Fanny Faivre

Anil Joshi

Erwan Bezard

Michel Barrot
email: mbarrot@inci-cnrs.unistra.fr

The hidden side of Parkinson's disease: studying pain, anxiety and depression in animal models

Keywords: Parkinson's disease, non-motor symptoms, pain, anxiety, depression

Parkinson's disease is a neurodegenerative disease leading to the loss of midbrain dopamine neurons. It is well known and characterized by motor symptoms that are secondary to the loss of dopamine innervation, but it is also accompanied by a range of various non-motor symptoms, including pain and psychiatric disorders such as anxiety and depression. These non-motor symptoms usually appear at early stages of the disease, sometimes even before the first motor symptoms, and have a dramatic impact on the quality of life of the patients. We review here the present state-of-the-art concerning pain, anxiety and depression-like parameters in animal models of Parkinson's disease.

Parkinson's disease is a neurodegenerative disorder classically known for the loss of dopamine neurons in the midbrain, and most often accompanied by the presence of cytoplasmic inclusions of α-synuclein proteins called Lewy bodies. However, although the disease is primarily related to the loss of the nigrostriatal pathway, several other brain areas are also degenerating (often to a lesser extent), including the locus coeruleus, the dorsal raphe nucleus, the nucleus basalis of Meynert, the pedunculopontine nucleus, with a cortical thinning occuring at later stage [START_REF] Ehringer | Distribution of noradrenaline and dopamine (3hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system[END_REF][START_REF] Halliday | Neuropathology of immunohistochemically identified brainstem neurons in Parkinson's disease[END_REF][START_REF] Jellinger | Pathology of Parkinson's disease. Changes other than the nigrostriatal pathway[END_REF][START_REF] Zarow | Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases[END_REF]. Synuclein pathology is not restricted either to the nigrostriatal pathway but displays extensive spread in the nervous system. Indeed, observations of post-mortem human brains [START_REF] Braak | Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages)[END_REF][START_REF] Braak | Staging of brain pathology related to sporadic Parkinson's disease[END_REF][START_REF] Braak | Stages in the development of Parkinson's disease-related pathology[END_REF] showed early Lewy bodies inclusions in the IX (glossopharyngeal) and X (vagal) nerves and in the olfactory bulbs, later spreading beyond these structures to include the lower raphe nuclei, the magnocellular portion of the reticular formation and the locus coeruleus, to then affect the substantia nigra pars compacta, and finally gradually invade the entire neocortex.

Clinically, Parkinson's disease is classically defined by a triad of motor symptoms: bradykinesia (i.e. a slowdown to initiate voluntary movements), muscle rigidity and resting tremors. Beside these classical symptoms, different non-motor symptoms can be present and sometimes even appear a long time before the first motor symptoms [START_REF] Bezard | Premotor parkinsonism models[END_REF][START_REF] Blanchet | Chronic pain and pain processing in Parkinson's disease[END_REF]Pont-Sunyer et al., 2015), which may lead to a misdiagnosis or delayed diagnosis [START_REF] O'sullivan | Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study[END_REF] and has a negative impact on the quality of life of the patients [START_REF] Nègre-Pagès | Chronic pain in Parkinson's disease: the cross-sectional French DoPaMiP survey[END_REF][START_REF] Rieu | Impact of Mood and Behavioral Disorders on Quality of Life in Parkinson's disease[END_REF]. Three major phases have thus been proposed to describe the development of Parkinson's disease [START_REF] Stern | Toward a redefinition of Parkinson's disease[END_REF].

The phase 1, the "preclinical Parkinson's disease", corresponds to the beginning of the αsynuclein accumulation in the central and/or the peripheral autonomic nervous system, in the absence of detectable clinical signs. The second phase, referred to either as "pre-motor" or "prodromal" phase, can exceed ten years before the clinical diagnosis of the disease and is usually associated to the apparition of non-motor symptoms due in part to extranigral alterations. It should also be noticed that early subtle motor symptoms can often be present in this prodromal phase of the disease [START_REF] Mahlknecht | The Concept of Prodromal Parkinson's Disease[END_REF]. During this phase, Parkinson's disease patient can display higher anxiety as early as 16 years before the diagnosis of the disease; and depression becomes significantly prevalent among Parkinson's disease patients in the last 2-3 years preceding the diagnostic [START_REF] Darweesh | Trajectories of prediagnostic functioning in Parkinson's disease[END_REF]. The phase 3 is the "motor Parkinson's disease", which is the one that is clinically visible and more easily diagnosed.

The non-motor symptoms include notably (but not exclusively) sleep disorders, gastrointestinal and autonomic symptoms (nausea, constipation), sensory symptoms (olfactory disturbance), pain and neuropsychiatric symptoms (depression, anxiety) [START_REF] Barone | The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease[END_REF][START_REF] Chaudhuri | Non-motor symptoms of Parkinson's disease: diagnosis and management[END_REF][START_REF] O'sullivan | Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study[END_REF][START_REF] Park | Non-motor symptoms in Parkinson's disease[END_REF]Pont-Sunyer et al., 2015).

The anxiety, depression and pain symptoms display significantly greater severity than in the general population [START_REF] Rana | Association of restless legs syndrome, pain, and mood disorders in Parkinson's disease[END_REF], and an increased frequency of the non-motor symptoms is associated with Parkinson's disease duration and severity [START_REF] Barone | The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease[END_REF].

Understanding the pathophysiological mechanisms underlying non-motor symptoms in

Parkinson's disease is important, but requires relevant pre-clinical models. Alterations concerning olfaction, sleep and the gastrointestinal tract are clinically well known [START_REF] Reichmann | Premotor Diagnosis of Parkinson's Disease[END_REF] and addressed in models of the disease [START_REF] Titova | Nonmotor Symptoms in Experimental Models of Parkinson's Disease[END_REF]. On the other hand, pain, anxiety and depression still remain understudied. In this review, we provide an overview of the present state-of-the-art in the field by rapidly presenting pain and mood non-motor symptoms in Parkinson's disease patients, by evoking the different pre-clinical models used in research and by detailing the literature on measures of nociception, anxiety-like and depression-like symptoms in rodent and non-human primate models of Parkinson's disease.

The non-motor symptoms in Parkinson's disease patients

This section provides a rapid overview of some clinical data concerning pain, anxiety and depression in Parkinson's disease. For more details concerning these clinical aspects, please refer to the following references [START_REF] Blanchet | Chronic pain and pain processing in Parkinson's disease[END_REF][START_REF] Chaudhuri | Non-motor symptoms of Parkinson's disease: diagnosis and management[END_REF][START_REF] Schapira | Non-motor features of Parkinson disease[END_REF].

1.1.Pain in Parkinson's disease (Figure 1)

Parkinson's disease patients exhibit sensory symptoms such as numbness, coldness, burning or pain [START_REF] Koller | Sensory symptoms in Parkinson's disease[END_REF]. Pain is one of the often neglected non-motor symptoms for which there is no truly effective treatment [START_REF] Wasner | Pains in Parkinson disease--many syndromes under one umbrella[END_REF], even though it was already noted in the original description of the disorder by James Parkinson. Nevertheless, it is the non-motor symptoms which is the most frequent in Parkinson's disease patients [START_REF] O'sullivan | Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study[END_REF], with a prevalence between 30% and 83% of the patients depending on the considered epidemiological study [START_REF] Allen | The Association Between Parkinson's Disease Motor Impairments and Pain[END_REF][START_REF] Beiske | Pain in Parkinson's disease: Prevalence and characteristics[END_REF][START_REF] Nègre-Pagès | Chronic pain in Parkinson's disease: the cross-sectional French DoPaMiP survey[END_REF][START_REF] Wasner | Pains in Parkinson disease--many syndromes under one umbrella[END_REF].

Clinical data showed that both pain thresholds and tolerance to pain are significantly lower in Parkinson's disease patients compared to the control population [START_REF] Blanchet | Chronic pain and pain processing in Parkinson's disease[END_REF][START_REF] Zambito Marsala | Spontaneous pain, pain threshold, and pain tolerance in Parkinson's disease[END_REF], and that these patients can suffer from a variety of different pain [START_REF] Beiske | Pain in Parkinson's disease: Prevalence and characteristics[END_REF][START_REF] Lee | A Survey of Pain in Idiopathic Parkinson's Disease[END_REF]. Because of the variety of pain expressed by Parkinson's disease patients, a classification was proposed to identify different types by using criterions such as "topography, duration, frequency, aggravating factors, temporal and topographical relationship to Parkinson's disease, influence of motor complications, influence of antiparkinson medication, and patient's opinion about the relationship between pain and Parkinson's disease" [START_REF] Wasner | Pains in Parkinson disease--many syndromes under one umbrella[END_REF]. Such classification led to separate pain directly/partly related to Parkinson's disease itself, indirectly related to it (i.e. aggravated by Parkinson's disease) and unrelated to the disease itself (Figure 1) [START_REF] Blanchet | Chronic pain and pain processing in Parkinson's disease[END_REF][START_REF] Nègre-Pagès | Chronic pain in Parkinson's disease: the cross-sectional French DoPaMiP survey[END_REF][START_REF] Wasner | Pains in Parkinson disease--many syndromes under one umbrella[END_REF].

Pain in Parkinson's disease can be a nociceptive pain, defined by the International Association for the Study of Pain as "pain that arises from actual or threatened damage to nonneural tissue and is due to the activation of nociceptors" (https://www.iasp-pain.org/). Those include for example pain that is associated with the motor disturbances and partly due to muscle rigidity. Indeed, rigidity, akinesia, postural abnormality or dystonia can lead to musculoskeletal nociceptive pain and back pain [START_REF] Wasner | Pains in Parkinson disease--many syndromes under one umbrella[END_REF]. Patients can also display neuropathic pain, i.e. "pain caused by a lesion or disease of the somatosensory nervous system", which may be of peripheral origin, such as radicular pain, or of central one [START_REF] Blanchet | Chronic pain and pain processing in Parkinson's disease[END_REF][START_REF] Wasner | Pains in Parkinson disease--many syndromes under one umbrella[END_REF]. Miscellaneous pain, which cannot be classified in the above two categories, can also be observed. Those include for example akathisia (i.e. restless legs syndrome) and pain associated with depression, which is the one that appears mostly during the prodromal phase [START_REF] Schapira | Non-motor features of Parkinson disease[END_REF][START_REF] Wasner | Pains in Parkinson disease--many syndromes under one umbrella[END_REF] (Fig. 1). The patients with pain more directly related to Parkinson's disease itself are often younger at non-motor and motor disease onsets and show higher parkinsonism severity than those without pain or with pain unrelated to the disease [START_REF] Nègre-Pagès | Chronic pain in Parkinson's disease: the cross-sectional French DoPaMiP survey[END_REF][START_REF] Zambito Marsala | Spontaneous pain, pain threshold, and pain tolerance in Parkinson's disease[END_REF]. The gender has also an influence, with women more frequently reporting pain symptoms [START_REF] Beiske | Pain in Parkinson's disease: Prevalence and characteristics[END_REF][START_REF] Zambito Marsala | Spontaneous pain, pain threshold, and pain tolerance in Parkinson's disease[END_REF]. The loss of dopamine in the basal ganglia may partly explain the changes in pain thresholds; however, the absence of a total recuperation of these symptoms with dopaminergic medication suggests also a role of nondopaminergic mechanisms in the appearance or maintenance of pain symptoms [START_REF] Brefel-Courbon | Effect of levodopa on pain threshold in Parkinson's disease: a clinical and positron emission tomography study[END_REF][START_REF] Schapira | Non-motor features of Parkinson disease[END_REF].

