Nonmotor Symptoms in Experimental Models of Parkinson's Disease

CHAPTER THREE

Nonmotor Symptoms in Experimental Models of Parkinson’s Disease Nataliya Titova*,1, Anthony H.V. Schapira†, K Ray Chaudhuri‡,§, Mubasher A. Qamar‡,§, Elena Katunina*, Peter Jenner¶ *Federal State Budgetary Educational Institution of Higher Education “N.I. Pirogov Russian National Research Medical University” of the Ministry of Healthcare of the Russian Federation, Moscow, Russia † UCL Institute of Neurology, London, United Kingdom ‡ National Parkinson Foundation International Centre of Excellence, King’s College London and King’s College Hospital, London, United Kingdom § The Maurice Wohl Clinical Neuroscience Institute, King’s College London, National Institute for Health Research (NIHR) South London and Maudsley NHS Foundation Trust and King’s College London, London, United Kingdom ¶ Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Experimental Models of PD and the Occurrence of Nonmotor Symptoms 3. Relating NMS in Experimental Models of PD to Pathophysiology 3.1 Altered Olfaction 3.2 Altered Cardiovascular Function 3.3 Alterations in Sleep 3.4 Alteration in Gastrointestinal Tract 3.5 Alterations in Bladder Functions 3.6 Alterations in Mood and Cognition 3.7 Alteration in Perception, Psychosis, and Vision 4. Conclusions and Observations References

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Abstract Nonmotor symptoms of Parkinson’s disease (PD) range from neuropsychiatric, cognitive to sleep and sensory disorders and can arise from the disease process as well as from drug treatment. The clinical heterogeneity of nonmotor symptoms of PD is underpinned by a wide range of neuropathological and molecular pathology, affecting almost the entire range of neurotransmitters present in brain and the periphery. Understanding the neurobiology and pathology of nonmotor symptoms is crucial to the

International Review of Neurobiology, Volume 133 ISSN 0074-7742 http://dx.doi.org/10.1016/bs.irn.2017.05.018

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effective treatment of PD and currently a key unmet need. This bench-to-bedside translational concept can only be successful if robust animal models of PD charting the genesis and natural history of nonmotor symptoms can be devised. Toxin-based and transgenic rodent and primate models of PD have given us important clues to the underlying basis of motor symptomatology and in addition, can provide a snapshot of some nonmotor aspects of PD, although the data are far from complete. In this chapter, we discuss some of the nonmotor aspects of the available experimental models of PD and how the development of robust animal models to understand and treat nonmotor symptoms needs to become a research priority.

1. INTRODUCTION Developing experimental models of Parkinson’s disease (PD) is essential to the understanding of the pathophysiology, symptomatology, and natural history of the disorder (Duty & Jenner, 2011). Rodent and primate models have been extensively used to study the motor symptoms of PD and the side effects of dopaminergic therapy, such as dyskinesia and “wearing off.” However, despite the nonmotor symptoms (NMS) of PD emerging as one of the defining challenges for understanding this complex heterogenous, multineurotransmitter-driven condition (Chaudhuri, Healy, & Schapira, 2006), the development of robust experimental models in which to study specific NMS in PD remains a key unmet need. A major reason relates to the fact that experimental models of PD have almost exclusively addressed the effects of dopaminergic neuron loss and dopamine replacement therapy (DRT) on the motor symptoms of PD. Most studies have focused on the destruction of the nigrostriatal pathway by using toxins such as 6-hydroxydopamine (6-OHDA) in rodent models or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse and primate models (Duty & Jenner, 2011). But these do not reflect the widespread pathological and biochemical changes that occur in PD and which underpin the origins of many of NMS (Jellinger, 2015; Titova, Padmakumar, Lewis, & Chaudhuri, 2016; Todorova, Jenner, & Ray Chaudhuri, 2014). Some NMS in PD show some response to dopaminergic medication, and one of the objectives of this chapter is to explore whether the commonly used toxin-based models have a role to play in understanding the basis of NMS and their potential treatment. The alternative approach that has been employed is to use experimental models of gene defects known to underlie inherited forms of the illness or

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increase susceptibility or risk to developing PD. Genetic modifications in mice have been attempted reflecting overexpression of wild-type α-synuclein or the mutated form or expression of other proteins implicated in inherited PD (such as the parkin mutation) or increased risk of PD (such as GBA mutations) (McDowell & Chesselet, 2012). Again, we will explore the extent to which these models express NMS in addition to motor deficits. In this chapter, we will discuss some of the attempts that are being made to develop experimental models that may help in understanding the pathophysiology underlying key NMS involving changes in both the central and peripheral nervous systems in PD. In many cases, this relates to NMS that have been detected in the various experimental models originally developed for studying motor dysfunction in PD.

