No Direct Projection is Observed from the Substantia Nigra to the Dorsal Vagus Complex in the Rat

Wang, Zhiyong; Lian, Hui; Cai, Qingqing; Song, Haiyan; Zhang, Xiaoli; Zhou, Li; Zhang, Yimin; Zheng, Li‐Fei; Zhu, Jinxia

doi:10.3233/jpd-130279

Cited by 29 publications

(24 citation statements)

References 45 publications

(54 reference statements)

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“…Artificial expression/inoculation of αS in the vagal nerve successfully induced αS immunoreactivity in dmX neurons as expected . Even though downward projections from SN to LC (Fig. , interrupted line with arrowhead) and those from LC to dmX (Fig.…”

Section: Where and How Lewy Pathology Spreads In The Human Brainsupporting

confidence: 72%

An order in Lewy body disorders: Retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal/multifocal Lewy body disease

Uchihara

2016

Neuropathology

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Initial clinical recognition of "paralysis agitans" by James Parkinson was expanded by Jean-Martin Charcot, who recognized additional clinical findings of his own, such as slowness (distinct from paralysis), rigidity (distinct from spasticity) and characteristic countenance. Charcot assembled these findings under the umbrella of "Parkinson disease (PD)". This purely clinical concept was so prescient and penetrating that subsequent neuropathological and biochemical evidences were ordered along this axis to establish the nigra-central trinity of PD (dopamine depletion, nigral lesion with Lewy bodies: LBs). Although dramatic efficacy of levodopa boosted an enthusiasm for this nigra-centralism, extranigral lesions were identified, especially after identification of alpha-synuclein (αS) as a major constituent of LBs. Frequent αS lesions in the lower brainstem with their presumed upward spread were coupled with the self-propagating property of αS molecule, as a molecular template, to constitute the prion-Braak hypothesis. This hybrid concept might expectedly explain clinical, structural and biochemical features of PD/dementia with Lewy bodies (DLB) as if they were stereotypic. In spite of this ordered explanation, recent studies have demonstrated unexpectedly that αS lesions in the human brain, as well as their corresponding clinical manifestations, are much more disordered. Even with such a chaos of LB disorders, affected neuronal groups are uniformly characterized by hyperbranching axons, which may facilitate distal-dominant degeneration and retrograde progression of LB-related degeneration along axons as a fundamental structural order to template LB disorders. This "structural template" hypothesis may explain why: (i) some selective groups are prone to develop Lewy pathology; (ii) their clinical manifestations (especially non-motor components) are vague and generalized without somatotopic accentuation; (iii) distal axons and terminals are preferentially affected early, which is clinically detectable as reduced myocardial uptake of metaiodobenzylguanidine in PD/DLB. Because each Lewyprone system develops LBs independently, their isolated presentation as "focal LB disease" or their whatever combinations as "multifocal LB disease" are a more plausible framework to explain clinicopathological diversities of LB disorders. Clinical criteria are now being revised to integrate these clinicopathological disorders of PD/DLB. To gain closer access to the reality of the human brain, it is necessary to facilitate more interactions between clinicopathological and experimental fields so that both are mutually critical and complementary for improved diagnosis and treatment.

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Section: Where and How Lewy Pathology Spreads In The Human Brainsupporting

confidence: 72%

An order in Lewy body disorders: Retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal/multifocal Lewy body disease

Uchihara

2016

Neuropathology

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“…2i). Since it has been reported that the LC projects mainly to the SNr [6, 55], it seems plausible that the additional asyn pathology of the SNr was caused by asyn propagation through LC connections. Though neuronal connectivity is necessary, additional factors might contribute to the anatomical pattern of asyn pathology propagation [32].…”