1.2.Anxiety and depression in Parkinson's disease

There is a notable comorbidity of mood disorders with Parkinson's disease [START_REF] Dissanayaka | Anxiety disorders in Parkinson's disease: prevalence and risk factors[END_REF]. Moreover, the risk to be diagnosed with Parkinson's disease is significantly increased in patients that have already been diagnosed with affective disorders [START_REF] Nilsson | Increased risk of developing Parkinson's disease for patients with major affective disorder: a register study[END_REF], which reflect the fact that these psychiatric pathologies are part of the early non-motor symptoms appearing during the prodromal phase of the disease [START_REF] Jacob | Occurrence of depression and anxiety prior to Parkinson's disease[END_REF]. Mood disorders can indeed appear 5 to 20 years before the motor symptoms [START_REF] Shiba | Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study[END_REF].

According to the Diagnostic and Statistical Manual of Mental Disorders, 5 th edition (American Psychiatric Association, 2013), "anxiety disorders include disorders that share features of excessive fear and anxiety and related behavioral disturbances". 34 to 65% of Parkinson's disease patients experience anxiety, including panic disorders, generalized anxiety disorder or social phobia [START_REF] Barone | The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease[END_REF][START_REF] Chaudhuri | Non-motor symptoms of Parkinson's disease: diagnosis and management[END_REF][START_REF] Dissanayaka | Anxiety disorders in Parkinson's disease: prevalence and risk factors[END_REF][START_REF] Park | Non-motor symptoms in Parkinson's disease[END_REF][START_REF] Schapira | Non-motor features of Parkinson disease[END_REF][START_REF] Szatmari | Neuropsychiatric symptoms in untreated Parkinson's disease[END_REF]. The risk to develop these disorders has been observed to be much higher (ninefold) in "younger" patients (<62 years old) than in older subjects [START_REF] Dissanayaka | Anxiety disorders in Parkinson's disease: prevalence and risk factors[END_REF]. The pathophysiological basis for these symptoms is however not clearly identified yet. Beside alterations in dopaminergic system, including a correlation between striatal dopamine transporter availability and anxiety [START_REF] Erro | Anxiety is associated with striatal dopamine transporter availability in newly diagnosed untreated Parkinson's disease patients[END_REF][START_REF] Moriyama | Increased dopamine transporter density in Parkinson's disease patients with Social Anxiety Disorder[END_REF][START_REF] Weintraub | Striatal dopamine transporter imaging correlates with anxiety and depression symptoms in Parkinson's disease[END_REF], a structural change in amygdala size has also been proposed to contribute to this symptom [START_REF] Vriend | A smaller amygdala is associated with anxiety in Parkinson's disease: a combined FreeSurfer-VBM study[END_REF]. Moreover, a loss of noradrenaline neurons in the locus coeruleus [START_REF] Bertrand | Qualitative and quantitative analysis of locus coeruleus neurons in Parkinson's disease[END_REF][START_REF] Delaville | Noradrenaline and Parkinson's disease[END_REF][START_REF] German | Disease-specific patterns of locus coeruleus cell loss[END_REF][START_REF] Hughes | Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases[END_REF] and of serotonin cells in the dorsal raphe [START_REF] Kish | Biochemistry of Parkinson's disease: is a brain serotonergic deficiency a characteristic of idiopathic Parkinson's disease?[END_REF] has been described in patients, which could also contribute to the presence of anxiety and depression [START_REF] Marsh | Depression and Parkinson's disease: current knowledge[END_REF][START_REF] Remy | Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system[END_REF][START_REF] Schapira | Non-motor features of Parkinson disease[END_REF].

Depressive disorders are common psychiatric disorders characterized by the presence of a sad, empty or irritable mood, accompanied by somatic and cognitive changes that impact everyday life function. According to the World Health Organization, they affect 300 million people worldwide (http://www.who.int/). Approximatively 40% of the patients with Parkinson's disease display depressive disorders [START_REF] Burn | Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson's disease[END_REF][START_REF] Chaudhuri | Non-motor symptoms of Parkinson's disease: diagnosis and management[END_REF][START_REF] Cummings | Depression and Parkinson's disease: a review[END_REF][START_REF] Jacob | Occurrence of depression and anxiety prior to Parkinson's disease[END_REF]. Anhedonia and apathy are frequent symptoms that can occur during the prodromal phase [START_REF] Ishihara | A systematic review of depression and mental illness preceding Parkinson's disease[END_REF]Pont-Sunyer et al., 2015), which leads to the fact that, at time of Parkinson's disease diagnosis, the proportion of patients who already consulted for depression is more than twice higher than in the control population [START_REF] Leentjens | Higher incidence of depression preceding the onset of Parkinson's disease: a register study[END_REF]. Classical antidepressant drugs as well as deep brain stimulation and L-DOPA therapy can be useful to improve these symptoms [START_REF] Czernecki | Motivation, reward, and Parkinson's disease: influence of dopatherapy[END_REF]Schapira et al., 2017). Even if the detailed mechanism underlying depression is unknown, different hypotheses have been proposed. Indeed, alterations in the monoaminergic systems [START_REF] Chaudhuri | Non-motor symptoms of Parkinson's disease: diagnosis and management[END_REF][START_REF] Reichmann | Premotor Diagnosis of Parkinson's Disease[END_REF][START_REF] Schapira | Non-motor features of Parkinson disease[END_REF], as well as in structural and metabolic alterations in brain regions known for their implication in affective disorders, such as the hippocampus and the amygdala [START_REF] Huang | Neuroimaging markers of motor and nonmotor features of Parkinson's disease: an 18f fluorodeoxyglucose positron emission computed tomography study[END_REF][START_REF] Surdhar | Intact limbic-prefrontal connections and reduced amygdala volumes in Parkinson's disease with mild depressive symptoms[END_REF][START_REF] Van Mierlo | Depressive symptoms in Parkinson's disease are related to decreased hippocampus and amygdala volume[END_REF], may likely contribute to the depressive symptoms in Parkinson's disease.

Animal models to study Parkinson's disease

This section mostly focuses on animal models (rodents and monkeys) of Parkinson's disease for which data related to pain, anxiety or depression like behaviors are available. For a more exhaustive view of existing models, readers can consult following reviews [START_REF] Bastías-Candia | Revisiting the Paraquat-Induced Sporadic Parkinson's Disease-Like Model[END_REF][START_REF] Bové | Neurotoxin-based models of Parkinson's disease[END_REF][START_REF] Creed | New Developments in Genetic rat models of Parkinson's Disease[END_REF][START_REF] Francardo | Modeling Parkinson's disease and treatment complications in rodents: Potentials and pitfalls of the current options[END_REF][START_REF] Grandi | Animal models of early-stage Parkinson's disease and acute dopamine deficiency to study compensatory neurodegenerative mechanisms[END_REF][START_REF] Koprich | Animal models of α-synucleinopathy for Parkinson disease drug development[END_REF][START_REF] Volta | LRRK2 mouse models: dissecting the behavior, striatal neurochemistry and neurophysiology of PD pathogenesis[END_REF].

2.1.Toxin-induced Parkinson's disease models

The more widely used models of Parkinson's disease are based on 6-hydroxydopamine (6-OHDA), a drug that selectively acts on catecholamine containing terminals and cells bodies [START_REF] Ungerstedt | 6-Hydroxy-dopamine induced degeneration of central monoamine neurons[END_REF]. Due to its homology with dopamine and noradrenaline, 6-OHDA is caught by plasma membrane dopamine and noradrenaline transporters to enter into cells. It accumulates into the cytosol, producing reactive oxygen species that are toxic to the cell and quinones that inactivate biological macromolecules important to neuronal integrity [START_REF] Bové | Neurotoxin-based models of Parkinson's disease[END_REF][START_REF] Dauer | Parkinson's disease: mechanisms and models[END_REF][START_REF] Sachs | Mechanisms of action of 6-hydroxydopamine[END_REF]. 6-OHDA does not easily cross the brain-blood barrier, it is thus injected directly into the structure of interest, either in the area of dopamine cell bodies (substantia nigra pars compacta), in the dopamine passing fibers (medial forebrain bundle) or at terminal level (striatal complex) [START_REF] Blum | Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease[END_REF][START_REF] Gubellini | Animal models of Parkinson's disease: An updated overview[END_REF][START_REF] Mcdowell | Animal models of the non-motor features of Parkinson's disease[END_REF]. This 6-OHDA administration induces a degeneration of dopamine neurons, leading to motor impairments that partially mimic the motor-symptoms of Parkinson's disease [START_REF] Bové | Neurotoxin-based models of Parkinson's disease[END_REF][START_REF] Ungerstedt | 6-Hydroxy-dopamine induced degeneration of central monoamine neurons[END_REF]. The injection can be unilateral, producing a hemiparkinsonism model with asymmetric circling behaviors that can be used to test treatments for motor symptoms [START_REF] Bové | Neurotoxin-based models of Parkinson's disease[END_REF][START_REF] Dauer | Parkinson's disease: mechanisms and models[END_REF][START_REF] Hefti | Circling behavior in rats with partial, unilateral nigro-striatal lesions: effect of amphetamine, apomorphine, and DOPA[END_REF][START_REF] Ungerstedt | Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system[END_REF]. The bilateral injection in the mesencephalic region of dopamine cell bodies can however induce a notable mortality of the animals, due to adverse effects such as aphagia, adipsia and seizures [START_REF] Bezard | A tale on animal models of Parkinson's disease[END_REF][START_REF] Bové | Neurotoxin-based models of Parkinson's disease[END_REF][START_REF] Ungerstedt | Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system[END_REF], which limits in part this direct targeting of cell bodies. As 6-OHDA is toxic for all catecholamine neurons, a pretreatment with a blocker of noradrenaline re-uptake and/or catabolism (monoamine oxidase B inhibitor) may be used to protect noradrenaline neurons and have a more specific dopamine lesion. However, it has also been proposed that administration of 6-OHDA without such neuroprotection may lead to a richer phenotype that better mimics Parkinson's disease [START_REF] Bezard | Animal models of Parkinson's disease: limits and relevance to neuroprotection studies[END_REF].

