FORUM REVIEW ARTICLE

Causes and Consequences of Degeneration of the DorsalMotor Nucleus of the Vagus Nerve in Parkinson’s Disease

James G. Greene

Abstract

Significance: Parkinson’s disease (PD) is no longer considered merely a movement disorder caused by de-generation of dopamine neurons in the midbrain. It is now recognized as a widespread neuropathologicalsyndrome accompanied by a variety of motor and nonmotor clinical symptoms. As such, any hypothesisconcerning PD pathogenesis and pathophysiology must account for the entire spectrum of disease and not solelyfocus on the dopamine system. Recent Advances: Based on its anatomy and the intrinsic properties of itsneurons, the dorsal motor nucleus of the vagus nerve (DMV) is uniquely vulnerable to damage from PD. Fibersin the vagus nerve course throughout the gastrointestinal (GI) tract to and from the brainstem forming a close linkbetween the peripheral and central nervous systems and a point of proximal contact between the environment andareas where PD pathology is believed to start. In addition, DMV neurons are under high levels of oxidative stressdue to their high level of a-synuclein expression, fragile axons, and specific neuronal physiology. Moreover,several consequences of DMV damage, namely, GI dysfunction and unrestrained inflammation, may propagate avicious cycle of injury affecting vulnerable brain regions. Critical Issues: Current evidence to suggest the vagalsystem plays a pivotal role in PD pathogenesis is circumstantial, but given the current state of the field, the timeis ripe to obtain direct experimental evidence to better delineate it. Future Directions: Better understanding ofthe DMV and vagus nerve may provide insight into PD pathogenesis and a neural highway with direct brainaccess that could be harnessed for novel therapeutic interventions. Antioxid. Redox Signal. 00, 000–000.

Introduction

Parkinson’s disease (PD) is a common neurologicaldegenerative disorder affecting 1% of individuals over 55

years of age, the cardinal features of which are related tomotor function: resting tremor, rigidity or stiffness, brady-kinesia or slowness of movement, and postural instability(71). Additionally, PD is associated with a multitude ofnonmotor symptoms, including disturbances of sleep, cog-nition, mood, autonomic regulation, and gastrointestinal (GI)function (230). As therapy for the motor features of PD hasadvanced dramatically, treatments of the nonmotor symp-toms of the disorder have lagged behind to the point that theyhave become some of the most common and frustratingproblems faced by PD patients (230). For example, more than8/10 hospital admissions for PD are directly due to nonmotorsymptoms, and the majority of disability in later stage PD isrelated to symptoms that do not respond to levodopa, the mosteffective motor therapy for PD (128, 266, 287).

Much as the recent understanding of PD as a clinicalsyndrome broadened from one focused narrowly on motorsymptoms, so has the understanding of PD as a neuropatho-logical syndrome broadened from one focused on dopamineneurons in the midbrain substantia nigra to one encompassingwidespread regions of the central nervous systems (CNS) andperipheral nervous systems (PNS) (16, 17, 35, 159). In ad-dition to the substantia nigra, neuronal loss has been con-vincingly described for noradrenergic neurons in the pontinelocus ceruleus, cholinergic and noradrenergic neurons insympathetic centers in the spinal cord and periphery, andcholinergic neurons in the dorsal motor nucleus of the vagusnerve (DMV) in the medulla, among other areas (19, 86, 95,96, 103, 104, 119, 131, 209). Furthermore, the pathologicalhallmark of PD, Lewy bodies as detected by abnormal a-synuclein (AS) immunoreactivity, is spread through an evenwider variety of neurochemical subtypes, including cells inthe olfactory bulb, cerebral cortex, pontine raphe, spinal cord,and enteric nervous system (ENS) (16, 35, 77, 139, 165).

Department of Neurology, Emory University, Atlanta, Georgia.

ANTIOXIDANTS & REDOX SIGNALINGVolume 00, Number 00, 2014ª Mary Ann Liebert, Inc.DOI: 10.1089/ars.2014.5859

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Thus far, data indicate that many of these areas are morevulnerable than the midbrain dopamine neurons to Parkin-sonian pathology and death. In fact, the extreme focus onpathology in dopamine neurons over the past century mayhave limited our understanding of PD as a more systemicneurological disorder (159, 169, 261).

This view of PD is more a rediscovery than a new one.When James Parkinson first described the disorder in 1817,he described a multitude of nonmotor symptoms and hy-pothesized that the ‘‘proximate cause’’ was a ‘‘diseased stateof the medulla spinalis.extending, as the disease proceeds,to the medulla oblongata (216).’’ Frederic Lewy describedthe pathological hallmark of PD, the Lewy body, in the early1900s in the basal forebrain and medulla before noting themin the midbrain (172, 173). As the field has returned to con-sidering PD as a systemic disease, many theories concerningits pathophysiology focused solely on dopamine neuronshave required reevaluation. Although the dopaminergicphenotype is still an important component related to selectiveneuronal vulnerability in PD, it is not the only one. In par-ticular, anatomical and pathophysiological links between thePNS and CNS and the specific subtypes of affected neuronswithin each are prerequisites to any comprehensive theory ofPD pathogenesis.