2. EXPERIMENTAL MODELS OF PD AND THE OCCURRENCE OF NONMOTOR SYMPTOMS The limitations of toxin-based models of PD have already been highlighted in terms of the restricted pathology and biochemical change that fails to reflect the widespread and progressive degeneration that occurs in PD. At first glance, this would seem to be a major obstacle as most NMS are thought to have a nondopaminergic origin. However, more careful study of those models that are restricted to producing mainly loss of nigrostriatal dopaminergic neurons has shown that NMS can be observed. Simply looking at the changes reported in 6-OHDA-lesioned rats and in MPTP-treated primates illustrates that near total destruction of the striatal dopaminergic input can be associated with an altered sense of smell, altered gastrointestinal function, cardiac and bladder function, sleep, and cognition, among others (Tables 1 and 2). Behavioral and nonmotor analysis that can be and has been performed in various experimental models of PD are shown in Table 1. While the presence of NMS in classical experimental models might suggest a dopaminergic origin in PD, the differences between these experimental models and clinical PD should be borne in mind. For example, olfaction is thought to be an early premotor component of NMS in PD that is not necessarily related to striatal dopaminergic loss. However, the control of olfaction is complex (see later), and it may be that the extensive loss of basal ganglia dopaminergic input in toxin-based models can also lead to changes in the circuitry controlling olfaction. Similar arguments can be applied to

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Table 1 Behavioral Analysis Performed in Experimental Models of PD in Relation to Nonmotor Symptoms Nonmotor Symptoms Tests Utilized Outcomes Utilized

Hyposmia and anosmia

• Buried pellet test • Novel scent test • Social olfactory

Cognitive decline/ dysfunction

• • • •

Depression

• Forced swim test • Tail suspension test • Sucrose preference

Learned helplessness Abnormal sucrose preference

Anxiety

• Elevated plus maze • Open field, light–dark

Novelty suppressed feeding

Habituation Dishabituation Inability to scent discrimination (block test) Inability to seek novel scents Novel object recognition Radial arm maze T-maze Morris water maze

Conditioning of fear Discriminative avoidance task Failure of recognition

exploration Sleep dysfunction

• Sleep latency • Wakefulness • Vigilance

Polysomnography EEG EOG Telemetry Actigraphy

Gastrointestinal dysfunction

• Stool frequency • Solid/liquid gastric

Colonic motility assessment Bead latency Isometric muscular force recording (enteric)

emptying

EEG, electroencephalogram; EOG, electrooculography. Adapted from Taylor, T. N., Greene, J. G., & Miller, G. W. (2010). Behavioral phenotyping of mouse models of Parkinson’s disease. Behavioural Brain Research, 211(1), 1–10. http://dx.doi.org/10.1016/j.bbr. 2010.03.004.

understanding why the toxin-based models show alterations in gastrointestinal function and sleep that are normally associated with earlier prodromal stages of PD. Genetic models of PD also show changes in behavior related to NMS as they occur in man. While altered olfaction, sleep, and gastrointestinal function have been reported, many of the changes relate to the neuropsychiatric aspects of PD, such as anxiety and depression (Table 3). This could reflect the nature of the testing carried out in the laboratories where these mice

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Table 2 Toxin-Induced Models of Parkinson’s Disease and the Expression of Nonmotor Symptoms Toxin Models Nonmotor Symptoms Authors

6-OHDA-lesioned rodents

• • • • • • • •

Duty and Jenner Olfaction (2011) Sensory/pain threshold Sleep/wakefulness Circadian rhythms Cognitive function Altered cardiovascular function Bladder hyperactivity Altered motility of gastrointestinal tract

Intragastric rotenone • α-Synuclein accumulation in dorsal Pan-Montojo administration in mice et al. (2010) vagal nucleus • Potential for investigating autonomic symptoms such as constipation MPTP-treated mice

• Olfaction • Sleep dysfunction • Gastrointestinal dysfunction

Taylor, Greene, and Miller (2010)

MPTP-treated primates

• • • • • •

Duty and Jenner (2011)

Bladder hyperreflexia Constipation Drooling Altered cardiovascular function Sleep disturbance Cognitive disturbance

MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OHDA, hydroxydopamine

were studied. Alternatively, it might be a reflection of the differences that exist between the toxin-based models and the genetic models of PD. Most genetic models of PD result in little if any pathology in the substantia nigra. The pathological changes that do occur are often limited to protein accumulation or affect brain regions outside of the basal ganglia. So, they raise the challenge of attempting to correlate the pattern of pathological change to the origin of individual NMS, although they do have added value in that the changes observed are often progressive and more closely reflect the progression of disease as it occurs in man. Accepting the limitations of the experimental models as they currently exist, we have next attempted to determine whether the use of these models discloses anything about the pathophysiology of the array of NMS in PD

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Table 3 Genetic and Transgenic Experimental Model of PD Exhibiting Nonmotor Symptoms Genetic Models/ Transgenic Nonmotor Symptoms Authors

α-Synucleinoverexpressing mice

• • • •

Olfaction Autonomic Constipation Sleep (circadian dysfunction) • Cognition

Chesselet et al. (2012)

LRRK2-overexpressing mice

• Gastrointestinal

Bichler, Lim, Zeng, and Tan (2013)