The use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mimic the disease was discovered in the 1980's, after the observation that an accidental production of MPTP during the manufacture of a synthetic opioid drug could lead to symptoms similar to those observe in Parkinson's disease in users of this drug [START_REF] Blum | Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease[END_REF][START_REF] Davis | Chronic Parkinsonism secondary to intravenous injection of meperidine analogues[END_REF][START_REF] Langston | Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis[END_REF]. In animal research, MPTP is mainly used in non-human primates and in mice, even though rodents are less sensitive to its toxicity [START_REF] Schober | Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP[END_REF], especially rats in which dopamine neurons are resistant to systemic delivery of MPTP [START_REF] Betarbet | Animal models of Parkinson's disease[END_REF][START_REF] Bové | Neurotoxin-based models of Parkinson's disease[END_REF][START_REF] Boyce | Repeated administration of N-methyl-4-phenyl 1,2,5,6-tetrahydropyridine to rats is not toxic to striatal dopamine neurones[END_REF]Chiueh et al., 1984b;[START_REF] Sahgal | N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) affects locomotor activity without producing a nigrostriatal lesion in the rat[END_REF]. However, local intracerebral delivery of the active metabolite MPP+ can induce dopamine neuron loss in rats and in guinea-pigs (Chiueh et al., 1984a). The effects of MPTP depend on various parameters, such as the administration mode, species and age [START_REF] Blum | Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease[END_REF]. Due to its facility to cross the brain-blood barrier, MPTP is classically administered through systemic injection [START_REF] Bankiewicz | Preclinical Models of Parkinson's Disease[END_REF]. After such injection, MPTP enters the brain and is metabolized in 1methyl-4-phenyl-2,3-dihydropyridinium ion (MPP+). The MPP+ binding site is located in the electron leak site, within the complex I of the electron transport chain of the mitochondria [START_REF] Betarbet | Animal models of Parkinson's disease[END_REF]. MPP+ inhibits the complex I of the mitochondrial electron transport chain, leading to significant ATP depletion, production of reactive oxygen species and cell loss, particularly in the nigrostriatal pathway which is the brain region the most sensitive to the compound, but not the only one [START_REF] Betarbet | Animal models of Parkinson's disease[END_REF][START_REF] Chan | Rapid ATP loss caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mouse brain[END_REF][START_REF] Dauer | Parkinson's disease: mechanisms and models[END_REF][START_REF] Engeln | Widespread Monoaminergic Dysregulation of Both Motor and Non-Motor Circuits in Parkinsonism and Dyskinesia[END_REF][START_REF] Fabre | Effect of MPTP on brain mitochondrial H2O2 and ATP production and on dopamine and DOPAC in the striatum[END_REF].

The above two toxins are the most used to model Parkinson's disease, but other drugs can be found in the literature. Rotenone is a compound used as pesticide which easily crosses the brain-blood barrier, entering neuron mitochondria through the same mechanism as MPP+ and inhibiting mitochondrial complex I [START_REF] Dauer | Parkinson's disease: mechanisms and models[END_REF][START_REF] Heinz | Mechanistic Investigations of the Mitochondrial Complex I Inhibitor Rotenone in the Context of Pharmacological and Safety Evaluation[END_REF][START_REF] Li | Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production[END_REF]. It produces α-synuclein accumulation and causes a degeneration of the nigrostriatal dopaminergic pathway following oxidative stress [START_REF] Betarbet | Chronic systemic pesticide exposure reproduces features of Parkinson's disease[END_REF][START_REF] Betarbet | Animal models of Parkinson's disease[END_REF]. In rodents, rotenone can be administrated by systemic injections or by stereotaxic delivery directly into the brain. However, its use is strongly limited by the high mortality that follows its administration at high doses [START_REF] Antkiewicz-Michaluk | 1-methyl-1,2,3,4-tetrahydroisoquinoline protects against rotenone-induced mortality and biochemical changes in rat brain[END_REF]. Based on epidemiological toxicology, the herbicide paraquat (1,1'-dimethyl-4,4'-bypyridinium dichloride), the fungicide maneb (Mnethylene-1,2-bisdithiocarbamate) and the cycad flour (from cycas micronesica) are also used to model Parkinson's disease. Paraquat is in fact a structural analog of MPP+, the active metabolite of MPTP [START_REF] Betarbet | Animal models of Parkinson's disease[END_REF][START_REF] Bové | Neurotoxin-based models of Parkinson's disease[END_REF]. Its systemic injections induce αsynuclein accumulation and causes degeneration of dopamine neurons of the substantia nigra pars compacta [START_REF] Dauer | Parkinson's disease: mechanisms and models[END_REF][START_REF] Manning-Bog | The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein[END_REF][START_REF] Mccormack | Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat[END_REF][START_REF] Mcdowell | Animal models of the non-motor features of Parkinson's disease[END_REF]. Maneb easily crosses the brain-blood barrier neuron and causes damage in the substantia nigra pars compacta and the striatum, leading to locomotor and coordination impairments. Combined exposure to maneb potentiates the effect of paraquat [START_REF] Bastías-Candia | Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: Relevance to sporadic Parkinson's disease[END_REF][START_REF] Thiruchelvam | Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype[END_REF]. Finally, mice fed with cycad flour exhibit α-synuclein accumulation in multiple brain regions and dopamine neuron loss in the substantia nigra pars compacta, which induces cognitive deficits and Parkinson's disease-like symptoms [START_REF] Mcdowell | Animal models of the non-motor features of Parkinson's disease[END_REF][START_REF] Wilson | Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour[END_REF].

Moreover, it has been shown that an intranigral, intrastriatal or intra-pallidal injection of lipopolysaccharides induces an inflammation process associated with the activation of microglia. This inflammation favors a degeneration of the dopamine neurons of the nigrostriatal pathway and lead to locomotor impairments similar to the ones seen in other models of Parkinson's disease [START_REF] Castaño | Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system[END_REF][START_REF] Liu | Lipopolysaccharide Animal Models for Parkinson's Disease[END_REF]Zhang et al., 2005).

Lastly, injections of Lewy body extracts from post mortem Parkinson's disease patients in the substantia nigra pars compacta or the striatum in mice or monkey induce a progressive nigrostriatal degeneration. In mice, this degeneration is accompanied by an astrogliosis in the substantia nigra and impaired motor coordination and balance in the pole test [START_REF] Recasens | Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys[END_REF].

2.2.Genetic models of Parkinson's disease

While Parkinson's disease is often sporadic, familial forms have also been described which are due to autosomal dominant or recessive genetic mutations [START_REF] Singleton | The genetics of Parkinson's disease: progress and therapeutic implications[END_REF], and corresponding animal models have been developed.

In 1997, a family form of Parkinson's disease caused by a mutation of the α-synuclein gene (SNCA gene) was discovered [START_REF] Polymeropoulos | Mutation in the alpha-synuclein gene identified in families with Parkinson's disease[END_REF]. This mutation consists of a single base pair change from a guanine to an adenosine at position 209, leading to an alanine to threonine substitution in the protein at position 53 (p.A53T) [START_REF] Polymeropoulos | Mutation in the alpha-synuclein gene identified in families with Parkinson's disease[END_REF].

Other point mutations of the SNCA gene were also linked to familial forms of Parkinson's disease, such as the p.A30P mutation [START_REF] Krüger | Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease[END_REF] corresponding to an alanine to proline substitution in the position 30 of the protein and the p.E46K mutation [START_REF] Zarranz | The new mutation, E46K, of alpha-synuclein causes[END_REF] corresponding to a glutamic acid to lysine substitution in position 46. All of these mutations lead to an autosomal dominant form of the disease [START_REF] Hernandez | Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance[END_REF]. Beside these point mutations, whole locus duplication or triplication of the SNCA gene has also been reported as a cause of family forms of the disease [START_REF] Ibáñez | Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease[END_REF][START_REF] Singleton | alpha-Synuclein locus triplication causes Parkinson's disease[END_REF], the number of SNCA copies correlating with the early-onset and severity of the disease, suggesting a dose dependent effect [START_REF] Ibáñez | Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease[END_REF]. The discovery of these different familial forms was the starting point for the development of transgenic models for the study of Parkinson's disease.

To explore the function of the α-synuclein protein and its implication in the disease, several lines of transgenic mice expressing either the wild-type or a mutated (p.A53T or p.A30P) human α-synuclein were produced (for review, see [START_REF] Fernagut | Alpha-synuclein and transgenic mouse models[END_REF]. The first transgenic mouse overexpressing human α-synuclein used the wild-type form of the protein under the control of the plateled-derived growth factor β promoter [START_REF] Fernagut | Alpha-synuclein and transgenic mouse models[END_REF][START_REF] Masliah | Dopaminergic loss and inclusion body formation in alphasynuclein mice: implications for neurodegenerative disorders[END_REF], leading to α-synuclein accumulation in synapses from the neocortex, the hippocampus, the substantia nigra and the olfactory regions [START_REF] Masliah | Dopaminergic loss and inclusion body formation in alphasynuclein mice: implications for neurodegenerative disorders[END_REF]. However, the use of other promoters and/or forms of α-synuclein can lead to different patterns and levels of α-synuclein expression and of behavioral phenotypes [START_REF] Fernagut | Alpha-synuclein and transgenic mouse models[END_REF]. For example, α-synuclein expression driven by the Thy-1 promoter has been used to produce various transgenic lines that differ in terms of presence [START_REF] Kahle | Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha -synuclein in human and transgenic mouse brain[END_REF][START_REF] Rockenstein | Differential neuropathological alterations in transgenic mice expressing alphasynuclein from the platelet-derived growth factor and Thy-1 promoters[END_REF] or absence [START_REF] Rabl | Early start of progressive motor deficits in Line 61 α-synuclein transgenic mice[END_REF] of α-synuclein accumulation in the striatum or in the presence [START_REF] Fleming | Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein[END_REF][START_REF] Rabl | Early start of progressive motor deficits in Line 61 α-synuclein transgenic mice[END_REF] or absence [START_REF] Kahle | Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha -synuclein in human and transgenic mouse brain[END_REF] of motor impairment. This variability is not only related to the chosen protein form (wildtype or mutated) but may also be related to the transgene insertion site [START_REF] Chesselet | In vivo alpha-synuclein overexpression in rodents: a useful model of Parkinson's disease?[END_REF]).