The DMV and the vagus nerve provide such a link. Lo-cated in the lower brainstem, the DMV contains widelyramified neurons projecting to nearly every part of the pe-riphery. In addition, the vagal complex has extensive inter-connections to the rest of the brain. Stimulation of the nervehas profound effects in both central and peripheral directionswith the vagal nerve stimulation widely used as a treatmentfor epilepsy and depression refractory to medications andexperimentally used for its cardioprotective, antiasthmatic,anti-inflammatory, and GI promotility effects (32, 59, 116,154, 181, 245, 271).

In this review, I will review the basic anatomy of the DMV,discuss the impact of PD on the nucleus, and review potentialconsequences of and causes for DMV degeneration in PD.

Functional Anatomy of the Vagus Nerve and DMV

The vagus nerve is a mixed cranial nerve (the 10th) thatcontains (in descending order of abundance) (i) afferentvisceral sensory (predominantly autonomic) fibers from theheart, lungs, GI tract and accessory organs (spleen, liver,gallbladder), sweat glands, and other areas; (ii) efferent vis-ceral motor (autonomic) fibers to a roughly similar distribu-tion of tissues; (iii) efferent somatic motor fibers to severalskeletal muscles of the pharynx and larynx; (iv) afferentspecial sensory fibers mediating taste in portions of thepharynx; and (v) afferent general sensory fibers from parts ofthe ear and surrounding skin (Fig. 1) (234).

Vagus nerve functions are regulated by a central auto-nomic network that integrates visceroceptive, humoral, andenvironmental information and modulates autonomic, endo-crine, behavioral motor, emotional, attentional, and anti-nociceptive output (18, 45, 182). The structures forming thecentral autonomic network are widely distributed at all levelsof the nervous system, including the cerebral cortex, basalforebrain, basal ganglia, midbrain, thalamus, hypothalamus,pons, and medulla (45, 46, 180, 202). Although less well-studied than for motor function, the basal ganglia appear toplay a similar comparator role in autonomic function mod-ulating the iterative processing of the central network; bothanatomical and neurophysiological connections have beendescribed (5, 54, 67, 90, 92, 105, 112, 118, 138, 158, 176,178, 183, 223–225, 259, 264).

The DMV is a paired nucleus on each side of the caudalmedulla that runs longitudinally along the dorsomedial as-pect of the brainstem (Fig. 1). It gives rise to preganglionic

FIG. 1. Anatomy of the DMV and vagus nerve. (A) Schematic of a ventral view of the human brainstem noting theapproximate location of the DMV. (B) Schematic of a cross section of the human brainstem at the level of the medullaindicating different components of the vagus nerve. DMV, dorsal motor nucleus of the vagus nerve; GI, gastrointestinal;NTS, nucleus of the tractus solitarius; Nuc., nucleus; n., nerve.

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parasympathetic autonomic fibers that innervate the GI tractand accessory organs from the distal third of the esophagus toapproximately the splenic flexure of the colon, although thereis some evidence for more distal projections (22). Cardiovas-cular preganglionic parasympathetics arise predominantlyfrom the nucleus ambiguus rather than the DMV (206).

DMV neurons have thin, widely ramified axons with min-imal myelination that are among the longest in the body (33,169). This is in contradistinction to other fibers in the vagusnerve (afferent and somatic motor efferent) with adjacent lo-cations in the medulla that have more robustly myelinatedneurites with simpler branching structures. Acetylcholine isthe major neurotransmitter for DMV neurons, although othersare thought to function as cotransmitters, including substanceP and catecholamines.

Parasympathetic innervation from the DMV is importantfor control of GI motility and reflexes, especially in thestomach (219, 237, 267, 268). About 25%–30% of fibers inthe abdominal vagus nerve are efferent fibers that modulatefunction of the ENS, a semi-autonomous network of neuronslining the entire alimentary canal to control GI function(142). Individual axons from DMV neurons ramify widelyinto an extensive network contacting nearly every entericneuron, especially in the proximal GI tract (Fig. 2) (22, 205).Vagotomy has long been known to result in GI dysfunction;less well known are GI complications due to pathologicallesions of the DMV itself (240, 241, 254).

In addition to its classical function as a modulator of GIfunction, the DMV has recently been described as a potent in-hibitor of inflammation via the cholinergic anti-inflammatorypathway (32, 248, 279). Studies have shown that activation ofvagal parasympathetics attenuates the systemic inflammatoryresponse to a variety of insults, including endotoxin admin-istration (32). This effect is mediated via the a7 subunit ofthe nicotinic acetylcholine receptor, which is expressed onmacrophages (279). In addition to the anti-inflammatory ef-fect of vagus nerve stimulation, physical or pharmacologicalvagotomy has a proinflammatory effect, in which the branchof the vagus nerve that innervates the spleen has been shownto be particularly important (137, 222, 246). The afferent

signaling for this iterative inflammatory/anti-inflammatoryloop has both neural and humoral components and is mod-ulated by multiple central and systemic signaling mecha-nisms (76, 208, 220, 221, 247, 248, 288, 289).