Section: Discussionmentioning

confidence: 99%

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

et al. 2019

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The conversion of endogenous alpha-synuclein (asyn) to pathological asyn-enriched aggregates is a hallmark of Parkinson’s disease (PD). These inclusions can be detected in the central and enteric nervous system (ENS). Moreover, gastrointestinal symptoms can appear up to 20 years before the diagnosis of PD. The dual-hit hypothesis posits that pathological asyn aggregation starts in the ENS, and retrogradely spreads to the brain. In this study, we tested this hypothesis by directly injecting preformed asyn fibrils into the duodenum wall of wild-type rats and transgenic rats with excess levels of human asyn. We provide a meticulous characterization of the bacterial artificial chromosome (BAC) transgenic rat model with respect to initial propagation of pathological asyn along the parasympathetic and sympathetic pathways to the brainstem, by performing immunohistochemistry at early time points post-injection. Induced pathology was observed in all key structures along the sympathetic and parasympathetic pathways (ENS, autonomic ganglia, intermediolateral nucleus of the spinal cord (IML), heart, dorsal motor nucleus of the vagus, and locus coeruleus (LC)) and persisted for at least 4 months post-injection. In contrast, asyn propagation was not detected in wild-type rats, nor in vehicle-injected BAC rats. The presence of pathology in the IML, LC, and heart indicate trans-synaptic spread of the pathology. Additionally, the observed asyn inclusions in the stomach and heart may indicate secondary anterograde propagation after initial retrograde spreading. In summary, trans-synaptic propagation of asyn in the BAC rat model is fully compatible with the “body-first hypothesis” of PD etiopathogenesis. To our knowledge, this is the first animal model evidence of asyn propagation to the heart, and the first indication of bidirectional asyn propagation via the vagus nerve, i.e., duodenum-to-brainstem-to-stomach. The BAC rat model could be very valuable for detailed mechanistic studies of the dual-hit hypothesis, and for studies of disease modifying therapies targeting early pathology in the gastrointestinal tract.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02040-w) contains supplementary material, which is available to authorized users.

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“…A number of neuro-anatomical tracer studies have demonstrated the existence of relevant neuronal interconnections [12][13][14][15][16][17][18][19][20][21][22][23][24] (summarized in Figure 1). Most studies employed classical retrograde and anterograde staining techniques such as horseradish peroxidase, fluorogold, and phaseolus vulgaris leucoagglutinin in rodents, cats, and monkeys.…”

Section: Neuro-anatomical Pathways Subserving A-syn Propagationmentioning

confidence: 99%

“…First, the most relevant mono-synaptic interconnections necessary for the hypothesized stereotypical a-syn spreading pattern 3 have been demonstrated. The DMV is connected to the raphe nuclei and locus coeruleus (LC), 12,17,19,22 which are in turn connected to the substantia nigra. 12,18,23 Importantly, no direct mono-synaptic pathways have been found between the DMV and the nigra, 12 which could conceivably introduce a time lag for the a-syn propagation from the lower brain stem to the mesencephalon.…”

Section: Neuro-anatomical Pathways Subserving A-syn Propagationmentioning

confidence: 99%

How does parkinson's disease begin? Perspectives on neuroanatomical pathways, prions, and histology

Borghammer

2017

Movement Disorders

120

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Parkinson's disease (PD) is a multisystem disorder with involvement of the peripheral nervous system. Misfolding and aggregation of α-synuclein is central to the pathogenesis of PD, and it has been postulated that the disease may originate in olfactory and gastrointestinal nerve terminals. The prion-like behavior of α-synuclein has been convincingly demonstrated in vitro and in animal models of PD. Lewy-type pathology have been detected in peripheral organs many years prior to PD diagnosis, and 2 independent studies have now suggested that truncal vagotomy may be protective against the disorder. Other lines of evidence are difficult to reconcile with a peripheral onset of PD, most importantly the relative scarcity of post mortem cases with isolated gastrointestinal α-synuclein pathology without concomitant CNS pathology. This Scientific Perspectives article revisits some important topics with implications for the dual-hit hypothesis. An account of the neuroanatomical pathways necessary for stereotypical α-synuclein spreading is presented. Parallels to the existing knowledge on true prion disorders, including Creutzfeld-Jakob disease, are examined. Finally, the vagotomy studies and the somewhat inconsistent findings in the growing literature on peripheral α-synuclein pathology are discussed. It is concluded that the dual-hit hypothesis remains a potential explanation for PD pathogenesis, but several issues need to be resolved before more firm conclusions can be drawn. © 2017 International Parkinson and Movement Disorder Society.

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No Direct Projection is Observed from the Substantia Nigra to the Dorsal Vagus Complex in the Rat

Cited by 29 publications

References 45 publications

An order in Lewy body disorders: Retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal/multifocal Lewy body disease

An order in Lewy body disorders: Retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal/multifocal Lewy body disease

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

How does parkinson's disease begin? Perspectives on neuroanatomical pathways, prions, and histology

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