An expression of the wild-type [START_REF] Lim | Forebrain overexpression of alpha-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption[END_REF][START_REF] Nuber | Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease[END_REF] or the p.A30P mutated [START_REF] Marxreiter | Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice[END_REF] human α-synuclein driven by the calmodulin-dependent protein kinase IIα promoter induces a degeneration of neurons in the dentate gyrus, the olfactory bulb and in some midbrain and forebrain regions [START_REF] Lim | Forebrain overexpression of alpha-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption[END_REF][START_REF] Marxreiter | Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice[END_REF][START_REF] Nuber | Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease[END_REF]. This α-synuclein accumulation leads to cognitive and progressive motor impairments [START_REF] Nuber | Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease[END_REF]. Interestingly, if the construct was repressed until weaning, no neuronal loss was observed in the hippocampal region, indicating that the dentate gyrus neurons are more vulnerable during development than after maturation [START_REF] Lim | Forebrain overexpression of alpha-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption[END_REF]. Transgenic mice expressing either wild-type or A53T mutated α-synuclein under the mouse prion protein promoter display age-dependent intracytoplasmic neuronal α-synuclein inclusions [START_REF] Giasson | Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein[END_REF] and motor impairments that lead to paralysis and death a few days after the first motor symptoms due to motoneuron loss [START_REF] Giasson | Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein[END_REF][START_REF] Giraldo | Locomotor differences in mice expressing wild-type human α-synuclein[END_REF]. In this model, intracerebral injections of preformed α-synuclein fibrils in young asymptomatic mice accelerate the formation of intracellular inclusions and the development of neurological symptoms [START_REF] Luk | Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice[END_REF].

To more specifically target α-synuclein expression to dopamine neurons (which is a useful model of dopamine cell loss but does not reflect the more widespread expression observed in both central and peripheral nervous system in patients), lines of transgenic mice with a truncated wild-type [START_REF] Tofaris | Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders[END_REF] or mutated (p.A53T) [START_REF] Wakamatsu | Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice[END_REF] α-synuclein expression under the control of the tyrosine hydroxylase promoter were developed. These mice display pathological α-synuclein-positive inclusions in the substantia nigra and in the olfactory bulb, and a decrease in striatal dopamine levels associated with a progressive reduction of the spontaneous activity [START_REF] Tofaris | Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders[END_REF][START_REF] Wakamatsu | Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice[END_REF].

In addition to the classical transgenic models exposed above, the use of adeno-associated viral vectors to overexpress α-synuclein has also been developed. This overexpression in the midbrain induces a nigrostriatal degeneration and the formation of insoluble α-synuclein aggregates in mice, rats and non-human primates [START_REF] Bourdenx | Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression[END_REF][START_REF] Ip | AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson's disease[END_REF][START_REF] Ulusoy | Viral vector-mediated overexpression of α-synuclein as a progressive model of Parkinson's disease[END_REF]. This method reproduces many characteristics of the pathology and provides an interesting model in both rodents and primates [START_REF] Ulusoy | Viral vector-mediated overexpression of α-synuclein as a progressive model of Parkinson's disease[END_REF].

Mutations in the PARK8 gene coding for the leucine-rich repeat kinase 2 (LRRK2) protein have also been described to be associated with familial autosomal-dominant and sporadic forms of Parkinson's disease [START_REF] Funayama | A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1[END_REF][START_REF] Healy | Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study[END_REF][START_REF] Paisán-Ruiz | LRRK2: cause, risk, and mechanism[END_REF].

Mutations of this protein mostly target the GTPase and kinase domains of the protein [START_REF] Dawson | Genetic animal models of Parkinson's disease[END_REF][START_REF] Gubellini | Animal models of Parkinson's disease: An updated overview[END_REF] and cause late-onset forms of the disease [START_REF] Dawson | Genetic animal models of Parkinson's disease[END_REF][START_REF] Healy | Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study[END_REF]. Transgenic mice with bacterial artificial chromosome (BAC) expressing LRRK2 R1441C/G (i.e. mutation in the GTPase domain) have been used to model

Parkinson's disease, showing age-dependent and progressive motor symptoms but no nigrostriatal degeneration [START_REF] Li | Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease[END_REF]. The development of LRRK2 knock-in mice also failed to produce the classical brain alterations of the disease, such as dopamine cell degeneration or α-synuclein accumulation [START_REF] Bezard | Animal models of Parkinson's disease: limits and relevance to neuroprotection studies[END_REF][START_REF] Dawson | Genetic animal models of Parkinson's disease[END_REF][START_REF] Volta | LRRK2 mouse models: dissecting the behavior, striatal neurochemistry and neurophysiology of PD pathogenesis[END_REF]. More conclusively, a rat LRRK2 model has been developed, using adenoviralmediated expression of LRRK2 G2019S mutation (i.e. mutation in the kinase) to induce a progressive degeneration of nigral dopamine neurons [START_REF] Dusonchet | A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2[END_REF].

Mutations in the PRKN gene (or PARK2), which encodes for parkin, an E3 ubiquitin ligase, were identified as a genetic cause of autosomal-recessive and early-onset Parkinson's disease, as well as of some forms of sporadic cases [START_REF] Gubellini | Animal models of Parkinson's disease: An updated overview[END_REF][START_REF] Dawson | Genetic animal models of Parkinson's disease[END_REF].

These parkin mutations lead to a loss-of-function and are responsible for a loss of substantia nigra pars compacta dopamine neurons without formation of Lewy bodies [START_REF] Dauer | Parkinson's disease: mechanisms and models[END_REF]. However, mouse models produced by partial or full deletion of the parkin gene exhibit few or no dopamine loss [START_REF] Itier | Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse[END_REF][START_REF] Perez | Parkin-deficient mice are not a robust model of parkinsonism[END_REF][START_REF] Von Coelln | Loss of locus coeruleus neurons and reduced startle in parkin null mice[END_REF] and only limited behavioral deficits [START_REF] Perez | Parkin-deficient mice are not a robust model of parkinsonism[END_REF]. On the other hand, the overexpression of the mutant human parkin using a BAC transgenic mouse model leads to a late-onset and progressive degeneration of dopamine neurons, associated with progressive motor deficits [START_REF] Dawson | Genetic animal models of Parkinson's disease[END_REF][START_REF] Gubellini | Animal models of Parkinson's disease: An updated overview[END_REF]Lu et al., 2009).

Mutations in the PINK-1 (PTEN-induced putative kinase 1) gene can cause autosomal recessive forms of the disease [START_REF] Dawson | Genetic animal models of Parkinson's disease[END_REF][START_REF] Gubellini | Animal models of Parkinson's disease: An updated overview[END_REF][START_REF] Valente | PINK1 mutations are associated with sporadic early-onset parkinsonism[END_REF]. PINK-1 interacts with parkin to induce parkin-mediated autophagy of damaged mitochondria and thus protect cells from mitochondrial dysfunctions [START_REF] Gubellini | Animal models of Parkinson's disease: An updated overview[END_REF][START_REF] Lazarou | PINK1 drives Parkin self-association and HECT-like E3 activity upstream of mitochondrial binding[END_REF][START_REF] Narendra | Parkin is recruited selectively to impaired mitochondria and promotes their autophagy[END_REF]. However, similar to parkin null mice, PINK-1 knock-out mice do not display notable neurodegeneration of substantia nigra dopamine neurons, and show few or no Lewy body-like inclusions [START_REF] Gispert | Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration[END_REF][START_REF] Kitada | Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice[END_REF].

A missense mutation in the DJ-1 gene (PARK7) is responsible for an autosomal recessive and early-onset form of Parkinson's disease (Bonifati et al., 2003a(Bonifati et al., , 2003b;;[START_REF] Dawson | Genetic animal models of Parkinson's disease[END_REF][START_REF] Lim | Genetic models of Parkinson disease[END_REF]. DJ-1 knock out mice have been developed, but failed to show nigrostriatal dopaminergic loss. However, a reduced striatal dopamine release and a decreased locomotor activity has been observed, making this model interesting as model of early stages of the disease [START_REF] Chandran | Progressive behavioral deficits in DJ-1-deficient mice are associated with normal nigrostriatal function[END_REF][START_REF] Chen | Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice[END_REF][START_REF] Dawson | Genetic animal models of Parkinson's disease[END_REF][START_REF] Goldberg | Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1[END_REF][START_REF] Lim | Genetic models of Parkinson disease[END_REF][START_REF] Yamaguchi | Absence of dopaminergic neuronal degeneration and oxidative damage in aged DJ-1-deficient mice[END_REF].

Beside the above genetic models that are based on human gene mutations associated with the disease, other transgenic models have also been designed targeting the dopamine system.

One of these models is based on the mutation or the deletion of the homeobox transcription factor Pitx3 which is known to be selective to dopamine neurons, thus inducing a dopaminergic loss in the nigrostriatal pathway. The Pitx3-null mice exhibit different markers of the disease, including a decline in substantia nigra pars compacta cell number, a reduction in striatal dopamine release, and motor symptoms such as motor coordination impairment, body tremors and decreased locomotion [START_REF] Filali | Neurobehavioral Anomalies in the Pitx3/ak Murine Model of Parkinson's Disease and MPTP[END_REF][START_REF] Le | Pitx3 deficiency produces decreased dopamine signaling and induces motor deficits in Pitx3(-/-) mice[END_REF]. The Pitx3 416insG mutant mice, relying on a spontaneous mutation (an inserted G in position 416 of the Pitx3 gene in the chromosome 19), induces microphtalmia or anophtalmia and a loss of dopamine neurons in the substantia nigra, which induces motor impairment and increased nociceptive response [START_REF] Rosemann | Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice[END_REF]. Another interesting mouse model, MitoPark, has been obtained by selectively removing the mitochondrial transcription factor A (Tfam) from dopamine midbrain neurons. These transgenic mice model an adult-onset of the disease, with a progressive loss of dopamine cell bodies and terminals, associated with tremors, limb rigidity and a progressive decline of locomotion and rearing [START_REF] Ekstrand | Progressive parkinsonism in mice with respiratory-chaindeficient dopamine neurons[END_REF][START_REF] Galter | MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease[END_REF].