Pathophysiology of the DMV in PD

There are two main ways that PD may affect the vagalsystem. One is the direct impact of neuronal damage to vagusneurons. For example, loss of DMV innervation to the gutcauses GI problems by cutting a hard-wired pathway. Theother is the downstream deleterious effect of central neuro-degeneration on iterative processing of autonomic regulation.For example, from a motor standpoint, it is now accepted thatmotor parkinsonism is a circuit disorder, rather than a straightline from dopamine depletion to motor dysfunction. Given theevidence accumulated thus far, autonomic symptoms in PDmay be caused by both mechanisms. Whereas this review willprimarily focus on the direct damage accumulated by DMVneurons in PD, considering the DMV as one node in a dis-tributed network is helpful to place these findings in context.

Disrupted central regulation of DMV output

Loss of substantia nigra neurons and subsequent striataldopamine depletion is a primary driver of PD motor symp-toms by disrupting basal ganglia circuit function (39, 49, 61,101, 121, 171, 188, 189, 207, 249, 255). Loss of integrity inthe circuitry of the striatum increases the oscillatory activityin corticocortical loops by propagating to basal ganglia out-put nuclei (63, 69, 102, 187, 239). Experimental studies haveshown that pharmacological blockade of dopamine receptors(61, 87) or lesion of the nigrostriatal pathway (284, 285)increases the neuronal synchronization and oscillatory activityin the basal ganglia (40, 101, 121, 170, 280). In the parkin-sonian brain, dopaminergic drugs (127, 274) and deep brainstimulation have been found to reduce synchronization inconjunction with their therapeutic effect (70, 274). While thisabnormal circuit activity has been intensively investigated inregard to motor function, its contribution to other symptoms isless clear.

FIG. 2. Anatomy of inter-actions between the vagusnerve and enteric nervoussystem (ENS) in the GI tract.(A) Schematic of intercon-nections between the vagusand ENS. (B) Efferent nerveterminals from the DMV sur-rounding a neuronal ganglionin the myenteric plexus high-lighted by a-synuclein im-munostaining in a transgenicmouse. (C) Neurites in prox-imity to the intestinal lumenhighlighted by peripherin im-munostaining in a mouse(205). Arrows mark a neuritein an intestinal villus and ar-rowheads mark enteric neu-rons in ganglia.

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The relationship between dopamine depletion and auto-nomic dysfunction has been examined in a few previousstudies. In rats, the salivary response is dependent upon theactivity of dopamine receptors in the striatum and decreasedby striatal lesions (223–225). Baroreflex regulation of bloodpressure has been reported to be dependent on the nigros-triatal pathway in rodents (5, 67, 176, 178, 183). In addition,GI motility can be modulated by basal ganglia activity, es-pecially in the caudate (112, 158, 264). In some PD patients,deep brain stimulation in the subthalamic nucleus has beenreported to improve cardiovascular and GI dysfunction (134,161, 292).

More specific to the vagal system, animals with lesions ofthe nigrostriatal tract show reduced choline acetyltransferaseexpression in the DMV and decreased levels of acetylcholinein the gastric wall (291). Although dopamine receptors areexpressed by both cholinergic and catecholaminergic neu-rons in the DMV (43), a direct anatomical link between thetwo structures has not yet been demonstrated.

It is enticing to hypothesize that there are loop circuitsregulating the autonomic function analogous to those dem-onstrated for somatic motor control and that these loops maynot only link a distributed network of brain nuclei but also theperipheral and ENS. This is likely to be a fruitful area ofresearch in the future; however, at present, the existence anddysfunction of such loops are largely hypothetical, whiledirect pathological damage to the DMV has been clearly andrepeatedly demonstrated in PD patients.

Neuropathology of the DMV in PD

Although PD has predominantly been considered a diseaseof dopaminergic neurons in the substantia nigra, it has longbeen known that there is substantial neuropathology in otherareas. For example, extensive cell loss on the order of > 50%in the DMV has been described consistently in PD since 1925(82, 88, 126). This loss is age dependent in PD in that, olderage correlates with fewer DMV neurons; however, there is noage-dependent loss of DMV neurons in individuals withoutPD (95). Preganglionic parasympathetic neurons in the DMVare preferentially vulnerable to degeneration (82, 119, 120).

Lewy bodies, eosinophilic proteinaceous intracellular in-clusions that are a pathological hallmark of PD, were de-scribed in the DMV before their recognition in the substantianigra (172, 173, 226). Additionally, the DMV has been notedto have the highest number and density of ubiquitin-positivedegenerating neurites of any brain nucleus in PD. Intrigu-ingly, the density of degenerating neurites in the DMV cor-relates with the duration of PD, while the density in thesubstantia nigra does not (94).

In 1997, mutations in a-synuclein (AS) were described asan autosomal dominant cause of parkinsonism (231). Soonafter, it was described that AS was a major component ofLewy bodies in all cases of idiopathic PD (260). Thesefindings led to a renewed appreciation for Lewy pathologyand careful examination of its extent and character in PD.Using immunostaining techniques, AS aggregation, particu-larly in neurites, has been shown to be very prominent in theDMV (35, 145, 217).

Lewy neurites have been described in the ENS in nearly100% of PD patients at autopsy (Fig. 3) (6, 155, 236, 275–277). The vast majority ( > 97%) of ENS synuclein pathology

in PD is not cytoplasmic Lewy bodies in enteric neuron cellbodies, but neuritic Lewy pathology around the ENS, afinding that is recapitulated in AS transgenic mice (34, 276,277). The distribution of pathology in both humans andtransgenic mice mirrors that of efferent DMV innervation tothe ENS nearly exactly, where neuritic AS aggregation andLewy pathology are common proximally (stomach) and raredistally (rectum) (6, 17, 205, 276, 277).

