Further validation of the corridor task for assessing deficit and recovery in the hemi-Parkinsonian rat: Restoration of bilateral food retrieval by dopamine receptor agonism

doi:10.1016/j.bbr.2006.01.013

Behavioural Brain Research

Volume 169, Issue 2, 15 May 2006, Pages 352-355

https://doi.org/10.1016/j.bbr.2006.01.013 Get rights and content

Abstract

The corridor test is a newly developed test of sensorimotor integration that depends on a rat's ability to retrieve food from either side of its body. Rats with unilateral dopamine-depleting lesions neglect food on the contralateral side of their bodies, and selectively retrieve from the ipsilateral side. In the present study, the time-course for development of this deficit after injection of 6-hydroxydopamine into the striatum is determined using the corridor test. The ability of the dopamine receptor agonist, apomorphine, to reverse this impairment is also assessed. Lesioned rats developed an impairment in contralateral retrieval that was evident within a day (and stable for up to 2 weeks) after lesion surgery. Systemic injection of apomorphine significantly ameliorated this deficit, and restored the rats’ ability to collect food from both sides of their bodies. This study confirms that the corridor test is highly sensitive to dysfunction of the nigrostriatal dopamine system, and suggests that it might be a useful tool for screening pharmacological approaches to the treatment of Parkinson's disease.

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Acknowledgement

We thank Mr. Ambrose O’Halloran for constructing the corridor apparatus.