GBA-deficient mice

• Memory/attention

dysfunction • Olfactory dysfunction

Sardi et al. (2011)

dysfunction • Cognitive dysfunction Parkin knockout mice

• Anxiety • Cognition

DJ-1 knockout mice

• Cognitive dysfunction Aron et al. (2010)

VMAT2-deficient mice

• Olfactory • • • •

Zhu et al. (2007)

Taylor et al. (2009)

discrimination Delayed gastric emptying Sleep disturbances Anxiety-like behavior Depression

GBA, glucocerebrosidase; LRRK, leucine-rich repeat kinase; RBD, rapid eye movement behavior sleep disorder; VMAT, vesicular monoamine transporter.

occurring in man. We have necessarily limited this discussion to the NMS so far studied in experimental models of PD and so the following sections should be taken with that caveat in mind, although a range of NMS affecting both the central and peripheral nervous systems are included.

3. RELATING NMS IN EXPERIMENTAL MODELS OF PD TO PATHOPHYSIOLOGY 3.1 Altered Olfaction Hyposmia or anosmia is a poorly understood but almost ubiquitous NMS that is present in more than 90% of patients with PD and often preceding

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the onset of the motor syndrome of PD by many years. Olfactory deficits in rodent models of PD have been described, but the evidence remains controversial. In experiments on mice or rats receiving intranasal or intraperitoneal MPTP, olfaction was impaired and was associated with reduced levels of dopamine and noradrenaline in the olfactory bulb (Dluzen, 1992; Prediger et al., 2010). Following intranasal MPTP, impaired olfaction may, however, simply reflect damage to the olfactory epithelium and not a central change (Kurtenbach, Wewering, Hatt, Neuhaus, & L€ ubbert, 2013). Studies of olfaction in MPTP-treated primates are very limited. A cholinergic contribution to olfaction has been suggested as a reduced choline acetyltransferase (AChT) cell density in the inner layers of olfactory bundle was found following MPTP treatment (Mundinano et al., 2013). Cholinergic denervation was also seen in the horizontal limb of the diagonal band of Broca, which is in the basal forebrain and is the nucleus that gives rise to cholinergic centrifugal projections to the olfactory bundle (Fig. 1). In transgenic mice which overexpress human wild-type α-synuclein, olfactory deficits have also been reported (Fleming et al., 2008; Hansen et al., 2013; McDowell & Chesselet, 2012). There is progressive loss of the ability to detect and discriminate odors and concomitant α-synuclein accumulation in the olfactory bulb (Fleming et al., 2008; Hansen et al., 2013; McDowell & Chesselet, 2012). Interestingly there is no evidence for dopaminergic cell loss in the substantia nigra in these models. In other experiments, transgenic mice overexpressing GFP (α-synuclein-green

Temporal

Parietal

Visual Cingulate Frontal cortex

Tectum Medial habenula

Striatum

Olfactory bulb

Retrosplenial

Hippocampus

DR

To BLA

Thalamus

ICJ

ms vdb bas To EC hdb si

ldt ppt

LH

SN

Deep cerebellar n. LC Vestibular n. Cranial nerve n.

IPN Pons

Pontine Raphe reticular n. magnus

Reticular n.

Fig. 1 The cholinergic pathways in rodent brain showing prominent link with olfactory bundle (arrowed). Taken from Perez-Lloret, S., & Barrantes, F. J. (2016). Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease. npj Parkinson’s Disease, 2, 16001. http://dx.doi.org/10.1038/npjparkd.2016.1.

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fluorescent protein) show abnormal olfaction, a progressive motor syndrome as well as α-synuclein-green fluorescent protein (GFP) also display olfactory dysfunction as well as progressive motor impairment and α-synuclein-GFP also display olfactory dysfunction as well as progressive motor impairment and α-synuclein-GFP accumulation in the olfactory bulb (Hansen et al., 2013; Petit et al., 2013). Mice with a human α-synuclein A53T mutation develop progressive α-synuclein accumulation in the olfactory bulb and loss of glutamatergic and calcium-binding protein immunoreactivity, however, with no change in dopaminergic cells numbers (Ubeda-Banon, Saiz-Sanchez, de la Rosa-Prieto, & Martinez-Marcos, 2012). The functional implications are, however, unclear as olfaction was not assessed in this study. Overall, however, in rodents these findings are consistent with the known clinical knowledge that olfactory dysfunction occurs early in PD before dopaminergic motor deficits start. Cholinergic dysfunction may be the major underlying problem underpinning olfactory dysfunction in PD.

