutics; pars compacta; patch clamp; prevent; protein aggregation; reduce symptoms; response; sugar; synucleinopathy; tool

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.

项目摘要 最近的研究表明，特发性帕金森病(PD)是第二常见的 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，随后到达黑质的多巴胺能神经元。 康培达(SNPC)。事实上，胃轻瘫和便秘等胃肠道症状是发病的先兆 警察。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 迷走神经核团(DMV)，刺激SNPC时，可增加结肠动力。黑质-迷走神经通路是 在帕金森病的实验模型中受损，如刺激SNPC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，在该模型中，大鼠口服 除草剂百草枯(P)与糖结合蛋白凝集素(L)联合使用的亚阈值剂量 在人类饮食中普遍存在，可诱发左旋多巴反应性帕金森综合症。这样的P+L治疗也会诱发 病理性α-突触核蛋白在胃肠道以及DMV和SNPC中的产生，具有显著意义 多巴胺能SNPC神经元变性(~50%)。我们的初步数据显示，P+L治疗也 减慢胃盲肠运输，减弱结肠对SNPC兴奋的反应，并改变结肠 对脑干注射多巴胺的反应。与此同时，DMV神经元变得过度活跃， 弥补结肠动力减弱的影响。 根据我们的初步研究，这表明化学生成对黑质迷走神经的阻断 为了预防帕金森病的发生，我们提出了以下新的假说：“α-突触核糖核病- 相关胃肠动力低下诱导黑质-迷走神经通路的适应性异常可塑性，有利于进展 警局的。“我们进一步假设，纠正这种适应不良的神经可塑性将预防帕金森症。至 研究这一新的假说，我们将使用体内化学遗传学和电生理学的组合， 用解剖学和行为学方法在啮齿动物身上研究受影响的神经通路的作用 帕金森病相关的胃肠功能障碍与帕金森病的发病机制。

项目成果

The cross-hemispheric nigrostriatal pathway prevents the expression of levodopa-induced dyskinesias.

• DOI: 10.1016/j.nbd.2021.105491
• 发表时间: 2021-11
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Iyer V;Venkiteswaran K;Savaliya S;Lieu CA;Handly E;Gilmour TP;Kunselman AR;Subramanian T
• 通讯作者: Subramanian T

The substantia nigra modulates proximal colon tone and motility in a vagally-dependent manner in the rat.

黑质以迷走神经依赖性方式调节大鼠近端结肠张力和运动。

• DOI: 10.1113/jp284238
• 发表时间: 2023
• 期刊: The Journal of physiology
• 作者: Xing,Tiaosi;Nanni,Giorgia;Burkholder,CameronR;Browning,KirsteenN;Travagli,RAlberto
• 通讯作者: Travagli,RAlberto