Quantitative Assessment of Neurologic Deficits in a Chronic Progressive Murine Model of CNS Demyelination

Abstract

The precise factors involved in the development of a progressive motor dysfunction, a hallmark of immune-mediated demyelinating diseases such as multiple sclerosis, are not well defined. The ability to identify neurologic deficits that result in impaired motor performance early in disease may allow for the identification of therapeutic interventions that slow or eliminate the progression toward a permanent dysfunction. Here we describe the use of three objective, quantitative functional assays (spontaneous activity box, rotarod, and footprint analysis) to detect early neurologic deficits following the initiation of a demyelinating disease with Theiler's murine encephalomyelitis virus (TMEV). The results show that the assays are capable of revealing neurologic deficits at the early stages of the demyelinating disease process. These findings are the first to objectively characterize neurologic function in an animal model of progressive CNS demyelination.

Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

“…Footprint analysis along with digital surrogates have been used to examine gait alterations induced by striatal damage (Teunissen et al, 2001), genetic defects of Purkinje cells (Jiao et al, 2005), sensory neuropathy (Wietholter et al, 1990) and diffuse cerebral disease (McGavern et al, 1999). As is the case for human gait disorders, distinct footprint patterns can be ascribed to lesions of specific neural subsystems in mice.…”

HLA-DQ Polymorphism Influences Progression of Demyelination and Neurologic Deficits in a Viral Model of Multiple Sclerosis

“…This device monitors the ability of a mouse to stay on a rotating rod at constant speed or with acceleration as previously described (McGavern et al, 1999). Briefly, mice were trained with a constant speed assay for 3 days prior to collecting preinjection baseline data using an accelerated assay.…”

Assessment of hindlimb gait as a powerful indicator of axonal loss in a murine model of progressive CNS demyelination

“…We have demonstrated previously that reductions in forelimb and hindlimb stride length are progressive through the first 100 days of TMEV infection in susceptible mice [19], which coincides with the demyelinating phase of the disease [8]. However, no reductions in forelimb or hindlimb stride width were observed during this time period [19]. The present study describes a reduction in the hindlimb width of stride during the late, chronic stage of TMEV-induced demyelinating disease and addresses whether or not this functional abnormality is an indicator of the severity of spinal cord axonal loss observed at this time point.…”

“…rodriguez.moses@mayo.edu (M. Rodriguez For gait analyses, male / female SJL/ J (prototypic susceptible strain; n=34) and C57BL/6J (prototypic resistant strain; n=20) mice were purchased from The Jackson Laboratories (Bar Harbor, ME, USA) and injected intracerebrally at 8 weeks of age with 2×10 6 PFU of TMEV in a 10-μl volume (n=10 mice per strain) or 10 μl PBS (n=10 mice per strain) to serve as sham-infected controls. Forelimb and hindlimb width of stride was measured, as described previously [19]. Forelimb and hindlimb paws were painted with red and blue nontoxic paint (RoseArt Industries; Livingston, NJ).…”

“…Analysis of footprints in rodents has provided a useful functional assay for determining the effects of peripheral nerve injury / repair [9][10][11][12], experimental allergic neuritis [13], spinal cord injury / repair [14][15][16], drug-induced motor impairment [17], and x-irradiation [18]. We have demonstrated previously that reductions in forelimb and hindlimb stride length are progressive through the first 100 days of TMEV infection in susceptible mice [19], which coincides with the demyelinating phase of the disease [8]. However, no reductions in forelimb or hindlimb stride width were observed during this time period [19].…”