Non-motor symptoms in animal models of Parkinson's disease

3.1.Nociception and pain in rodent Parkinson's disease models (Figure 2)

According to the definition from the International Association for the Study of Pain, pain is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage". This sensory/emotional duality is a critical element. It distinguishes pain from nociception, which encompasses "the neural process of encoding noxious stimuli" and do not necessarily imply the presence of pain. However, distinguishing pain from nociception remains challenging in animal-based research, and tests that are referred to as "pain tests" are usually based on reflex responses that may reflect nociceptive responses [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF]. Moreover, because of the implication of reflex motor responses in most of the tests used to study nociception in rodents and the potential slow-down of motor reflexes in Parkinson's disease, it can also be challenging to correctly assess and interpret some nociceptive responses in rodent models of this disease.

Data reported below show that the nociceptive hypersensitivity observed in patients with

Parkinson's disease (response to evoked pain) can be reproduced in some of the animal models.

However, the presence of spontaneous pain, which may for example result from rigidity, akinesia, postural abnormality or dystonia, has not been studied yet in these models. While challenging, such question could now also be addressed in rodents. Indeed, procedures were developed in the past decade to test the aversive state induced by ongoing pain in rats and mice [START_REF] Barthas | The anterior cingulate cortex is a critical hub for pain-induced depression[END_REF][START_REF] Johansen | The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex[END_REF][START_REF] King | Unmasking the tonic-aversive state in neuropathic pain[END_REF][START_REF] Qu | Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy[END_REF][START_REF] Sellmeijer | Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences[END_REF]

Electrical sensitivity

The threshold responses to electrical shocks can be used to assess pain sensitivity. In such test, electrical stimuli of increasing intensities are delivered through a grid floor and the threshold intensity eliciting the first response (i.e. flinch, vocalization, jumping or running) is measured [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF]. Rats with a unilateral 6-OHDA lesion of the dopamine neurons show an hypersensitivity either in the ispsilateral [START_REF] Chen | Dopaminergic imaging of nonmotor manifestations in a rat model of Parkinson's disease by fMRI[END_REF] of the contralateral body side of the lesion [START_REF] Carey | Acute ipsilateral hyperalgesia and chronic contralateral hypoalgesia after unilateral 6-hydroxydopamine lesions of the substantia nigra[END_REF] (Table 1).

Mechanical sensitivity

Although different tests are available to assess the response to mechanical stimuli in rodents [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF], particularly in rats (von Frey filaments, Randall-Selitto's paw pressure test…), most of the data from Parkinson's disease rodent models found in the literature are based on the von Frey filaments test. Mechanical nociceptive thresholds are usually lower in animal models of Parkinson's disease, regardless of the rodent species (mice or rat) or of the chosen model (6-OHDA, MPTP, Pitx3) [START_REF] Cao | Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease[END_REF][START_REF] Charles | Alteration of nociceptive integration in the spinal cord of a rat model of Parkinson's disease[END_REF][START_REF] Chudler | Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine[END_REF][START_REF] Gee | The effects of subthalamic deep brain stimulation on mechanical and thermal thresholds in 6OHDAlesioned rats[END_REF]Gómez-Paz et al., 2017;[START_REF] Nascimento | Nociceptive Response to L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats[END_REF][START_REF] Park | Pain perception in acute model mice of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)[END_REF][START_REF] Rosemann | Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice[END_REF][START_REF] Saadé | Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons[END_REF][START_REF] Takeda | Unilateral lesions of mesostriatal dopaminergic pathway alters the withdrawal response of the rat hindpaw to mechanical stimulation[END_REF][START_REF] Takeda | Intrastriatal grafts of fetal ventral mesencephalon improve allodynia-like withdrawal response to mechanical stimulation in a rat model of Parkinson's disease[END_REF][START_REF] Wang | Attenuation of hyperalgesia responses via the modulation of 5-hydroxytryptamine signalings in the rostral ventromedial medulla and spinal cord in a 6-hydroxydopamine-induced rat model of Parkinson's disease[END_REF]Zengin-Toktas et al., 2013). While this mechanical hypersensitivity now appears as well established, there are some discrepancies among published reports using a unilateral lesion [START_REF] Charles | Alteration of nociceptive integration in the spinal cord of a rat model of Parkinson's disease[END_REF][START_REF] Chudler | Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine[END_REF][START_REF] Gee | The effects of subthalamic deep brain stimulation on mechanical and thermal thresholds in 6OHDAlesioned rats[END_REF]Gómez-Paz et al., 2017;[START_REF] Nascimento | Nociceptive Response to L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats[END_REF][START_REF] Saadé | Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons[END_REF][START_REF] Takeda | Unilateral lesions of mesostriatal dopaminergic pathway alters the withdrawal response of the rat hindpaw to mechanical stimulation[END_REF][START_REF] Takeda | Intrastriatal grafts of fetal ventral mesencephalon improve allodynia-like withdrawal response to mechanical stimulation in a rat model of Parkinson's disease[END_REF], with results that may differ regarding the time-course and/or the laterality of the hypersensivity. Changes in mechanical sensitivity have been correlated with decreased tyrosine hydroxylase expression in the substantia nigra pars compacta (Zengin-Toktas et al., 2013) and can be compensated by a neural transplantation of fetal ventral mesencephalon tissue in lesioned animals [START_REF] Takeda | Intrastriatal grafts of fetal ventral mesencephalon improve allodynia-like withdrawal response to mechanical stimulation in a rat model of Parkinson's disease[END_REF] (Table 1).

Painful rigidity of the face, chin or jaw and trigeminal neuralgia-like pain can be present in the prodromal phase of Parkinson's disease [START_REF] Waseem | Pain in Parkinson's disease. Common yet seldom recognized symptom is treatable[END_REF]. This trigeminal sensitivity can be tested in rodents with different approaches, using procedures assessing static or dynamic mechanical sensitivity. To test static (pressure) mechanical allodynia of the face, von Frey filaments can be applied to the vibrissae region. The bilateral lesion of the substantia nigra pars compacta leads to an increased nociceptive sensitivity of the two side of the face [START_REF] Dieb | Nigrostriatal dopaminergic depletion produces orofacial static mechanical allodynia[END_REF], while a unilateral lesion in the caudate/putamen does not affect this response [START_REF] Chudler | Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine[END_REF]. To test the dynamic mechanical allodynia, gentle air puff is applied on the animal face. Bilateral lesioned animals display a dynamic mechanical allodynia of the face, which is inversely correlated with the number of tyrosine hydroxylase positive cells [START_REF] Dieb | Lesion of the dopaminergic nigrostriatal pathway induces trigeminal dynamic mechanical allodynia[END_REF] (Table 1).

Thermal sensitivity

The tail flick test measures the withdrawal latency following tail exposure to a heat stimulus, by using an infrared heat beam or a warm-controlled water bath [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF][START_REF] Bars | Animal models of nociception[END_REF]. The response in this test is a nociceptive spinal reflex that is, however, influenced by descending controls from the brain. Mice with intraperitoneal injections of MPTP have reduced tail flick latency [START_REF] Park | Pain perception in acute model mice of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)[END_REF][START_REF] Rosland | Acute and long term effects of 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in tests of nociception in mice[END_REF], whereas Pitx3 416insG mutant mice showed no significant difference [START_REF] Rosemann | Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice[END_REF]. On the other hand, the literature concerning the thermal sensitivity in 6-OHDA models of Parkinson's disease is controversial, with opposite results that can be reported: increased latency [START_REF] Grossmann | The dependence of the anti-nociceptive effect of morphine and other analgesic agents on spinal motor activity after central monoamine depletion[END_REF][START_REF] Tassorelli | Behavioral responses and Fos activation following painful stimuli in a rodent model of Parkinson's disease[END_REF], no difference [START_REF] Gee | The effects of subthalamic deep brain stimulation on mechanical and thermal thresholds in 6OHDAlesioned rats[END_REF][START_REF] Morgan | 6-Hydroxydopamine lesions of the ventral tegmentum abolish D-amphetamine and morphine analgesia in the formalin test but not in the tail flick test[END_REF][START_REF] Ogata | Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion[END_REF] or decreased latency [START_REF] Dolatshahi | Ellagic acid improves hyperalgesia and cognitive deficiency in 6-hydroxidopamine induced rat model of Parkinson's disease. Iran[END_REF]Gómez-Paz et al., 2017;[START_REF] Haddadi | Chronic treatment with carvacrol improves passive avoidance memory in a rat model of Parkinson's disease[END_REF][START_REF] Nascimento | Nociceptive Response to L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats[END_REF][START_REF] Saadé | Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons[END_REF]. A possible explanation for these discrepancies could be the co-presence of thermal hypersensitivity and of reflex slow-down. Depending on the location and the extent of the lesion, and on the test procedure and temperature settings, one or the other aspect may be predominant, which highlights the potential difficulty to interpret tail-flick results in these models. (Table 1).

The hot plate test measures the response to nociceptive heat by placing the animal on a plate at fixed and controlled temperature, often set in the 52 to 55°C range with a 0.1°C precision.

The latency before the apparition of a withdrawal behavior, such as paw licking, paw withdrawal or eventually jumping, is measured [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF][START_REF] Bars | Animal models of nociception[END_REF]. Usually, whatever the model (MPTP or 6-OHDA) and the species (mouse or rat) that is used, the articles report an increased pain sensitivity [START_REF] Chen | Dopaminergic imaging of nonmotor manifestations in a rat model of Parkinson's disease by fMRI[END_REF][START_REF] Dolatshahi | Ellagic acid improves hyperalgesia and cognitive deficiency in 6-hydroxidopamine induced rat model of Parkinson's disease. Iran[END_REF][START_REF] Gee | The effects of subthalamic deep brain stimulation on mechanical and thermal thresholds in 6OHDAlesioned rats[END_REF][START_REF] Lin | Activation of striatal dopamine receptors induces pain inhibition in rats[END_REF][START_REF] Nascimento | Nociceptive Response to L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats[END_REF][START_REF] Park | Pain perception in acute model mice of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)[END_REF][START_REF] Rosland | Acute and long term effects of 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in tests of nociception in mice[END_REF][START_REF] Saadé | Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons[END_REF]. In the paw immersion test, consisting in placing the animal's paw in a water bath at a fixed and controlled temperature, rats with 6-OHDA lesion in the ventral tegmental area and the substantia nigra displayed a decreased withdrawal latency, i.e. a hypersensitivity, concerning the paw contralateral to the lesion [START_REF] Saadé | Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons[END_REF] (Table 1).