It has been suggested that AS neuritic pathology affects theDMV very early in the course of PD, and furthermore, neu-ritic AS pathology in the GI tract occurs at least as early, if notearlier (33–35). In fact, Braak has proposed a pathologicalstaging system of PD based on AS pathology derived fromcharacterization of AS neuritic pathology in brains from PDpatients as well as aged patients where incidental AS neuriticpathology was found on neuropathological examination (33,35). The scheme proposes that PD pathology begins in theDMV, with subsequent spread of AS pathology rostrally fromthe DMV to pontine nuclei (locus ceruleus, raphe), to mid-brain (substantia nigra), and last, to the cortical areas. This

FIG. 3. Examples of Lewy bodies in the GI tract. (A)Lewy body in a myenteric ganglion in the ileum from a PDpatient highlighted by a-synuclein immunostaining. (B)Lewy bodies in the mucosa and submucosa in the stomachfrom a PD patient highlighted by a-synuclein im-munostaining (6). PD, Parkinson’s disease.

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model is quite controversial, with some authors in agreementand others less so (41, 144, 145, 177, 217). In particular, atheory of progressive pathogenesis based on cross-sectionalpostmortem data and the assumption that patients with inci-dental Lewy pathology would ultimately develop PD isproblematic. However, there is uniform agreement that theDMV is consistently and severely affected by PD pathologyearly in the disease course.

Consequences of DMV Degeneration in PD

Given the functions of the vagus nerve, there are multiplepotential consequences to dysfunction and degeneration ofthe DMV that may impact PD patients, including GI dys-function and unchecked inflammation. In addition to directimpact on patient symptoms and quality of life, damage toDMV neurons could contribute to a feed-forward cycle in thepathophysiology of PD whereby loss of DMV functionworsens neuropathology (Fig. 4).

GI dysfunction

GI dysfunction is a prominent nonmotor symptom in PDthat occurs in nearly every patient at some point in his or herillness (85, 227, 228). Symptoms span the entire alimentarytract and include early satiety and nausea from delayed gas-tric emptying, bloating from poor small bowel coordination,and constipation and defecatory dysfunction from impairedcolonic transit (84, 85, 196, 227).

A comprehensive survey of PD patients in the late 1980’sfound that problems with saliva occurred in 70% of PD pa-tients, dysphagia (trouble swallowing) in 52%, nausea in 24%,and constipation in 29%, whereas the same symptoms werereported by less than 10% of age-matched control individuals.In addition, defecatory dysfunction was reported by two-thirdsof PD patients—twice the control prevalence (84).

Subsequent studies have confirmed the high frequency ofGI abnormalities in PD. Abnormal gastric emptying has beendescribed in 43%–88% of PD patients and can worsen as PDprogresses (79, 106, 107, 125, 153, 201). Interestingly, ob-jective gastric motility abnormalities are frequently detected

even in PD patients without subjective GI complaints (50).The incidence rate of constipation in PD has been estimatedto be anywhere from 29% to 81%, and problems with defe-cation are also much more common in PD (*60%) than inage-matched controls (*25%) (83, 250, 256, 257).

GI dysfunction has many important consequences for PDpatients. First, GI symptoms negatively impact the quality oflife. They have significant psychosocial impact by causingalterations in eating habits, contributing to feelings of em-barrassment, and invoking the need for social and caregiveradjustment (196, 250). Second, GI dysfunction in PD is as-sociated with serious, possibly life-threatening complica-tions, including pulmonary aspiration, weight loss,malnutrition, megacolon, and intestinal pseudo-obstruction(1, 12, 85, 147, 190, 204, 251). Third, GI dysfunction dra-matically impacts motor PD symptoms by causing erraticabsorption of oral medications, motor fluctuation, and med-ication side effects (10, 79, 80, 106, 107, 156, 201). Finally, ithas recently been hypothesized that GI disturbance may be asentinel event in the manifestation of PD. Constipation canappear decades before motor symptoms in PD, and recentdata from a large-scale study suggest that constipation isassociated with an increased risk of future PD (2, 269).

The majority of GI symptoms have objective correlatesrelated to abnormal motility of the GI tract. For example, notonly do patients describe symptoms of early satiety andbloating but also they have evidence that slowed stomachmotility and delayed gastric emptying are responsible forthose symptoms (50, 79, 107). Similarly, patients experi-encing constipation have objective evidence for slowed co-lonic transit, and patients with defecatory dysfunction haveelectrophysiologic sphincter abnormalities (8, 9, 84, 143).The total GI tract transit time is also significantly prolongedin PD (66).

In addition to dysmotility, it has recently been suggestedthat PD patients have increased GI permeability and gutleakiness. Two small studies have indicated using noninva-sive testing that absorption of nonmetabolizable sugars isgreater in PD patients, implying that permeability across theGI mucosa is higher (89, 252). One has shown an increase in

FIG. 4. Damage to the DMV may prop-agate a vicious cycle of neuronal damagein PD. This is a schematic hypothesis of theinvolvement of the DMV in PD pathogenesis.Factors intrinsic and extrinsic to the DMVcontribute to pathology in an iterative cycle.The trigger or starting point for such a cycleis not known.