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Citation Excerpt :
In addition, the PFF rats had less retrieved-eaten and more retrieved-fallen pellets suggesting sensorimotor problems. While the 6-OHDA PD model shows signs of neglect in the corridor test (Fitzsimmons et al., 2006), we did not find this in the PFF rats, despite the partial denervation in striatum. This absence of hemispatial neglect is in agreement with our previous data in a non-human primate PD model based on unilateral a-syn overexpression via rAAV, which showed a similar level of nigral neuronal death to the current model (Eslamboli et al., 2007).
Alpha-synuclein (a-syn) can aggregate and form toxic oligomers and insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal Lewy bodies are a major pathological characteristic of Parkinson's disease (PD). These fibrillar structures can act as seeds and accelerate the aggregation of monomeric a-syn. Indeed, recent studies show that injection of preformed a-syn fibrils (PFF) into the rodent brain can induce aggregation of the endogenous monomeric a-syn resulting in neuronal dysfunction and eventual cell death.
We injected 8 μg of murine a-syn PFF, or soluble monomeric a-syn into the right striatum of rats. The animals were monitored behaviourally using the cylinder test, which measures paw asymmetry, and the corridor task that measures lateralized sensorimotor response to sugar treats. In vivo PET imaging was performed after 6, 13 and 22 weeks using [¹¹C]DTBZ, a marker of the vesicular monoamine 2 transporter (VMAT2), and after 15 and 22 weeks using [¹¹C]UCB-J, a marker of synaptic SV2A protein in nerve terminals. Histology was performed at the three time points using antibodies against dopaminergic markers, aggregated a-syn, and MHCII to evaluate the immune response.
While the a-syn PFF injection caused only mild behavioural changes, [¹¹C]DTBZ PET showed a significant and progressive decrease of VMAT2 binding in the ipsilateral striatum. This was accompanied by a small progressive decrease in [¹¹C]UCB-J binding in the same area. In addition, our histological analysis revealed a gradual spread of misfolded a-syn pathology in areas anatomically connected to striatum that became bilateral with time. The striatal a-syn PFF injection resulted in a progressive unilateral degeneration of dopamine terminals, and an early and sustained presence of MHCII positive ramified microglia in the ipsilateral striatum and substantia nigra.
Our study shows that striatal injections of a-syn fibrils induce progressive pathological synaptic dysfunction prior to cell death that can be detected in vivo with PET. We confirm that intrastriatal injection of a-syn PFFs provides a model of progressive a-syn pathology with loss of dopaminergic and synaptic function accompanied by neuroinflammation, as found in human PD.
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Parkinson's disease (PD) is a neurodegenerative disorder described by severe motor symptoms involving postural imbalance, uncontrolled shake, slowness of motion and rigidity. Searching for a natural remedy for PD to overcome the common adverse effects of conventional treatments, the neuroprotective effects of three dose levels (50, 100, and 200 mg/kg) of Pulicaria undulata essential oil (PUEO) in rotenone-induced model in male Wistar rats were investigated. PUEO was analyzed by GC and GC/MS resulting in the identification of twenty-one compounds. Carvotanacetone was the major component (80.14%). The middle and high doses of PUEO attenuated rotenone-induced behavioral deficits besides, hindering the decrease in striatal dopamine and ATP levels, with partial retardation in rotenone-induced body weight loss. Biochemical assessments illustrated that PUEO mitigated rotenone-induced increment in striatal interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS). The reduction in malondialdehyde and increase in glutathione striatal contents depicted its antioxidant potential. Molecular docking study of carvotanacetone might justify the observed normalization of the elevated iNOS level induced after exposure to rotenone. This is the first study indicating the ability of PUEO to protect rats against rotenone-induced PD via anti-inflammatory and antioxidant activities with the ability to reduce α-synuclein gene expression.
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In most patients, Parkinson’s disease is thought to emerge after a lifetime of exposure to, and interaction between, various genetic and environmental risk factors. One of the key genetic factors linked to this condition is α-synuclein, and the α-synuclein protein is pathologically associated with idiopathic cases. However, α-synuclein pathology is also present in presymptomatic, clinically “normal” individuals suggesting that environmental factors, such as Parkinson’s disease-linked agricultural pesticides, may be required to precipitate Parkinson’s disease in these individuals. In this context, the aim of this study was to assess the behavioural and neuropathological impact of exposing rats with a subclinical load of α-synuclein to subclinical doses of the organic pesticide, rotenone. Rats were randomly assigned to two groups for intra-nigral infusion of AAV_2/5-GFP or AAV_2/5-α-synuclein. Post viral motor function was assessed at 8, 10 and 12 weeks in the Corridor, Stepping and Whisker tests of lateralised motor function. At week 12, animals were performance-matched to receive a subsequent intra-striatal challenge of the organic pesticide rotenone (or its vehicle) to yield four final groups (Control, Rotenone, AAV_2/5-α-synuclein and Combined). Behavioural testing resumed one week after rotenone surgery and continued for 5 weeks. We found that, when administered alone, neither intra-nigral AAV-α-synuclein nor intra-striatal rotenone caused sufficient nigrostriatal neurodegeneration to induce a significant motor impairment in their own right. However, when these were administered sequentially to the same rats, the interaction between the two Parkinsonian challenges significantly exacerbated nigrostriatal neurodegeneration which precipitated a pronounced impairment in motor function. These results indicate that exposing rats with a subclinical α-synuclein-induced pathology to the pesticide, rotenone, profoundly exacerbates their Parkinsonian neuropathology and dysfunction, and highlights the potential importance of this interaction in the etiology of, and in driving the pathogenesis of Parkinson’s disease.
Differential pattern of motor impairments in neurotoxic, environmental and inflammation-driven rat models of Parkinson's disease
2016, Behavioural Brain Research
Citation Excerpt :
This was completed on both the ipsilateral and contralateral sides of the rat’s body. The Corridor Test of contralateral neglect was completed as previously described [7,11]. Briefly, the rat was placed into a long corridor and was allowed to freely retrieve CocoPops® from pots plated at intervals on the left and the right-hand sides of the corridor.