3.2 Altered Cardiovascular Function The main brunt of cardiovascular problems in PD arises from cardiac autonomic dysfunction which may affect 80% of PD patients at various stages (Goldstein et al., 2000). 58% may experience orthostatic hypotension which may even precede motor PD (Goldstein, 2006). Animal model studies exploring cardiovascular problems in PD are infrequent. Overexpression of human wild-type α-synuclein causes an impaired baroreflex in mice (Fleming et al., 2013), and this appears to occur prior to striatal dopamine content changes. Mice expressing A53T, mutant α-synuclein, show abnormal autonomic control of the heart which is evident as elevated resting heart rate and an impaired cardiovascular stress response and reduced parasympathetic activity (Griffioen et al., 2013). In rodents, dysregulation in central noradrenergic and dopaminergic systems has previously shown to alter the baroreceptor function as well, and these observations suggest that central catecholamine system dysfunction is the major underlying component of cardiovascular autonomic dysfunction in PD (Holchneider et al., 2002). Cardiac 123I-metaiodobenzylguanidine, a physiological analogue of noradrenaline, is often used for clinical investigation of cardiac innervation in PD patients. It has also been used in MPTP-treated mice, showing decreased cardiac noradrenergic transporter (NET) uptake and an overall reduction in circulating noradrenaline levels (Amino et al., 2008; Fukumitsu, Suzuki,

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Fukuda, & Kiyono, 2009; Fukumitsu et al., 2006; Takatsu et al., 2002). This is, however, in contrast to the findings by Goldstein, Li, Holmes, and Bankiewicz (2003) who reported an acute increase in 18-fluorodopa uptake on positron emission tomography (PET) scanning in MPTP-administered monkeys. Total loss of 11C-m-hydroxyephedrine PET uptake in 6-OHDA-treated monkeys has also been reported (Joers et al., 2012). 6-OHDA injections into rat medial forebrain bundle (MFB) have been used to investigate the role of dopamine loss and relationship to cardiovascular changes. 6-OHDA injection into the MFB caused a decrease in nocturnal heart rate, while injection into the ventral tegmental area (VTA) causes circadian blood pressure regulation changes (Fleming, 2011). Ariza, Sisdeli, Crestani, Fazan, and Martins-Pinge (2015) showed bilateral 6-OHDA injection into the substantial nigra of rats, lowers the medial arterial pressure, and simultaneously downregulates the heart rate and sympathetic activity. MFB, VTA, and nigra are closely involved in the pathological process of PD, and these studies, therefore, confirm the role of the brainstem and nigra, underpinning cardiovascular homeostasis and rhythm in PD. Both central catecholamine system dysfunction and a peripheral component (cardiac NET uptake-related studies) appear to drive cardiovascular autonomic dysfunction in PD.

3.3 Alterations in Sleep Sleep is abnormal in almost all patients with PD and comprises a range of symptoms related to both the disease and drug treatment (Manni, Terzaghi, Sartori, Mancini, & Pacchetti, 2004). Specific neurochemical dysfunction underlying sleep problems in PD is complex, and noradrenergic, serotoninergic, dopaminergic, and orexin systems have all been implicated. Changes in sleep patterns have been investigated in both toxin-induced and genetic models of PD involving both rodents and primates as shown in Table 4. Experimental studies showed that systemic MPTP injection in nonhuman primates caused a severe disruption of sleep–wake cycle and architecture (Fig. 2) (Barraud et al., 2009). In these animals, there was reduced sleep efficacy that was seen to persist for many years after MPTP administration. Primary dysregulation of rapid eye movement (REM) sleep along with increased daytime sleepiness (naps) occurred before the motor symptoms were unmasked after MPTP exposure. A dopaminergic basis to the

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Table 4 Experimental Models of PD and Sleep Dysfunction Authors

Study Title

Animal Model

Symptoms Studied

Duty and Animal models of Parkinson’s 6-OHDA-lesioned Sleep/ disease: a source of novel rodents wakefulness, Jenner circadian (2011) treatments and clues to the rhythms, RBD cause of the disease Chesselet Progressive mouse model of α-Synuclein et al. Parkinson’s disease: the Thy1- overexpressor (ASO ¼ Thy1(2012) aSyn (line 61) mice aSyn) mice

Circadian rhythm, insomnia

Duty and Animal models of Parkinson’s MPTP-treated Jenner primates disease: a source of novel (2011) treatments and clues to the cause of the disease

Sleep–wake cycle. REM sleep/RBD

Taylor et al. (2009)

Altered sleep latency

VMAT2-deficient Nonmotor symptoms of Parkinson’s disease revealed in mice an animal model with reduced monoamine storage capacity

6-OHDA, 6-hydroxydopamine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; RBD, REM sleep behavior disorder; REM, rapid eye movement; VMAT2, vesicular monoamine transporter 2. Taken from Sokolov, E., & Chaudhuri, K. R. (2017). Oxford textbook of sleep disorders (Vol. 25).

observed sleep dysfunction was likely as there was decreased dopamine turnover measured after a single MPTP injection. In the long term, at 90 days, there was partial reemergence of REM sleep which paralleled the partial adaptation of the animals to the motor deficits induced by MPTP through compensatory mechanisms. Others have reported that rats with lesions of the periaqueductal gray, which contain some dopaminergic cells, show increased sleep periods and somnolence (Rye & Jankovic, 2002). A direct influence of dopamine in the regulation of REM sleep has also been described in rodent experiments using dopamine transporter knockout mice and the use of haloperidol, a D2 dopamine receptor antagonist (Dzirasa et al., 2006; Lima, Andersen, Reksidler, Vital, & Tufik, 2007). In a rodent study, mice given MPTP over 5 days developed an increase in REM sleep during both light and dark phases. In these mice, histological examination showed a 30% decrease in nigral dopaminergic neurons (Monaca et al., 2004). However, the effects may be transient as in a follow up study by the same group, the nigrostriatal pathway remained damaged for up to 60 days, while REM sleep was restored within 40 days after initial