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Escherichia coli density in the epithelium and lamina propriaand an indication that PD patients have greater exposure tobacterial endotoxin (89). These findings correlated with ab-normal AS immunoreactivity and markers of neuroin-flammation; however, data are scarce, and the extent andcauses of increased gut permeability are unknown.

Despite the frequency of GI dysfunction and GI neuro-pathology in PD, it is not clear whether or not there is acausal relationship between the two findings, and clinico-pathological correlation studies have only begun to beperformed (6, 72, 89, 164, 165). Recent evidence from co-lon biopsies indicates both synuclein aggregation and neu-ronal loss in the submucosal plexus of the ENS possiblycorrelated with GI symptoms in some way (163, 165, 232).This is in contradistinction to the myenteric plexus of theENS which, although it contains a greater burden of synu-clein pathology, does not exhibit loss of neurons (6). As faras the potential role of vagal pathology, there is a casereport of motor fluctuations first developing in a PD patientimmediately after vagotomy (78). In addition, transgenicanimals expressing abnormal AS in the DMV exhibit age-dependent GI dysfunction similar to that seen in PD in theabsence of synuclein pathology in enteric neurons them-selves (205). Experience from the midbrain suggests thatclinical symptoms in PD are driven primarily by neuronalloss rather than aggregation of a-synuclein, so quantitativeevaluation of neuron populations that control GI motility isan important step toward determining the pathological un-derpinnings of GI symptoms in PD. In this regard, explo-ration of DMV pathology is more advanced than that forother neuronal populations that modulate GI motility sinceneuronal loss has been convincingly described in PD;however, no direct correlations between vagal pathologyand GI symptoms have been completed (82, 88, 126). Ob-viously, these would be difficult studies to perform, sincepathological evaluation of the DMV necessarily occurspostmortem, but organizations such as the Arizona Parkin-son’s Disease Consortium and the Banner Sun Health Re-search Institute Brain and Body Donation Program haverecently begun to address this need (6). Equally intriguing isthe potential to use advanced imaging techniques such asfunctional magnetic resonance imaging to monitor DMVactivity in real time in PD patients or animal models with GIsymptoms (150, 186, 268, 270, 282, 283).

Unchecked inflammatory responses

Activated microglia, accumulation of proinflammatory cy-tokines, nuclear factor kappa B pathway activation, and oxi-dative damage to proteins have all been described in the brainsof individuals with PD (132, 262, 263). Intriguingly, themidbrain from patients or primates exposed to the dopa-mine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) years earlier (supposedly a one-time event) displayedsimilar microglia activation and signs of active neurodegen-eration at autopsy suggesting that common mechanismsmay underlie degeneration induced by divergent triggers (14,160, 195). In addition, the chronic use of nonsteroidal anti-inflammatory drugs, in particular, ibuprofen, has been asso-ciated with a lower incidence of PD (51, 52, 253).

Experimental evidence from rodent models also supports arole for both innate and adaptive immune system modulation

of dopamine neuron survival. Exposure of dopamine neuronsto the gram-negative bacterial endotoxin lipopolysaccharide,after either direct infusion into the midbrain or intraperitonealinjection, results in delayed loss of dopamine neurons asso-ciated with persistent neuroinflammation in the midbrain (91,98, 99, 235). Even dopaminergic damage caused by nonin-flammatory insults such as MPTP or 6-hydroxydopamine isprevented by blockade of proinflammatory cytokines such astumor necrosis factor a, inhibition of cyclooxygenase, oralteration of adaptive immunity by transfer of T lymphocytes(20, 37, 91, 136, 168, 194, 242, 243, 265). Importantly,transient initiation factors (i.e., toxins, bacterial or viral in-fections, particulate matter, and pesticides) may trigger anactive, self-perpetuating cycle of chronic neuroinflammation(i.e., increased production of chemokines, cytokines, reactiveoxygen species/reactive nitrogen species, and adhesionmolecules by activated microglia), which serves to furtherpromote clustering of activated microglia around dopamineneurons and may contribute to irreversible neuronal dys-function and cell death (13, 38).

Although selective loss of midbrain dopamine neuronsfrom the substantia nigra pars compacta is the typically rec-ognized pathological hallmark of PD, as discussed above,many levels of the nervous system are pathologically affectedby PD, with the DMV, one of the most severely and earliestaffected spots (82, 88, 126). The usual interpretation of thesefindings has been that the same pathological processes thatimpact dopamine neurons affect DMV neurons. That maycertainly be correct; however, the early involvement of theDMV and a broader vagal system may have additional im-plications for PD pathogenesis. In particular, the possibilitythat early loss of DMV neurons and a resultant deficiency ofvagal anti-inflammatory signaling exacerbate damage todopamine neurons is intriguing because if true, it would opena window of opportunity to protect dopamine neurons in PD.Whereas not explored in any neurodegenerative diseases todate, the hypothesis that anti-inflammatory actions mediatedby the vagus nerve could be neuroprotective is gainingtraction in other brain diseases such as stroke and traumaticbrain injury (53, 133, 154). It has been known for years thatpeople who smoke have a lower incidence of PD and thatnicotine is protective in animal model systems (30, 117, 149,233, 238). Given that the anti-inflammatory effects of thevagus are dependent on stimulation of nicotinic acetylcholinereceptors, it is possible that the protective effect of nicotineagainst PD is explained by the anti-inflammatory effects ofnicotinic receptor activation (148, 214).

