Rodent models of Parkinson's disease: beyond the motor symptomatology

Abstract

Parkinson's disease (PD) is classically characterized by motor symptoms; however, non-motor symptoms (NMS) are increasingly recognized as relevant in disease-state, given the associated alterations in mood (depression and anxiety) and cognition. Here, particularly in regards to NMS, we aimed to compare the motor, emotional and cognitive behavior of three animal models of PD that trigger dopaminergic (DAergic) degeneration on both brain hemispheres: (i) the 6-hydroxydopamine (6-OHDA, 8 or 6 μg) lesion model; (ii) the paraquat (PQ) induced model, and (iii) a genetic model based on α-synuclein overexpression (α-syn). 6-OHDA and α-syn vector were injected bilaterally in the substantia nigra pars compacta (SNpc) of adult male Wistar rats; as for PQ delivery, micro-osmotic pumps were implanted in the interscapular region. Motor deficits were observed in all models, with histological analysis of tyrosine hydroxylase positive cells in the SNpc revealing a significant loss of DAergic neurons in all animal models. In addition, the α-syn animal model also presented a reduction in exploratory activity, and the 6-OHDA and PQ animals displayed a significant increase in both depressive- and anxiety-like behavior. Interestingly, cognitive impairment (working memory) was only observed in the 6-OHDA model. Overall, these PD models are suitable for mimicking the motor symptoms associated to PD, with each encompassing other relevant NMS components of the disorder that may prove beneficial for further studies in PD.

Nitrosative and cognitive effects of chronic l-DOPA administration in rats with intra-nigral 6-OHDA lesion

“…This has been widely shown by several studies with intra-nigral 6-OHDA or MPTP lesion (Miyoshi et al, 2002;Bellissimo et al, 2004;Ferro et al, 2005;Perry et al, 2005;Francardo et al, 2011;Campos et al, 2013). These same dynamics of cognitive impairments shown in this model have been observed in the early phase of PD in patients who do not present the motor impairment but do exhibit precisely the same SWM deficits (Owen et al, 1992(Owen et al, , 1997Dubois and Pillon, 1997;Lewis et al, 2003).…”

“…This cognitive deficit occurs primarily due to the depletion of DA caused by denervation in the SNpc, and the loss of the dopaminergic projections that innervate both the dorsal striatum and mPFC, which directly participate in SWM performance (Miyoshi et al, 2002;Ferro et al, 2005;Da Cunha et al, 2006;Tadaiesky et al, 2008;Campos et al, 2013). The loss of neurons in the SNpc induced a retraction or reduction of dendritic spines in the medium spiny neurons and pyramidal neurons of the striatum and PFC respectively (Solis et al, 2007).…”

Adipose-Derived Human Mesenchymal Stem Cells Induce Long-Term Neurogenic and Anti-Inflammatory Effects and Improve Cognitive but not Motor Performance in a Rat Model of Parkinson's Disease

“…AD-MSC localized often around blood vessels or in the arachnoid mater -two microenvironments that provide a protective microenvironment for the survival and differentiation of resident and exogenous stem cells due to their stem cell niche-like characteristics [42][43][44], and due to circulating growth factors [45,46]. This is in line with prior studies showing working memory deficits upon 6-OHDA lesioning [48]. The increased hippocampal neurogenesis of AD-MSC treated versus nontreated Parkinsonian animals was functionally related with improved memory test performance, as shown by significantly less WME made by AD-MSC versus 6-OHDA animals.…”

Pink1 −/− Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology

“…Consequently, studying humans in the prodromal period is often difficult due to methodological limitations. Thus, animal models of PD offer a means to circumvent these limitations in order to characterize underlying neuropathology, disease mechanisms, and identify potential treatments for dysphagia during the early stages of PD [20–22]. …”