A

B

REM sleep 25

Wake after sleep onset

MPTP monkeys

20

Saline monkeys %

%

15 10

Monkey # 1

5 0 0

5

10

15

20

25

30

70 60 50 40 30 20 10 0

35 Days

0

5

10

MPTP

15

20

25

30

35 Days

MPTP 2 mm

C

D

Sleep efficacy 100

Monkey # 4

Daytime napping 100 80

75 %

%

60 40

50

20 2 mm

25 0

5

10

15

20

MPTP

25

30

35 Days

0 0

5

10

15

20

25

30

35 Days

MPTP

Fig. 2 Abnormalities of REM sleep in MPTP-lesioned primate. Taken from Barraud, Q., Lambrecq, V., Forni, C., McGuire, S., Hill, M., Bioulac, B., et al. (2009). Sleep disorders in Parkinson’s disease: The contribution of the MPTP non-human primate model. Experimental Neurology, 219(2), 574–582. http://dx.doi.org/10.1016/j.expneurol.2009.07.019.

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MPTP exposure (Laloux et al., 2008). Interestingly, melatonin which regulates the circadian pattern of sleep–wakefulness was also affected with a decrease in the expression of melatonin receptors in the substantia nigra and melatonin secretion. Recently Belaid, Adrien, Karachi, Hirsch, and Francois (2015) reported that MPTP-induced monkeys experience sleep disorders that are slightly improved by levodopa treatment. Dual treatment of these monkeys with levodopa and melatonin showed there to be an improvement in overall sleep. The cause of this effect is unknown and could be related to a neuromodulating effect of melatonin (Antolin et al., 2002; Dabbeni-Sala, Di Santo, Franceschini, Skaper, & Giusti, 2001). Recently a sleep dominant subtype of PD has been described, some having a “narcoleptic” phenotype. In these patients, loss of orexin-containing neurons in the lateral hypothalamus has been considered to be responsible (Manni et al., 2004). Orexin control of the dopaminergic system in primate models of PD has been studied in MPTP-treated macaques (Bensaid et al., 2015). Orexin A and orexin B neurons were colocalized in the hypothalamus (Fig. 3A). In addition, orexin A and orexin B immunoreactivity was A

Ox-A

Ox-B

Merge

B

Orexin-A

Orexin-B

Merge

Fig. 3 Immunoreactivity of orexin A and orexin B neurons in the hypothalamus (A), merge showing both neurons together, and pars compacta of the substantia nigra (B) in MPTP-treated macaques. Taken from Bensaid, M., Tande, D., Fabre, V., Michel, P. P., Hirsch, E. C., & Francois, C. (2015). Sparing of orexin-A and orexin-B neurons in the hypothalamus and of orexin fibers in the substantia nigra of 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine-treated macaques. The European Journal of Neuroscience, 41(1), 129–136. http://dx.doi.org/10.1111/ejn.12761.

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seen in the VTA as well as in substantia nigra close to the tyrosine hydroxylase expressing dendrites (Fig. 3B), suggesting that orexin pathways may have a regulatory effect on nigral dopaminergic neurons. However, no loss of orexin neurons was found after MPTP treatment. The speculation is that more extensive and greater damage to the dopaminergic system might be needed for the depletion of orexin neurons as selective nigral lesions do not cause orexin depletion. These studies in primates and rodent models suggest that central dopaminergic mechanisms and brainstem centers (VTA, ventral periaqueductal gray matter, as well as mesolimbic and mesocortical dopaminergic projections) play a key role in the regulation of sleep–wake cycle at least in the early motor stages of PD (Lu, Jhou, & Saper, 2006).

3.4 Alteration in Gastrointestinal Tract Gastrointestinal dysfunction affects the entire length of the gastrointestinal tract in PD, and ranges from drooling and dribbling of saliva, dysphagia, impaired and delayed gastric emptying, constipation, and impaired defecatory function such as incomplete emptying (Fasano, Visanji, Liu, Lang, & Pfeiffer, 2015). MPTP, rotenone, and 6-OHDA have been used in rodents and primates to study gastrointestinal dysfunction. In both toxin models and rodents overexpressing wild-type or A53T mutant α-synuclein, there is evidence of slowed intestinal motility and constipation, a key manifestation of NMS in PD (Colucci et al., 2012; Drolet, Cannon, Montero, & Greenamyre, 2009; Noorian et al., 2012; Wang et al., 2012). In transgenic mice overexpressing human wild-type α-synuclein, there is a reduction in fecal water content as well as fecal pellet output in addition to increased whole-gut transit time as seen with constipation (Hallett, McLean, Kartunen, Langston, & Isacson, 2012). In 6-OHDA-lesioned rats, delayed gastric emptying is evident as occurs in the early premotor stages of PD. In the colon of the 6-OHDA-lesioned rats, AChT immunoreactivity remained unchanged, while there was selective loss in dopamine D2 receptor density (Chaumette et al., 2009). MPTP-treated monkeys show increased nitric oxide synthase immunoreactive neurons along with a decrease in tyrosine hydroxylase immunoreactivity, while cholinergic immunoreactivity was unchanged. Perhaps importantly, changes in contractility were seen in isolated distal colon tissue, suggesting that central dopaminergic loss leads to adaptive changes in the innervation and functioning of the gut. A reduced expression of D2 dopamine receptor expression in the proximal