Causes of DMV Degeneration in PD

There are myriad proposed mechanisms of neurode-generation in PD with the precise one likely a combinationof environmental and host factors, including genetics. Thissection will review proposed causes of neurodegenerationwith a focus on the unique qualities of DMV neurons thatmay make them particularly susceptible to damage in PD. Inaddition, the consequences of damage to DMV neuronsdescribed above are likely contributors to a feed-forwardcycle in the pathophysiology of PD (Fig. 4). A slowerGI transit increases the exposure to potentially toxic en-vironmental agents, increases inflammation by alteringthe luminal microbiotic environment, and disrupts brain-

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gut feedback loops; increased epithelial permeability hassimilar consequences. For example, although runaway in-flammation may be a consequence of DMV damage, it mayalso be a contributing cause.

Inflammation and neuroinflammation

Although it has not yet been studied, DMV neurons aretheoretically susceptible to many of the same inflammatoryinsults as dopamine neurons. Perhaps, more prescient withregard to the role of inflammation in PD is the unique positionbridging the central and PNS. In fact, DMV neurons arepotentially exposed to a myriad of inflammatory insults viaaxon terminals in proximity to the GI lumen and, as such, theoutside world (Fig. 2). This anatomy has led to the provoc-ative idea that PD may be caused by an unidentified envi-ronmental agent that gains access to the CNS via the GI tractand vagus nerve (36).

The anatomy (or highway) to support such a theory is fairlywell known (193, 198). More intriguingly, mice exposed tothe influenza virus not only show viral infection in serialprogression from the ENS to the DMV to substantia nigradopamine neurons but evidence of AS aggregation, micro-glial activation, and neurodegeneration in the same regions(140). This raises the possibility that a localized, transientevent could propagate in time and space to become a wide-spread self-sustaining neurodegenerative cycle.

A clinical association between the GI tract and inflam-mation in PD is just starting to be investigated, but recentepidemiologic and clinical evidence suggests a link. Pro-inflammatory cytokines and markers of glial activation areupregulated in the colon from PD patients (75). In addition,eradication of Helicobacter pylori (a common cause of gas-tric inflammation and ulcers) modifies PD progression andclinical deterioration (28, 81). Moreover, serum Helicobacterantibody profile may predict the presence, severity, andprogression of PD (281). Recently, a polymorphism in theCARD15 gene previously associated with inflammatory bo-wel disease (IBD) has been associated with PD (26); viceversa, LRRK2, a causative PD mutation, is a susceptibilitylocus for IBD (15). Another putative PD gene, NR4A2, hasalso been linked to GI inflammation (122, 162). In rats, IBDexacerbates in vivo damage to midbrain dopamine neurons byan inflammation-mediated process (273).

As discussed in the next section, recent evidence suggeststhat one potential trigger agent could be aggregated synucleinitself acting via a prion-like mechanism (124). In addition topropagation of pathology by direct transfer, synuclein cantrigger neuroinflammation, causing activation of macrophages,microglia, and astrocytes (3, 167). In fact, neuroinflammationand AS dysfunction can potentiate each other in animal modelsystems and drive chronic neurodegeneration (98, 100).

AS aggregation

Genetic abnormalities in AS cause parkinsonism clinicallyindistinguishable from idiopathic PD; pathological data aremore limited but indicate a similar distribution of Lewy pa-thology and neuronal loss (231, 258). As described above, ASis a major component of Lewy bodies in all cases of PD, andall types of neurons lost in PD display AS-positive Lewypathology (260). The converse is not necessarily true in that itis not clear every neuron containing aggregated AS invari-

ably dies in PD. In addition, the toxic nature of AS is stillbeing debated, and it is possible that aggregation is an attemptat a cytoprotective response rather than a cause of neuronaldeath (7, 60). Regardless of those caveats, hypotheses aboutmechanisms of neurodegeneration in PD must address AS.

The distribution of pathological AS aggregation has beendiscussed above, but AS in its native form is also expressed inDMV neurons. In rodents, AS is expressed at high levels inDMV neurons as compared with other neurons affected in PD(175). In addition, AS is very highly expressed in all efferentaxons from the DMV to the ENS, and there is also expressionof native AS in a proportion of enteric neurons (229). Giventhe widely ramified nature of each DMV axon, the burden ofnative synuclein expression in the GI tract is substantial,particularly in proximal segments like the stomach, whichcorrelates with the distribution of AS neuritic pathologyobserved in PD (6).

