Abstract
The severe motor impairment in the MS animal model experimental autoimmune encephalomyelitis (EAE) obstructs the assessment of cognitive functions. We developed an experimental system that evaluates memory faculties in EAE-affected mice, irrespective of their motor performance, enabling the assessment of cognitive impairments along the disease duration, the associated brain damage, and the consequences of glatiramer acetate (GA) treatment on these manifestations. The delayed-non-matching to sample (DNMS) T-maze task, testing working and long term memory was adapted and utilized. Following the appearance of clinical manifestations task performances of the EAE-untreated mice drastically declined. Cognitive impairments were associated with disease severity, as indicated by a significant correlation between the T-maze performance and the clinical symptoms in EAE-untreated mice. GA-treatment conserved cognitive functions, so that despite their exhibited mild motor impairments, the treated mice performed similarly to naïve controls. The cognitive deficit of EAE-mice coincided with inflammatory and neurodegenerative damage to the frontal cortex and the hippocampus; these damages were alleviated by GA-treatment. These combined findings indicate that in addition to motor impairment, EAE leads to substantial impairment of cognitive functions, starting at the early stages and increasing with disease aggravation. GA-treatment, conserves cognitive capacities and prevents its disease related deterioration.
Highlights
Multiple sclerosis (MS) has traditionally been regarded as a demyelinating inflammatory disease that focally affects the central nervous system (CNS) white matter
To evaluate the cognitive deficits inflicted by EAE, when motor impairments impede tasks performance, we designed an experimental scheme that allowed assessing long term and working memory faculties, irrespective of motor functions
Training was performed in seven sessions, each daily session consisted of six ‘forced-choice’ runs
Summary
Multiple sclerosis (MS) has traditionally been regarded as a demyelinating inflammatory disease that focally affects the central nervous system (CNS) white matter. It is recognized that gray matter damage in MS is widespread, underlying the long-term irreversible neurological impairment, especially the cognitive deterioration, manifested in up to 70% of patients as deficits in memory, learning, attention, processing speed or executive functions[3,4,5,6,7]. Using quantitative MRI analysis, it was shown that GA-treatment of MS patients for one year leads to a significant increase in the NAA:Cr ratio compared to pre-treatment values, implying axonal metabolic recovery and protection from sub-lethal axonal injury[26] These neuroprotective and repair processes may counteract the neurodegenerative disease-pathology that underlie cognitive impairments. The traditional delayed-non-matching to sample (DNMS) T-maze was adapted to minimize the physical demands and to focus on the choices the mice made, revealing working and long-term memory deficits This enabled specific assessment of cognitive deficits along the disease duration and evaluation of the associated tissue damage. We show that the EAE-induced cognitive deficits coincide with gray matter damages in the frontal cortex and throughout the hippocampus, and these damages can be reduced by GA-treatment
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