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and distal area of colon occurs in 6-OHDA-lesioned rats with a consequent reduced efficiency of peristalsis as judged by a decrease in intraluminal pressure and frequency of peristaltic events (Colucci et al., 2012). A central dopaminergic component to altered gastric motility may be present as both apomorphine and levodopa infusions improve gastrointestinal motility. Importantly, the apomorphine effect is not blocked by the peripheral dopamine antagonist domperidone (Pellegrini et al., 2016). Cholinergic mechanism may also be operative, and alterations in cholinergic cells in the dorsal motor nucleus of the vagus (DMV) have been reported (Zheng et al., 2011). In 6-OHDA-lesioned rat, reduced number of ChAT-positive neurons in the DMV (the origin of parasympathetic afferent nerves) was shown which resulted in slowing down of the gastric transit time. Two separate mechanisms may control the enteric cholinergic neurotransmission. The extent of cholinergic transmission in the enteric nervous system is likely to be regulated by two opposing mechanisms. Serotonin 5-HT4 receptor-related activity leads to excitation and promotion of motility (Liu, Rayport, Jiang, Murphy, & Gershon, 2002), while dopamine D2 receptor activity appears to mediate inhibition (Anlauf, Schafer, Eiden, & Weihe, 2003). The role of endogenous serotonergic control of intestinal motility has also been studied, and 5-HT transporter knockout mice show higher and stronger colorectal motility with elevated extracellular 5-HT levels (Liu et al., 2002).

3.5 Alterations in Bladder Functions Urinary symptoms are common in PD and a cause of significant morbidity. Urinary function has been investigated in animal models, such as in rats, whereby 6-OHDA-induced unilateral lesions of the nigrostriatal pathway caused bladder hyperreflexia. Similar results are seen with MPTP lesioning in nonhuman primates (Albanese, Jenner, Marsden, & Stephenson, 1988; Soler, Fullhase, Santos, & Andersson, 2011; Yoshimura, Kuno, Chancellor, De Groat, & Seki, 2003; Yoshimura, Mizuta, Kuno, Sasa, & Yoshida, 1993). These changes can be reversed by electrical stimulation of the substantia nigra as well as with direct injection of dopamine into the striatum. In PD, urinary urgency comprises frequency and incontinence and is indicated by detrusor overactivity in animal models. A complex interaction of inhibitory effect of the basal ganglia on micturition (de Groat, 2006) and the A-10 cells of the VTA-mesolimbic dopaminergic fibers as well as the periaqueductal gray area control bladder activity (Liu et al., 2004).

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Experiments in 6-OHDA-treated rats with lesions in the VTA caused more severe detrusor overactivity than lesions in substantia nigra (Hashimoto et al., 1997), suggesting VTA control is more relevant. The effect of dopamine agonists has also been investigated. Dopamine D1 receptor agonists (e.g., SKF 38393) improve bladder function, whereas the commonly used dopamine D2 agonists either have no effect or make bladder function worse (Yoshimura, Mizuta, Yoshida, & Kuno, 1998). Improved bladder function has also been reported after stem cell transplants in the median forebrain bundle of 6-OHDA-lesioned rats (Soler et al., 2012). These data suggest that a centrally mediated dopamine-related mechanism may underpin bladder hyperreflexia in PD. Broadly these experiments suggest a dual nervous system control of bladder and bowel dysfunction in PD. It is likely that central brain pathology largely leads to bladder dysfunction as seen in PD (such as overactive bladder function). This may operate through abnormality of dopamine-driven basal ganglia circuit, which normally operates to suppresses the micturition reflex (Sakakibara, Uchiyama, Yamanishi, Shirai, & Hattori, 2008). However, local and peripheral lesion the enteric region causes bowel dysfunction mainly in the form of slow transit and decreased phasic contraction. This may also occur via abnormal dopaminergic enteric nervous system circuit which normally augments and helps propagation of the peristaltic reflex in the gut.