The exact pathophysiological mechanisms of neuronaldeath related to AS are unknown, but hypotheses abound.One involves oligomerization, fibrillation, and aggregation,in which native or mutant AS forms toxic multimeric con-structs that disrupt cellular processes (130). Another is thatoverexpression or mutation of AS causes abnormalities inmitochondrial morphology and function (135, 191). Directmitochondrial accumulation of AS with resultant complex Iinhibition has been reported in cellular models, rat brain, andPD brains (74, 179, 212, 213). A third suggests that over-expression of AS disrupts axonal transport and causes mor-phological changes in nerve terminals before cell body loss(56, 166). Another implicates increased generation of toxicoxygen or nitrogen free radical species causing indiscrimi-nate cellular damage or specific activation of downstreamapoptotic pathways (31, 135). Finally, impaired proteindegradation may facilitate all the possible mechanisms listedabove by accelerating accumulation of abnormal, misfolded,or aggregated AS (24). At present, it seems most likely thatall of the above mechanisms interact to form a complicatedinterconnecting pathophysiological network either caused orexacerbated by AS.

Particularly interesting for DMV neurons, whose terminalfields nearly abut the GI lumen, has been the recent findingthat AS and its associated pathology can propagate from cellto cell (124). The question was initially raised after a post-mortem neuropathological evaluation of neuronal transplantsplaced into the striatum of PD patients in the 1980’s revealedAS pathology and neurodegeneration in the transplanted cells(151, 152, 174). Subsequently, it was discovered that AS cantransfer from neuron to neuron and seed pathology in thereceiving neuron by a prion-like mechanism both in vitro andin vivo (73, 123, 192, 199, 200). Pathological forms of AShave been shown to induce Lewy-like pathology in normalmice and even more remarkably, to cause selective degen-eration of dopamine neurons after injection into the striatum(184, 185, 192). This process apparently involves extracel-lular release of AS, perhaps transynaptically, although theprecise mechanisms and location of transfer have not yetbeen conclusively determined (4, 62).

Defective axonal transport

A common theme in the neuropathology of PD that hasemerged over the last few years is the prominence of

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pathology in neurites. The earliest dopaminergic pathology inPD is thought to be a loss of axons projecting to the posteriorputamen (21, 64, 157, 244). Similar pathology to dopamineterminal fields in the striatum has been described in animalmodels of PD, including MPTP treatment in primates andmice and rotenone intoxication in rats, and the damage isapparent before loss of dopamine cell bodies in the substantianigra (42, 58, 129). Axonal damage has also been describedin other sites of PD pathology, such as the hippocampus,

where it is thought to correlate with cognitive dysfunction(23, 97). This has led to a theory suggesting that PD neuro-pathology may be a dying-back phenomenon progressingfrom loss of synaptic function to distal axonopathy andeventually to neuronal death (Fig. 5) (68, 110, 197, 286).

This has also been a burgeoning theme in the study of theautonomic nervous system in PD. AS neuritic pathology isoften the most prominent, only, or perhaps the earliest pa-thology observable in areas relevant to GI motility (6, 34,276). As discussed above, the DMV is not only a prominentsite of Lewy pathology in PD but also one of the mostcommon brain areas to be affected by incidental Lewy pa-thology, which is typically manifest as neuritic AS aggre-gation (35, 278).

Notwithstanding the general belief that axonal damage isthe earliest manifestation of PD pathology, there have beenfew direct investigations into the involvement of axon ter-minals in PD symptomatology and pathogenesis and none innoncatecholaminergic neurons, such as those in the DMV.However, investigations of the cardiac peripheral sympa-thetic nervous system in PD provide some interesting paral-lels. Sympathetic terminal loss is the neuropathologicalcorrelate to cardiovascular symptoms associated with par-kinsonism (110, 111). In the heart, cross-sectional postmor-tem studies suggest that damage to cardiac sympathetic nerveterminals precedes axon loss in the sympathetic nervoussystem and functions as a herald of neuron cell body pa-thology and loss (77, 93, 210, 211). DMV axons are very longand lightly myelinated meaning they may be particularlyvulnerable to axon-mediated injury, since their terminals arefar from the cell body at the end of a poorly protected andmetabolically demanding axon.

Mechanisms of nerve terminal and axon damage in PDhave not been fully elucidated (Fig. 6). Dopaminergic tox-ins like MPTP are concentrated in terminals by uptake viathe dopamine transporter whereupon they inhibit mito-chondria causing degeneration; this mechanism is active to alesser extent in norepinephrine neurons, like those in thepontine locus ceruleus (141, 203). Abnormal catecholamine

FIG. 5. PD as a dying-back neuropathy. This is a sche-matic hypothesis of a-synuclein aggregation and neuronalloss in the DMV in PD that begins in nerve terminals andaxons. As disease progresses, terminals and axons degeneratecausing symptoms. The process ultimately causes cell bodyloss in the DMV. Adapted from Orimo et al. (211).

FIG. 6. Nerve terminal degeneration in PD. This is a schematic hypothesis concerning possible mechanisms of DMVterminal damage in PD. There is a complex inter-relationship between a-synuclein, axon transport abnormalities, mito-chondrial dysfunction, inflammation, and oxidative stress. AS, a-synuclein; RNS, reactive nitrogen species; ROS, reactiveoxygen species.

