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.

Keywords: 6-OHDA; Parkinson's disease; motor deficits; non-motor symptoms; paraquat; rat; α-synuclein.

Figure 1

Dopaminergic cell loss induced by PQ, α-syn overexpression and 6-OHDA. Eleven weeks after lesion, the animals were sacrificed and the substantia nigra region was processed for tyrosine hydroxylase (TH) immunohistochemistry (A). Representative photomicrographs of midbrain sections immunostained for TH are presented in (B). Data are expressed as the percentage of control animals and represent the mean ± s.e.m. of at least five animals per group. ^*P < 0.05 and ^**P < 0.01 compared to control.

Figure 2

Motor performance of PQ (A), α-syn (B) or 6-OHDA (C) treated animals measured as latency to fall in accelerating rotarod test. Data are presented as mean ± s.e.m. ^**p < 0.01.

Figure 3

Effects of PQ delivery (A), α-syn overexpression (B) or 6-OHDA injection (C) on paw reaching performance. Performance of rats in the paw reaching test is expressed as mean ± s.e.m. number of eaten pellets. ^*p < 0.05 and ^**p < 0.01.

Figure 4

Locomotory and exploratory activity. Differences in total distance traveled (A–C), time in rest (D–F), number of ambulatory episodes (G–I) and number of rearings (J–L). Data expressed as mean ± s.e.m. ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001.

Figure 5

Anxiety-like behavior in the elevated-plus maze. Data on percentage of time in open arms (A–C), and number of entries in closed arms (D–F). Data expressed as mean ± s.e.m. ^*p < 0.05 and ^***p < 0.001.

Figure 6

Forced swimming test (A–F) for depressive-like behavior. Data regarding latency to immobility (A–C) and immobility time (D–F). Presence of anhedonia, assessed through the sucrose preference test (G–I). Total sucrose and water consumption during the sucrose preference test (J–L). Data expressed as mean ± s.e.m. ^*p < 0.05 and ^**p < 0.01.

Figure 7

Cognitive behaviors. Animals were challenged with three tasks that differed in their cognitive requirements. Working memory performances of sham and injured animals are compared, PQ (A), α-syn (B) and 6-OHDA (C) animals. Similarly, spatial reference memory performance is plotted in graphs (D–F) and reversal learn task performances (G–I). The four quadrants of the pool are assigned with letters N, E, S, W; the actual and the former platform positions are, respectively, N and S. ^*p < 0.05.