One of the reasons proposed for the paucity of drug discovery for Parkinson’s disease is the lack of relevant animal models of the condition. Parkinson’s disease has been modelled extensively using the selective neurotoxin, 6-hydroxydopamine (6-OHDA). However, as this model bears little etiological resemblance to the human condition, there has been a drive to develop models with improved etiological validity. Two such models are those induced by the pesticide, rotenone, and the inflammagen, lipopolysaccharide (LPS). However, to date, these models have been poorly characterised in terms of their motor profiles and have never been directly compared to the more established models. Thus, the aim of this study was to characterise the behavioural profile of the rotenone and LPS models, and to compare them with the 6-OHDA model. Animals underwent baseline testing on the Stepping, Whisker, Corridor and Cylinder Tests of motor function. They were then grouped for unilateral intra-striatal infusion of 6-OHDA, rotenone or LPS. Motor testing continued for ten weeks after which the rats were processed for immunohistochemical analysis of nigrostriatal integrity. We found that, although all neurotoxins induced a similar level of nigrostriatal neurodegeneration, neither the rotenone nor LPS models were associated with amphetamine-induced rotation, and they were associated with significantly less pronounced and stable impairments in the spontaneous tasks than the 6-OHDA model. In conclusion, this study demonstrates key differences in the pattern of motor dysfunction induced by Parkinsonian neurotoxins which should be taken into consideration when selecting the most appropriate model for Parkinson’s disease preclinical studies.
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The emergence of glucagon-like peptide-1 as a crucial contender in modifying neurodegenerative diseases in the preclinical studies has instigated interest in investigating the antiparkinsonian effect of dipeptidyl peptidase (DPP)-4 inhibition. Notably, saxagliptin (SAX), the DPP-4 inhibitor, recently showed efficacy in ameliorating streptozotocin-induced Alzheimer's disease; however, its effect on Parkinson's disease (PD) has not yet been elucidated. In a rat rotenone (ROT) model, SAX prominently improved motor performance as well as muscle coordination and corrected akinesia. Moreover, SAX preserved substantia nigra pars compacta tyrosine hydroxylase (TH) immunoreactivity while halting the reduction in the striatal TH, dopamine (DA) and complex I. Meanwhile, SAX prevented the ROT-induced increment of striatal DPP-4 and the decline in cAMP, ATP/ADP and brain-derived neurotropic factor levels. Improvement in striatal energy level was associated with partial hindrance of ROT-induced body weight reduction. In addition, through its anti-inflammatory potential, SAX decreased the ROT-induced nuclear factor-κΒ, inducible nitric oxide synthase, tumor necrosis factor-α, intracellular adhesion molecule-1 and myeloperoxidase. The antiapoptotic marker B-cell lymphoma-2 was enhanced by SAX, versus reduction in caspase-3 and its intrinsic apoptotic activator cytochrome C. Furthermore, SAX amended alterations induced by ROT in the thiobarbituric acid reactive substances and the transcriptional factor Nrf-2 level. In conclusion, SAX can be introduced as a novel approach for the management of PD based on the remarkable improvement in motor functions denoting antiparkinsonian efficacy via antioxidant, anti-inflammatory, antiapoptotic, neuroprotective and neurorestorative mechanisms. These effects were linked to DPP-4 inhibition, reduced neurodegeneration and enhanced DA synthesis.
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Citation Excerpt :
The osmotic minipumps (Alzet®, model 2ML4) for delivery of rotenone or vehicle were also subcutaneously implanted (through a small incision on the back of the rat) under isofluorane anaesthesia (5% in O2 for induction and 2% in O2 for maintenance) 13 weeks after viral infusion. The Corridor Test of contralateral neglect has been described in more detail elsewhere [24,25]. In brief, hungry rats (deprived of food overnight) were placed into a long, narrow alleyway (150 cm) and were free to retrieve food reward (crisped rice cereal (CocoPops®)) from pots on the left and right sides.
Despite the widely held belief that Parkinson's disease is caused by both underlying genetics and exposure to environmental risk factors, it is still widely modelled in preclinical models using a single genetic or neurotoxic insult. This single-insult approach has resulted in a variety of models that are limited with respect to their aetiological, construct, face and/or predictive validity. Thus, the aim of the current study was to investigate the interplay between genes and the environment as an alternative approach to modelling Parkinson's disease. To do so, rats underwent stereotaxic surgery for unilateral delivery of the Parkinson's disease-associated gene, α-synuclein, into the substantia nigra (using AAV vectors). This was followed 13 weeks later by subcutaneous implantation of an osmotic minipump delivering the Parkinson's disease-associated pesticide, rotenone (2.5 mg kg⁻¹ day⁻¹ for 4 weeks). The effect of the genetic and environmental insults alone or in combination on lateralised motor performance (Corridor, Stepping and Whisker Tests), nigrostriatal integrity (tyrosine hydroxylase immunohistochemistry) and α-synucleinopathy (α-synuclein immunohistochemistry) was assessed. We found that exposing AAV-α-synuclein-treated rats to rotenone led to a model in which the classical Parkinson's disease triad of progressive motor dysfunction, nigrostriatal neurodegeneration and α-synucleinopathy was evident. However, delivering rotenone systemically was also associated with bilateral motor dysfunction and loss of body weight. Thus, although we have shown that Parkinson's disease can be modelled in experimental animals by combined exposure to both genetic and environmental risk factors, this approach is limited by systemic toxicity of the pesticide rotenone. Direct intracerebral delivery of rotenone may be more useful in longer-term studies as we have previously shown that it overcomes this limitation.

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Short communicationFurther validation of the corridor task for assessing deficit and recovery in the hemi-Parkinsonian rat: Restoration of bilateral food retrieval by dopamine receptor agonism

Abstract

Section snippets

Acknowledgement

Brit Res Bull

Exp Neurol

Life Sci

Neuroscience

Exp Neurol

Neuroscience

Neuropharmacology

Short communication
Further validation of the corridor task for assessing deficit and recovery in the hemi-Parkinsonian rat: Restoration of bilateral food retrieval by dopamine receptor agonism