In the radiant heat paw-withdrawal test, often referred to as the Hargreaves's method [START_REF] Hargreaves | A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia[END_REF], a controlled heat beam system is directed toward the plantar surface of the animal's hind paws in order to measure the withdrawal latency [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF]. In this test, Pitx3 416insG mutant mice [START_REF] Rosemann | Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice[END_REF], rats at 3 weeks following 6-OHDA lesion of the caudate/putamen nuclei [START_REF] Chudler | Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine[END_REF] rats with 6-OHDA lesion of the right medial forebrain bundle [START_REF] Charles | Alteration of nociceptive integration in the spinal cord of a rat model of Parkinson's disease[END_REF], rats at 4 and 5 weeks following 6-OHDA bilateral lesion of the striatum [START_REF] Cao | Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease[END_REF] and rats with bilateral lesion of the substantia nigra pars compacta at 2 and 4 weeks post-surgery [START_REF] Wang | Attenuation of hyperalgesia responses via the modulation of 5-hydroxytryptamine signalings in the rostral ventromedial medulla and spinal cord in a 6-hydroxydopamine-induced rat model of Parkinson's disease[END_REF], displayed hyperalgesia as illustrated by decreased paw withdrawal latencies (Table 1).

Cold sensitivity is more rarely tested but can be assessed by for example applying a drop of acetone on the animal's paw. Rat with a unilateral lesion of the substantia nigra pars compacta, but not control animals, exhibit nocifensive responses such as paw withdrawal, licking, shaking or rubbing (Gómez-Paz et al., 2017), showing the presence of a cold allodynia.

Response to nociceptive chemical exposure 20

The intradermal injection of a formalin solution models short-term inflammatory pain. It results in paw withdrawal, licking, biting or shacking. In rodents, these responses are classically divided in 2 phases: an initial phase during the first 5 or 10 minutes after the injection, related to the stimulation of nociceptors; and a second phase, lasting between 20 to 40 min, corresponding to both inflammatory mechanisms and central sensitization within the dorsal horn [START_REF] Barrot | Tests and models of nociception and pain in rodents[END_REF][START_REF] Bars | Animal models of nociception[END_REF]. It has been shown that rats with 6-OHDA lesion, either in the cell bodies or terminals, displayed enhanced behavioral responses in the formalin test [START_REF] Cao | Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease[END_REF][START_REF] Chudler | Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine[END_REF]Gómez-Paz et al., 2017;[START_REF] Ogata | Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion[END_REF][START_REF] Tassorelli | Behavioral responses and Fos activation following painful stimuli in a rodent model of Parkinson's disease[END_REF], thus reflecting hyperalgesia. This hyperalgesia was however detected in the second phase only [START_REF] Chudler | Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine[END_REF][START_REF] Ogata | Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion[END_REF] or in both phases [START_REF] Cao | Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease[END_REF]Gómez-Paz et al., 2017;[START_REF] Tassorelli | Behavioral responses and Fos activation following painful stimuli in a rodent model of Parkinson's disease[END_REF], depending on the study. When formalin was delivered in the face (trigeminal pain) of rats with an unilateral striatal 6-OHDA lesion, grooming was significantly enhanced during the second [START_REF] Chudler | Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine[END_REF] or both phases of the test [START_REF] Maegawa | Neural mechanism underlying hyperalgesic response to orofacial pain in Parkinson's disease model rats[END_REF], reflecting an increased inflammatory pain response.

Changes in the formalin test following 6-OHDA lesion could also affect the sensitivity to pain relief, indeed midbrain 6-OHDA lesions suppressed D-amphetamine and morphine-induced analgesia in this test [START_REF] Morgan | 6-Hydroxydopamine lesions of the ventral tegmentum abolish D-amphetamine and morphine analgesia in the formalin test but not in the tail flick test[END_REF]. On the other hand, in a transgenic LRRK2 model of Parkinson's disease, mutant mice did not show alteration of formalin test responses [START_REF] Bichler | Non-motor and motor features in LRRK2 transgenic mice[END_REF], but this model displayed an overall limited range of symptoms. (Table 1)

In the writhing test, the irritant chemical are delivered intraperitoneally, which provokes abdominal contractions and twisting of dorso-abdominal muscles that can be quantified as an indicator of peritovisceral nociception [START_REF] Bars | Animal models of nociception[END_REF]. In Pitx3 416insG mutant mice, visceral pain following intraperitoneal acetic acid delivery was significantly enhanced [START_REF] Rosemann | Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice[END_REF] (Table 1).

3.2.Blink reflex abnormalities in Parkinson's disease models (Figure 2)

The blink reflex is related to the activity of the orbicularis oculi muscle and may be considered as a protective nociceptive response. The electrical stimulation of this muscle results in an electromyographic response composed of 2 different phases, the R1 and R2 components.

The R1 component is the early component, which is only present on the stimulated side. The R2 component is present in both sides and appears later [START_REF] Pearce | Observations on the blink reflex[END_REF]. In Parkinson's disease, patients exhibit a hyperexcitability of the blink reflex, with shorter latency, increased amplitude and an increased habituation index [START_REF] Esteban | Blink reflex in Huntingon's chorea and Parkinson's disease[END_REF]. In 6-OHDA lesioned rats, as in patients, a hyperexcitability of the blink reflex has also been observed, together with an impaired blink plasticity and a lower spontaneous blink rate [START_REF] Basso | Midbrain 6-hydroxydopamine lesions modulate blink reflex excitability[END_REF][START_REF] Kaminer | Effects of subthalamic deep brain stimulation on blink abnormalities of 6-OHDA lesioned rats[END_REF] (Table 1).

3.3.Anxiety-like and depression-like behaviors in rodent

Parkinson's disease models (Figure 3)

Animal studies concerning anxiety and depression in Parkinson's disease mainly focused on dopaminergic mechanism, which unlikely reflects the complexity underlying the occurrence of these symptoms in patients. There is still indeed a paucity of studies addressing, beyond dopamine, the role of the other alterations of the nervous system, in particular for early stages of the disease.

Anxiety-like behavior in Parkinson's disease models

Tests for anxiety-like behaviors in rodents, such as the elevated plus maze, the open field test and the hole-board test, are mostly based on exploratory behaviors in a novel environment.

They more specifically rely on the natural tendency of rodents to explore novel environments and their innate avoidance of open, illuminated and/or elevated environment, and their behavioral response to anxiolytic drugs leading them to behave against their nature.

In the elevated plus maze, anxiety-like behavior is expressed by an increased time spend in the closed arms (or decreased time in the open arms) of the test [START_REF] Pellow | Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat[END_REF]. This classical test has been used in various studies of experimental parkinsonism, but the motor disturbances present in some models may affect the response to this test, making important to have a control measure of locomotor activity (such as the number of crossing). Depending on the model, the species or the lesioned side, different findings were reported. In 6-OHDA models, most of the literature converge to report an increased anxiety-like profile in lesioned animals, corresponding to decreased time spent in the open arms of the test [START_REF] Bonito-Oliva | A mouse model of non-motor symptoms in Parkinson's disease: focus on pharmacological interventions targeting affective dysfunctions[END_REF][START_REF] Campos | Rodent models of Parkinson's disease: beyond the motor symptomatology[END_REF][START_REF] Delaville | Emerging dysfunctions consequent to combined monoaminergic depletions in Parkinsonism[END_REF][START_REF] Faggiani | Serotonergic neurons mediate the anxiolytic effect of l-DOPA: Neuronal correlates in the amygdala[END_REF][START_REF] Hui | Anxiolytic effects of prelimbic 5-HT(1A) receptor activation in the hemiparkinsonian rat[END_REF][START_REF] Jungnickel | Topology of intrastriatal dopaminergic grafts determines functional and emotional outcome in neurotoxin-lesioned rats[END_REF][START_REF] Silva | Time course study of microglial and behavioral alterations induced by 6-hydroxydopamine in rats[END_REF][START_REF] Sun | Activation of 5-HT₁A receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson's disease[END_REF][START_REF] Tadaiesky | Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease[END_REF]; but some articles reported no difference [START_REF] Carvalho | Behavioral characterization of the 6-hydroxidopamine model of Parkinson's disease and pharmacological rescuing of non-motor deficits[END_REF][START_REF] Matheus | Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats[END_REF] or even less anxietylike behavior [START_REF] Branchi | Nonmotor symptoms in Parkinson's disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model[END_REF]. In these 6-OHDA models, the present number of studies does not allow to conclude whether the presence/absence of anxiety could be related to the lesion side, to its unilateral/bilateral aspect or to the presence or no of a protection of noradrenergic fibers during the lesion procedure. However, a study showed that a co-lesion of either noradrenergic or serotonergic systems strongly potentiate anxiety-like behaviors after dopamine lesion [START_REF] Delaville | Emerging dysfunctions consequent to combined monoaminergic depletions in Parkinsonism[END_REF]. Increased anxiety in the elevated plus maze has also been reported once in the paraquat [START_REF] Campos | Rodent models of Parkinson's disease: beyond the motor symptomatology[END_REF] and lipopolysaccharide [START_REF] Hritcu | Intranigral lipopolysaccharide induced anxiety and depression by altered BDNF mRNA expression in rat hippocampus[END_REF] models in rats, while the 2 studies in MPTP models reported either a lack (in mice) [START_REF] Gorton | Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse[END_REF] or a presence (in rats) [START_REF] Ho | Effects of D-cycloserine on MPTPinduced behavioral and neurological changes: potential for treatment of Parkinson's disease dementia[END_REF] of increased anxiety. Results from neurotoxin-based models also mostly reported increased anxiety-like behaviors in other tests. This is the case for studies assessing social interactions [START_REF] Branchi | Nonmotor symptoms in Parkinson's disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model[END_REF][START_REF] Chiu | Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease[END_REF][START_REF] Eskow Jaunarajs | Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat[END_REF][START_REF] Matheus | Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats[END_REF], for the marble burying test [START_REF] Gorton | Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse[END_REF], for two third of the literature concerning the open field test [START_REF] Bonito-Oliva | A mouse model of non-motor symptoms in Parkinson's disease: focus on pharmacological interventions targeting affective dysfunctions[END_REF][START_REF] Eskow Jaunarajs | Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat[END_REF][START_REF] Hui | Anxiolytic effects of prelimbic 5-HT(1A) receptor activation in the hemiparkinsonian rat[END_REF][START_REF] Sun | Activation of 5-HT₁A receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson's disease[END_REF] and for one of the two publications using the hole-board test [START_REF] Campos | Rodent models of Parkinson's disease: beyond the motor symptomatology[END_REF].