3.6 Alterations in Mood and Cognition 3.6.1 Anxiety Anxiety, depression, and other neuropsychiatric problems occur in many patients with PD, either as part of the disease process or as nonmotor fluctuations. Using a modified maize test (elevated plus maze test) to assess anxiety, 6-OHDA-lesioned rats showed anxiety-like behavior with reductions in dopamine, noradrenaline, and serotonin levels (Tadaiesky et al., 2008). However, in another toxin model, the MPTP-treated mouse, this anxiety-like behavior was not replicated (Vuckovic et al., 2008). Alternative genetic models, such as the vesicular monoamine transporter 2 (VMAT2)deficient mice and parkin null mice, have also shown anxiety-like behavior using the elevated plus maze test (Taylor et al., 2009; Zhu et al., 2007). Following bilateral delivery of α-synuclein using a viral vector into the substantia nigra of rats, anxiety-like behavior was again observed (Campos et al., 2013).

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3.6.2 Depression Depression-like behavior can be elicited with the partial and bilateral lesioning of the nigrostriatal pathway using testing methods such as the forced swim test (Bonito-Oliva, Masini, & Fisone, 2014; Carnicella et al., 2014; Vuckovic et al., 2008). However, perhaps surprisingly, lesioning of the mesolimbic dopaminergic pathways did not replicate this depressive state (Drui et al., 2014). Dopaminergic and serotoninergic function is abnormal when the substantia nigra of 6-OHDA- and MPTP-lesioned depressed rodents is examined, suggesting that depression in PD may be driven by a combination of dopaminergic and serotoninergic mechanism (Taylor et al., 2009). 3.6.3 Apathy Apathy is a prominent NMS of PD, but animal model-based studies are sparse. Studies in nonhuman primates with MPTP lesioning show apathytype behavior that is likely, in part, to originate from the loss of dopaminergic neurons in the VTA of the brain. However, in clinical practice apathy is likely to arise from the involvement of multiple neurotransmitters, including acetylcholine and dopamine (Qamar et al., 2017; Titova et al., 2016). Complex neurochemistry underlies anxiety and depression, common NMS in PD. Dopaminergic, noradrenergic, and serotonergic mechanisms may all play a part. Apathy, on the other hand, seems to be mainly driven by cholinergic mechanisms and in part contributed to by dopaminergic mechanism. 3.6.4 Attention and Memory Cognitive dysfunction, mild cognitive impairment, and dementia remain a key challenge to the management of PD. Behavioral tests can be used which call into play various cognitive processes within the brain, and these have been utilized in experimental models of PD. Visuospatial attention, spatial working memory, set-shifting and reversal as well as decision making and impulsivity have been studied in rats and monkeys (Chudasama & Robbins, 2006). Behavioral problems arising from basal ganglia disorders such as PD have been explored by the delineation of discrete frontal corticostriatal pathways (Fig. 4). Both dopaminergic and cholinergic modulation of visual attention and working memory have been shown in rodent models (Chudasama, Dalley, Nathwani, Bouger, & Robbins, 2004; Chudasama & Robbins, 2004). In primates treated with low doses of MPTP to partially lesion the substantia nigra, changes in executive function and

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Fig. 4 Frontal corticostriatal pathways proposed to explain basal ganglia role in behavioral dysfunction in PD. Taken from Chudasama, Y., & Robbins, T. W. (2006). Functions of frontostriatal systems in cognition: Comparative neuropsychopharmacological studies in rats, monkeys and humans. Biological Psychology, 73(1), 19–38. http://dx.doi.org/10. 1016/j.biopsycho.2006.01.005.

visuospatial awareness are seen that reflect those occurring early in PD (Schneider & Kovelowski, 1990). Cognitive impairment in PD is a key challenge particularly in the advanced stages of PD, and dementia affects most patients in the long term. Aging is a key driver of dementia, and in transgenic mice overexpressing wild-type or mutant α-synuclein, cognitive changes have been reported to be associated with aging (Desplats et al., 2009). In another study, Hansen et al. (2011) showed that mice overexpressing wild-type α-synuclein demonstrate cognitive impairment and, in addition, develop neuropathology involving the hippocampal area. However, this observation is not supported by a study in transgenic mice expressing wild-type α-synuclein where no hippocampal cell loss was seen, but there was an extensive cholinergic deficit in the cortex (Magen et al., 2012). Memory can be studied using tests such as the Morris water maze task (Table 1). Using this task, MPTP-treated mice can show impairment of working memory, procedural memory, and spatial memory (Deguil et al., 2010; Luchtman, Meng, & Song, 2012; Miyoshi et al., 2002; Perry et al., 2004; Pothakos, Kurz, & Lau, 2009; Reksidler et al., 2008). In these MPTP mice, substantia nigra lesions appear to impact on their learning tasks which