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metabolism, such as that seen in mice with genetic hy-poactivity of the vesicular monoamine transporter 2, has alsobeen shown to preferentially damage catecholaminergicnerve terminals before causing selective degeneration ofcatecholaminergic cell bodies (44, 264). MPTP disrupts ax-onal transport, which can lead to terminal degeneration byinterfering with the provision of necessary cellular compo-nents, such as mitochondria (29, 31, 68, 109, 197). As aresult, mitochondria in axons and terminals are under par-ticular stress, and studies demonstrate that synaptic mito-chondria are highly vulnerable to mitochondrial complex Iinhibition (65). Overexpression of AS has recently beenshown to disrupt axonal transport and cause morphologi-cal changes in dopamine terminals before cell body loss incellular models and in mice (56, 166). When viewed inthe context of the central role that mitochondria may playin PD pathogenesis, current results suggest that the com-bination of disrupted axonal transport and mitochondrialdysfunction may be particularly damaging (27, 47, 68, 215,218, 272, 290).

High metabolic demand and oxidative stress

High cellular energy demand has been described as a ro-bust marker for selectively vulnerable neurons in a variety ofneurodegenerative diseases (57, 113, 114). In PD, neuronsvulnerable to parkinsonian neuropathology, including thosein the DMV, have a high rate of metabolic demand. Onefactor in that demand is axonal transport through long, thin,highly branched, poorly myelinated axons as discussed above(33, 169), but synaptic activity is the main driver of theneuronal metabolic demand and consumes the majority ofmitochondrial energy produced (11, 146). Axon morphologyplays a role in this demand as well, since neurons of thisshape tend to be highly metabolically active, at least partiallyas a result of the greater energy requirement for neurotrans-mission in such cells. Transmission is inherently slower insmall-caliber fibers and poor myelination means there islimited energy benefit from saltatory conduction. Ad-ditionally, the energy cost of terminal maintenance is highdue their long axon length and resultant axonal transportdemands.

Adding to these factors is the recent discovery that DMVneurons, in addition to other neurons susceptible to PD, arevulnerable to metabolic stress due to their intrinsic activitypatterns and the mechanisms by which those patterns aregenerated and maintained (108). Cholinergic DMV neuronsexhibit an autonomous pacemaker activity accompanied by arobust extracellular calcium entry that is only weakly buff-ered by endogenous proteins. Neuronal activity and calciumentry both factor into elevating mitochondrial oxidant stressin DMV neurons. These characteristics are not unique toDMV neurons, but present in several neuronal subtypesvulnerable to degeneration in PD, including dopamine neu-rons in the substantia nigra and noradrenergic neurons in thelocus ceruleus, thereby suggesting a common phenotype thatdefines neurons at risk in PD (47, 48, 261).

This hypothesis is yet to be fully tested in vivo, but oxi-dative metabolic stress related to mitochondrial dysfunctionhas been hypothesized to be intimately involved in PDpathogenesis (272, 290). A deficiency in complex I of theelectron transport chain has been consistently described in

PD, and the complex I inhibitors, MPTP and rotenone, mimicbehavioral and neuropathological features of PD in animalmodels (25, 27, 64, 215, 272, 290). As might be expected,cells more dependent on mitochondrial respiration are moresusceptible to mitochondrial inhibitors such as rotenone. Theearliest behavioral abnormality associated with systemicadministration of rotenone to rats is delayed gastric empty-ing, a result suggesting that neurons regulating GI motility,such as those in the DMV, may be particularly vulnerable tomitochondrial inhibition as is suggested by the recent phys-iological data (115).

Synthesis and Future Directions

The DMV is uniquely vulnerable to damage from PD. Thisselective vulnerability appears to be based both on its anat-omy and intrinsic properties of its neurons. From an ana-tomical standpoint, efferent fibers in the vagus nerve from theDMV course throughout the GI tract forming a close linkbetween the peripheral and CNS and a point of proximalcontact between the environment (in the GI tract lumen) andbrainstem areas where PD pathology is believed to be set inmotion. In addition, since the GI tract is the largest immuneorgan in the body, vagal terminals are particularly exposed todamaging inflammatory insults. Intrinsically, DMV neuronsare under high levels of oxidative stress due to their expres-sion level of AS, fragile axons, and specific neuronal physi-ology. Moreover, several consequences of DMV damage,namely, GI dysfunction and unrestrained inflammation, maybe the contributing causes of neurodegeneration and propa-gate a vicious cycle of injury that consumes the DMV andspreads to other vulnerable brain regions.

Although perhaps two among many, the DMV and vagusnerve may be crucial nodes in the network of pathophysi-ology that ultimately leads to PD. Their accessible anatomymay prove beneficial for PD therapeutics in the future if itcan be harnessed, via neural stimulation, gene therapy, ortargeted pharmacological intervention, to provide a systemin which to study PD pathogenesis and a highway with di-rect access to neurons particularly vulnerable to the diseaseprocess.

Author Disclosure Statement

Dr. Greene has no conflicts of interest.

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Address correspondence to:Dr. James G. Greene

Department of NeurologyEmory University

6009 Woodruff Memorial Research Building101 Woodruff Circle

Atlanta, GA 30322

E-mail: james.greene@emory.edu

Date of first submission to ARS Central, February 9, 2014;date of acceptance, March 4, 2014.

Abbreviations Used

AS¼ a-synucleinCNS¼ central nervous system

DMV¼ dorsal motor nucleus of the vagus nerveENS¼ enteric nervous system

GI¼ gastrointestinalIBD¼ inflammatory bowel disease

MPTP¼ 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinePD¼ Parkinson’s disease

PNS¼ peripheral nervous systemRNS¼ reactive nitrogen speciesROS¼ reactive oxygen species

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