Conversely, genetic models mostly showed either a lack of change [START_REF] Bichler | Non-motor and motor features in LRRK2 transgenic mice[END_REF][START_REF] Campos | Rodent models of Parkinson's disease: beyond the motor symptomatology[END_REF][START_REF] Caudal | Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons[END_REF][START_REF] Peña-Oliver | Lack of involvement of alphasynuclein in unconditioned anxiety in mice[END_REF] or a decrease [START_REF] George | Alpha-synuclein transgenic mice exhibit reduced anxiety-like behaviour[END_REF][START_REF] Oaks | Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function[END_REF][START_REF] Rothman | Neuronal expression of familial Parkinson's disease A53T α-synuclein causes early motor impairment, reduced anxiety and potential sleep disturbances in mice[END_REF][START_REF] Yamakado | α-Synuclein BAC transgenic mice as a model for Parkinson's disease manifested decreased anxiety-like behavior and hyperlocomotion[END_REF] in anxiety-like behavior in the elevated plus maze test, thus differing from the above mentioned neurotoxin-based models (Table 2). While changes in behavior were observed in the presence of a predator odor (TMT) in a genetic model [START_REF] Marxreiter | Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice[END_REF][START_REF] Nuber | Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease[END_REF], a lack of increased anxiety-related responses has also been reported in the light-dark test [START_REF] Peña-Oliver | Lack of involvement of alphasynuclein in unconditioned anxiety in mice[END_REF] and when looking at changes in body temperature under a stress condition [START_REF] Caudal | Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons[END_REF][START_REF] Paumier | Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease[END_REF]. In the open-field test, genetic models were even mostly associated with an increased time spent in the center area [START_REF] Oaks | Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function[END_REF][START_REF] Paumier | Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease[END_REF][START_REF] Rothman | Neuronal expression of familial Parkinson's disease A53T α-synuclein causes early motor impairment, reduced anxiety and potential sleep disturbances in mice[END_REF][START_REF] Yamakado | α-Synuclein BAC transgenic mice as a model for Parkinson's disease manifested decreased anxiety-like behavior and hyperlocomotion[END_REF], which would normally reflect lower anxiety [START_REF] Belzung | Chapter 4.11 Measuring rodent exploratory behavior[END_REF] (Table 2). However, increased locomotor activity in the open-field, which may interfere with anxiety-related data in this test, has for example been noted in Thy-1 α-synuclein mice [START_REF] Lam | Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human αsynuclein[END_REF]. Studies may thus still be needed to understand whether these discrepancies between neurotoxin-based and genetic models reflect biological differences between models, in particular in their respective impact on aminergic and limbic systems, or reflect technical challenges in appropriately testing anxiety-like behaviors.

Lastly, only one article mentioned anxiety-like behaviors in a non-human primate model of Parkinson's disease [START_REF] Niu | Early Parkinson's disease symptoms in α-synuclein transgenic monkeys[END_REF]. Authors analyzed potential ethological signs of anxiety (walking in circle, sucking on a finger or a toe, self-grasping) in 3 transgenic α-synuclein rhesus monkeys and observed increased stereotypic behaviors in one of them [START_REF] Niu | Early Parkinson's disease symptoms in α-synuclein transgenic monkeys[END_REF] (Table 2). However, such "case report" does not allow concluding between pathological consequence and individual characteristics as explanation. More interestingly, some studies are now proposing measures of "spontaneous" abnormal or atypical behaviors in order to identify depressive-like behaviors in non-human primates (Camus et al., 2013a[START_REF] Camus | Birth origin differentially affects depressive-like behaviours: are captive-born cynomolgus monkeys more vulnerable to depression than their wild-born counterparts?[END_REF][START_REF] Camus | Depressive-like behavioral profiles in captive-bred single-and socially-housed rhesus and cynomolgus macaques: a species comparison[END_REF]. Using rhesus monkeys or cynomologus macaques, it proposes to look at inactivity, feeding behaviors, social behaviors and body postures/orientations in these species. Applying this ethological approach to Parkinson's disease models still remains to be done.

Depression-like behavior in

Parkinson's disease models (Figure 4)

The forced swim test consists of placing the animal in a water-filled cylinder with no possibility to escape. After an initial period of activity, i.e. swimming or attempts at climbing, the animal will stop to move and only make movements necessary to let its head above water.

This immobility was qualified by Porsolt and colleagues as a characteristic of despair and resignation, and as a mean to screen antidepressant drugs because they reduce the duration of immobility in this test [START_REF] Porsolt | Depression: a new animal model sensitive to antidepressant treatments[END_REF]. Almost all studies with neurotoxin models of Parkinson's disease showed a decreased swimming time and/or increased immobility time [START_REF] Berghauzen-Maciejewska | Pramipexole but not imipramine or fluoxetine reverses the "depressive-like" behaviour in a rat model of preclinical stages of Parkinson's disease[END_REF][START_REF] Bonito-Oliva | A mouse model of non-motor symptoms in Parkinson's disease: focus on pharmacological interventions targeting affective dysfunctions[END_REF][START_REF] Branchi | Nonmotor symptoms in Parkinson's disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model[END_REF][START_REF] Campos | Rodent models of Parkinson's disease: beyond the motor symptomatology[END_REF][START_REF] Casas | Progesterone prevents depression-like behavior in a model of Parkinson's disease induced by 6hydroxydopamine in male rats[END_REF][START_REF] Chiu | Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease[END_REF][START_REF] Delaville | Emerging dysfunctions consequent to combined monoaminergic depletions in Parkinsonism[END_REF][START_REF] Hritcu | Intranigral lipopolysaccharide induced anxiety and depression by altered BDNF mRNA expression in rat hippocampus[END_REF][START_REF] Ilkiw | Dopaminergic Lesion in the Olfactory Bulb Restores Olfaction and Induces Depressive-Like Behaviors in a 6-OHDA Model of Parkinson's Disease[END_REF][START_REF] Liu | Serotonin₆ receptors in the dorsal hippocampus regulate depressive-like behaviors in unilateral 6-hydroxydopamine-lesioned Parkinson's rats[END_REF][START_REF] Matheus | Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats[END_REF][START_REF] Santiago | Induction of depressive-like behavior by intranigral 6-OHDA is directly correlated with deficits in striatal dopamine and hippocampal serotonin[END_REF][START_REF] Duman | Models of depression[END_REF][START_REF] Tadaiesky | Effects of SR141716A on Cognitive and Depression-Related Behavior in an Animal Model of Premotor Parkinson's Disease[END_REF], 2008;[START_REF] Tuon | Physical training prevents depressive symptoms and a decrease in brain-derived neurotrophic factor in Parkinson's disease[END_REF]. However, this effect is not always seen within the same time-frame, even in similar models [START_REF] Berghauzen-Maciejewska | Pramipexole but not imipramine or fluoxetine reverses the "depressive-like" behaviour in a rat model of preclinical stages of Parkinson's disease[END_REF][START_REF] Matheus | Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats[END_REF]. Moreover, due to the potential presence of motor deficits, caution should likely be present when interpreting forced swim test data in models of Parkinson's disease. With the use of transgenic models, data are less consistent, with reports of increased immobility [START_REF] Caudal | Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons[END_REF][START_REF] Taylor | Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity[END_REF], of no difference [START_REF] Bichler | Non-motor and motor features in LRRK2 transgenic mice[END_REF][START_REF] Campos | Rodent models of Parkinson's disease: beyond the motor symptomatology[END_REF] or of decreased immobility [START_REF] Nuber | Olfactory neuronspecific expression of A30P α-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages[END_REF][START_REF] Oaks | Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function[END_REF]. One hypothesis to explain these discrepancies would be that the deficits observed in genetic models could be progressive and age-dependent [START_REF] Taylor | Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity[END_REF] (Table 3).

Similar to the forced swim test, the tail suspension test is also based on an increased immobility response in a stress situation. In this test, used in mice only, the animal is suspended by its tail and the immobility time is measured. Acute antidepressant treatment given prior to the test is able to decrease this immobility [START_REF] Duman | Models of depression[END_REF]. If some studies reported longer immobility time in mouse models of Parkinson's disease [START_REF] Antunes | Protective effect of hesperidin in a model of Parkinson's disease induced by 6-hydroxydopamine in aged mice[END_REF][START_REF] Bonito-Oliva | A mouse model of non-motor symptoms in Parkinson's disease: focus on pharmacological interventions targeting affective dysfunctions[END_REF][START_REF] Taylor | Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity[END_REF][START_REF] Vucković | Memory, mood, dopamine, and serotonin in the 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury[END_REF], one third of the literature reported no difference with control animals [START_REF] Bichler | Non-motor and motor features in LRRK2 transgenic mice[END_REF][START_REF] Gorton | Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse[END_REF]. Again, this lack of phenotype has been proposed to be potentially related to the time-dependent development of the considered model [START_REF] Taylor | Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity[END_REF] (Table 3).

The sucrose preference test or sucrose consumption test is classically used as an indicator of anhedonia (lack of interest in rewarding stimuli), which is one of the symptoms that can be present in major depressive disorder. In pre-clinical models, the test usually consists in a twobottle choice paradigm, with free access to a bottle with sucrose and one of water. A lack of preference (50% of preference) would be a sign of anhedonia, but the total amount of sucrose intake can also be considered as a relevant parameter. Some studies reported no difference between animal models of Parkinson's disease and their controls [START_REF] Branchi | Nonmotor symptoms in Parkinson's disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model[END_REF][START_REF] Campos | Rodent models of Parkinson's disease: beyond the motor symptomatology[END_REF][START_REF] Gorton | Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse[END_REF][START_REF] Vucković | Memory, mood, dopamine, and serotonin in the 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury[END_REF], but most of published data showed a significant reduction in either sucrose consumption and/or sucrose preference [START_REF] Carvalho | Behavioral characterization of the 6-hydroxidopamine model of Parkinson's disease and pharmacological rescuing of non-motor deficits[END_REF][START_REF] Caudal | Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons[END_REF][START_REF] Chen | GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice[END_REF][START_REF] Delaville | Emerging dysfunctions consequent to combined monoaminergic depletions in Parkinsonism[END_REF][START_REF] Ilkiw | Dopaminergic Lesion in the Olfactory Bulb Restores Olfaction and Induces Depressive-Like Behaviors in a 6-OHDA Model of Parkinson's Disease[END_REF][START_REF] Kamińska | Depressive-like neurochemical and behavioral markers of Parkinson's disease after 6-OHDA administered unilaterally to the rat medial forebrain bundle[END_REF][START_REF] Krupina | The effect of parlodel on development of depressive syndrome in rats, caused by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)]. Biull[END_REF][START_REF] Liu | Serotonin₆ receptors in the dorsal hippocampus regulate depressive-like behaviors in unilateral 6-hydroxydopamine-lesioned Parkinson's rats[END_REF][START_REF] Matheus | Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats[END_REF][START_REF] Santiago | Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine[END_REF][START_REF] Silva | Time course study of microglial and behavioral alterations induced by 6-hydroxydopamine in rats[END_REF][START_REF] Tadaiesky | Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease[END_REF][START_REF] Vecchia | Effects of ketamine on vocal impairment, gait changes, and anhedonia induced by bilateral 6-OHDA infusion into the substantia nigra pars compacta in rats: Therapeutic implications for Parkinson's disease[END_REF]. As mentioned above, this difference can be time-dependent in the considered models [START_REF] Caudal | Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons[END_REF][START_REF] Matheus | Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats[END_REF][START_REF] Santiago | Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine[END_REF][START_REF] Santiago | Induction of depressive-like behavior by intranigral 6-OHDA is directly correlated with deficits in striatal dopamine and hippocampal serotonin[END_REF], and it has been suggested for both the forced swim test and the sucrose preference that adding a co-lesion of noradrenergic and serotonergic systems to the dopamine lesion favors depression-like behaviors [START_REF] Delaville | Emerging dysfunctions consequent to combined monoaminergic depletions in Parkinsonism[END_REF].