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in turn contribute to difficulties with motor learning and functioning (Da Cunha et al., 2001; Gevaerd et al., 2001). Other studies have attempted to uncover the biochemical changes that underlie the altered learning and retention ability of MPTP-treatedmice. Moriguchi, Yabuki, and Fukunaga (2012) showed a reduction in calcium–calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and impaired long-term potentiation (LTP) induction in the hippocampal CA1 region (Fig. 5). In addition, there was reduced AMPA-type glutamate receptor subunit 1 (GluR1) phosphorylation in the hippocampal CA1 region. Decreased CaMKII activity along with hippocampal-impaired LTP induction appears important for understanding the learning deficits seen in MPTP-treated mice models (Bonito-Oliva et al., 2014; Moriguchi et al., 2012). Cholinergic mechanisms underpinning cognitive dysfunction in PD have also been studied in animal models (Perez-Lloret & Barrantes, 2016). Ionotropic pentameric nicotinic acetylcholine receptors (nAChRs, a collection of neurotransmitter receptors including γ-amino butyric acid (GABA-A, GABA-C), glycine, serotonin (5-HT3), and bacterial homologs) have been implicated (Nys, Kesters, & Ulens, 2013). Animal model studies show that the α7 nAChR is highly expressed in the hippocampus, an area

Phosphorylation (% of control)

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Fig. 5 Reduced calcium–calmodulin-dependent protein kinase II (CaMKII) autophosphorylation (white bars) in the striatum of MPTP-treated mice. ERK, extracellular signal-regulated kinase; PKC, protein kinase c. Taken from Moriguchi, S., Yabuki, Y., & Fukunaga, K. (2012). Reduced calcium/calmodulin-dependent protein kinase II activity in the hippocampus is associated with impaired cognitive function in MPTP-treated mice. Journal of Neurochemistry, 120(4), 541–551. http://dx.doi.org/10.1111/j.1471-4159. 2011.07608.x.

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usually associated with cognitive dysfunction. The most commonly expressed subtype of nAChRs (α4β2 type) shows severe loss in Alzheimer’s disease (Banerjee et al., 2000). In PD, dysfunction of oligomeric pattern of nAChRs in the temporal area has been described, and currently, α7 nAChR ligands are being studied as cognitive enhancers in animal models (SadighEteghad, Talebi, Mahmoudi, Babri, & Shanehbandi, 2015). In general, evidence suggests that the greater the degree of cholinergic neuronal loss and related cholinergic projections to the cognitive function-associated brain regions (neocortex and hippocampus), the more severe the expression of dementia. This observation suggests that there is a close link of clinical manifestation of dementia and cholinergic cell loss in neurodegenerative conditions such as PD with dementia (Minger et al., 2000).

3.7 Alteration in Perception, Psychosis, and Vision Some MPTP-lesioned primates show “psychotic”-like behavior but only after dopaminergic drug treatment (Fox et al., 2010). Whether these are truly psychosis or bizarre drug-induced behaviors remains unclear. In MPTP-induced toxin models of primate’s intraocular injection of the catecholaminergic toxin, 6-OHDA causes alteration of visual fields and dark adaptation similar to visual deficits observed in PD (Ghilardi, BodisWollner, Onofrj, Marx, & Glover, 1988; Ghilardi, Marx, Bodis-Wollner, Camras, & Glover, 1989).

4. CONCLUSIONS AND OBSERVATIONS Experimental models that exhibit key NMS of PD remain a key unmet need, and a major research effort is needed to advance understanding of their complex pathophysiology. The models described in this chapter provide some piecemeal information on the expression and pathophysiology of NMS in PD. But so far there has been little pharmacological analysis of those NMS that can be studied, and consequently and disappointingly, there has not been any major improvement in therapeutic intervention for NMS in PD. This will not be an easy task under any circumstances as many NMS are partially responsive to DRT, while others are clearly nondopaminergic in origin, resulting from the degeneration of nondopaminergic nuclei, such as the locus coeruleus, raphe nuclei, and DMV ( Jellinger, 2015; Obeso et al., 2010; Todorova et al., 2014). As such, the currently employed toxin models of PD and NMS based around destruction of nigral dopaminergic neurons do not address NMS either in a holistic or an individual manner. Transgenic

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models of PD may become more useful in studying NMS in future. They would reflect the progression of pathology in PD unlike the toxin-based models, but so far, they have not exhibited the pattern of neuronal loss seen in PD. The earlier discussion, in fact, underlies the problems that need to be faced when trying to develop appropriate experimental models of the NMS of PD. The diverse and complex origins of NMS in relation to their underlying pathology, biochemical basis, and occurrence relative to the motor symptoms of PD demonstrate that they do not have a single underlying cause that can be readily mimicked experimentally (Jellinger, 2015). It would be almost impossible to develop robust models that reflect the complexity of the processes occurring in man. In many ways, a reversal of the bench-to-bedside model is required where clinicians need to identify which specific NMS are the most relevant and that individual NMS are then modeled based on specific pathological loss in an experimental animal. This is already feasible based on using combinations of toxins and existing stereotaxic protocols (and even in combination with the use of genetic models of PD). But there has been an unwillingness to take this path and to unravel the basis of NMS and to provide adequate pharmacological approaches to treatment, despite the unequivocal importance of such preclinical investigation to what is a major unmet need in PD. In addition, the provision of models involving the destruction of specific nuclei and selective biochemical change reflecting the differing patterns of the pathological advance of PD in man would have major importance to the subtyping of PD based on NMS in man (Marras & Chaudhuri, 2016).

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