Abstract
Poverty of spontaneous movement, slowed execution and reduced amplitudes of movement (akinesia, brady- and hypokinesia) are cardinal motor manifestations of Parkinson's disease that can be modeled in experimental animals by brain lesions affecting midbrain dopaminergic neurons. Most behavioral investigations in experimental parkinsonism have employed short-term observation windows to assess motor impairments. We postulated that an analysis of longer-term free exploratory behavior could provide further insights into the complex fine structure of altered locomotor activity in parkinsonian animals. To this end, we video-monitored 23 h of free locomotor behavior and extracted several behavioral measures before and after the expression of a severe parkinsonian phenotype following bilateral 6-hydroxydopamine (6-OHDA) lesions of the rat dopaminergic substantia nigra. Unbiased stereological cell counting verified the degree of midbrain tyrosine hydroxylase positive cell loss in the substantia nigra and ventral tegmental area. In line with previous reports, overall covered distance and maximal motion speed of lesioned animals were found to be significantly reduced compared to controls. Before lesion surgery, exploratory rat behavior exhibited a bimodal distribution of maximal speed values obtained for single movement episodes, corresponding to a “first” and “second gear” of motion. 6-OHDA injections significantly reduced the incidence of second gear motion episodes and also resulted in an abnormal prolongation of these fast motion events. Likewise, the spatial spread of such episodes was increased in 6-OHDA rats. The increase in curvature of motion tracks was increased in both lesioned and control animals. We conclude that the discrimination of distinct modes of motion by statistical decomposition of longer-term spontaneous locomotion provides useful insights into the fine structure of fluctuating motor functions in a rat analog of Parkinson's disease.
Highlights
Neurotoxin-induced degeneration of nigral dopamine neurons in experimental animals results in motor abnormalities relevant to motor symptoms of Parkinson’s disease (PD; Cenci et al, 2002)
STEREOLOGICAL COUNTING OF tyrosine hydroxylase (TH)-POSITIVE substantia nigra pars compacta (SNc) AND ventral tegmental area (VTA) NEURONS Bilateral injections of 15 μg 6-OHDA into the SNc resulted in extensive cell death of dopaminergic neurons in the SNc and intermediate cell death in the VTA (Figure 1C)
The estimated population of TH-positive neurons for combined SNc-regions of interest (ROI) was reduced by −95% in PD rats compared to controls
Summary
Neurotoxin-induced degeneration of nigral dopamine neurons in experimental animals results in motor abnormalities relevant to motor symptoms of Parkinson’s disease (PD; Cenci et al, 2002). In the prototypic toxin-induced rat model of PD, unilateral intracerebral 6-OHDA injections lead to the expression of a strictly lateralized hemiparkinsonian phenotype, the behavioral sequelae of which have been described in great detail. Compared to the unilateral 6-OHDA model, bilaterally lesioned rats have been used less commonly, they display a far more severe parkinsonian phenotype. In this respect, the slowness and scarcity of movement observed in the bilateral 6-OHDA rat model resembles more closely the marked expression of PD-like symptoms in monkeys treated systemically with 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (Bergman et al, 1990) and cardinal motor manifestations of human PD patients in advanced disease stages. The development of pronounced motor impairment in rats with severe bilateral 6-OHDA lesions is, often accompanied by aphagia, adipsia and abulia (Schallert et al, 1978; Sakai and Gash, 1994; Cass et al, 2005; Ferro et al, 2005)
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