A recent trend for addressing depression-like phenotypes in rodents is to consider alterations of naturally occurring behaviors of animals, such as grooming or nesting. The splash test consists in a pulverization of a sugar solution on the coat of the animal and the measure of the grooming time. A reduction in this grooming time may relate to apathy in human, which is one of the symptoms of major depressive disorder. A 6-OHDA lesion of the dorsal striatum

decreases grooming time at one week (but no more at 3 weeks) post-lesion [START_REF] Matheus | Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats[END_REF]. In A53T mutant mice, a deficit in overall grooming behavior is also present, particularly at 2 and 6 months of age [START_REF] Paumier | Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease[END_REF]. On the other hand, the nesting test consists in evaluating the quality of a nest made by the animal, with for example a score ranging from 0 to 4 or 5, 0 corresponding to an absence of nest and the highest score to a fully finished nest. This test is responsive to antidepressant drugs. A deficit and delay in cotton use for nest building has been observed in the Thy-1 α-synuclein mice [START_REF] Fleming | Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein[END_REF], which was proposed to be related to both deficits in fine motor skills and decreased motivation to build nest. In this test, both the A53T mutant mice [START_REF] Paumier | Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease[END_REF] and the MitoPark model [START_REF] Chen | GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice[END_REF] also display a significant deficit in nest building (Table 3).

The learned helplessness paradigm consists in the exposure to an inescapable stress (i.e. footshocks), followed by an active avoidance test. Pre-exposed animals that display a reduced ability to escape from the shocks [START_REF] Duman | Models of depression[END_REF] are qualified as "helpless". It is used as a model of either major depressive disorder or posttraumatic stress disorder, depending on the considered protocol. Both complete (98%) and partial (75% and 45%) 6-OHDA lesion increased the latency to escape shock presentation and the proportion of rats meeting "helpless" criteria [START_REF] Winter | Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats[END_REF] (Table 3). However, interpretation of those findings is not easy.

Indeed, independently from shock pre-exposure, it has been reported 40 years ago that 6-OHDA injections into dopamine cell bodies or terminals induces a decrease in the number of avoidance responses in the active avoidance test [START_REF] Delacour | Specificity of avoidance deficits produced by 6-hydroxydopamine lesions of the nigrostriatal system of the rat[END_REF][START_REF] Lin | Effects of brain monoamine depletion on thermoregulation, active avoidance, and food and water intake in rats[END_REF]. While such deficit can be present even in the absence of significant alteration in locomotor activity [START_REF] Delacour | Specificity of avoidance deficits produced by 6-hydroxydopamine lesions of the nigrostriatal system of the rat[END_REF], it is unsure whether it is reflecting a deficit in learning the avoidance procedure or it is reflecting an actual "helpless" state.

Conclusion

Beyond dopamine cell loss and motor symptoms, Parkinson's disease is a complex disease that leads to a variety of non-motor symptoms, including pain, anxiety and depression in a notable proportion of patients. For decades, experimental research on Parkinson's disease has focused on the motor symptoms as well as on the dopamine system. Indeed, until recently, most data in animal models were limited to dopaminergic alterations, which could not explain Parkinson's disease semiology, particularly in the early stage of the disease. A given symptom, however, may not necessarily arise from changes in a single given system. It can also be hypothesized that alterations in different systems (including the dopamine one) may add-on to a symptom and cumulatively contribute to its severity.

While the search for disease-modifying strategies is intense, the acknowledgment of the non-motor symptoms' burden upon Parkinson's disease patient's quality of life has only recently come to experimental researchers' attention, as witnessed by the relatively sparse and recent literature (Figure 5). Nevertheless, the present literature suggests that existing models of Parkinson's disease allow modeling non-motor symptoms, thus making possible to address mechanistic aspects and/or take such symptoms into consideration for preclinical testing of new therapeutic approaches. Preclinical studies of non-motor symptoms will however still require more systematic characterization to establish their presence/absence and time-line in various models, in order to provide standardization with robust and reliable outputs for some of them.

On the other hand, one might consider that individual variability in the presence/absence of these symptoms may be naturally present in experimental models as it is in patients, which may partly contribute to the heterogeneity in reporting these symptoms in experimental studies that are classically based on small cohorts. Progress would anyway require that these aspects of Parkinson's disease are more often tested and studied in rodent and non-human primate models.

5.

Parkinson displayed in the figure correspond to the number of publications relative to the test (see Table 1 for more details and references). 6-OHDA, 6-hydroxydopamine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 3 for more details and references). 6-OHDA, 6-hydroxydopamine; FST, forced swim test; LPS, lipopolysaccharide;

MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TST, tail suspension test. Tables Table 1. Nociception in Parkinson's disease models

Fig. 1 .

 1 Fig. 1. Classification of pain in Parkinson's disease (adapted from Wasner and Deuschl, 2012).Pain directly or partly related to PD can be either nociceptive pain, neuropathic pain or miscellaneous pain. Other types of pain include pain indirectly related to PD, pain that can be aggravated by the disease, and pain unrelated to PD. PD, Parkinson's disease.

Fig. 2 .

 2 Fig. 2.Nociceptive responses in animal models of Parkinson's disease. Various nociceptive modalities have been tested in models of the disease. For a majority of these modalities and animal models, the existing literature converges to highlight a nociceptive hypersensitivity. The heat modality, and in particular the tail-flick test, shows the highest heterogeneity in reported findings, which might be related to potential slow-down of some withdrawal reflexes. "n"

Fig. 3 .

 3 Fig. 3. Anxiety-like behaviors in animal models of Parkinson's disease. While in neurotoxinbased models of the disease most studies reported increased anxiety-like behaviors, literature is more controversial concerning genetic-based models of the disease. "n" displayed in the figure correspond to the number of publications relative to the test (see Table2for more details and references). 6-OHDA, 6-hydroxydopamine; EPM, elevated plus maze; LPS, lipopolysaccharide; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TMT, 2,3,5trimethyl-3-thiazoline (i.e. fox odor).

Fig. 4 .

 4 Fig. 4. Depressive-like behaviors in animal models of Parkinson's disease. Studies mostly reported the presence of depressive-like behaviors in models of Parkinson's disease, even though FST data are more variable in genetic-based models. "n" displayed in the figure correspond to the number of publications relative to the test (see Table3for more details and

Fig. 5 .

 5 Fig. 5. Number of publications reporting data on pain, anxiety and depression related parameters in animal models of Parkinson's disease.

  ://doi.org/10.1002/ana.10795Zengin-Toktas, Y., Ferrier, J., Durif, F., Llorca, P.-M., Authier, N., 2013. Bilateral lesions of the nigrostriatal pathways are associated with chronic mechanical pain hypersensitivity in rats. Neurosci. Res. 76, 261-264. https://doi.org/10.1016/j.neures.2013.05.003 Zhang, J., Stanton, D.M., Nguyen, X.V.,Liu, M., Zhang, Z., Gash, D., Bing, G., 2005. Intrapallidal lipopolysaccharide injection increases iron and ferritin levels in glia of the rat substantia nigra and induces locomotor deficits. Neuroscience 135, 829-838. https://doi.org/10.1016/j.neuroscience.2005.06.049

	and	Lewy	body	dementia.	Ann.	Neurol.	55,	164-173.

https

Table 2 .

 2 Anxiety-like behaviors in Parkinson's disease modelsTable 3. Depressive-like behaviors in Parkinson's disease models

Acknowledgments This work was supported by the Centre National de la Recherche Scientifique [contracts UPR3212 and UMR5293], the University of Strasbourg, the University of Bordeaux, the Agence Nationale de la Recherche [ANR-15-CE37-0005-02; Euridol ANR-17-EURE-0022], the Fondation pour la Recherche Médicale [FDT20170437322], the NeuroTime Erasmus Mondus Joint Doctorate and by a NARSAD distinguish investigator grant from the Brain and Behavior Research Foundation [24220]. 6.

Conflict of interest statement

The authors declare no conflict of interest. [START_REF] Basso | Midbrain 6-hydroxydopamine lesions modulate blink reflex excitability[END_REF]) [START_REF] Kaminer | Effects of subthalamic deep brain stimulation on blink abnormalities of 6-OHDA lesioned rats[END_REF] 6-OHDA, 6-hydroxydopamine; contralat., contralateral; ipsilat., ipsilateral; MPTP, 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine. Note that "6-OHDA" gathers various models, either unilateral or bilateral, and with different lesion sites, with or without neuroprotection of non-dopamine systems. [START_REF] Niu | Early Parkinson's disease symptoms in α-synuclein transgenic monkeys[END_REF] 6-OHDA, 6-hydroxydopamine; α-syn, α-synuclein; EPM, elevated plus maze; LPS, lipopolyssacharide; MPTP, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine; TMT, 2,3,5-trimethyl-3-thiazoline. Note that "6-OHDA" gathers various models, either unilateral or bilateral, with different lesion sites, and with or without neuroprotection of non-dopamine systems. [START_REF] Winter | Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats[END_REF]) 6-OHDA, 6-hydroxydopamine; α-syn, α-synuclein; FST, forced swim test; LH, learned helplessness ; LPS, lipopolyssacharide; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TST, tail suspension test. Note that "6-OHDA" gathers various models, either unilateral or bilateral, with different lesion sites, and with or without neuroprotection of non-dopamine systems.

7.