Relationship between BDNF expression in major striatal afferents, striatum morphology and motor behavior in the R6/2 mouse model of Huntington's disease.

Patients with Huntington's disease (HD) and transgenic mouse models of HD show neuronal loss in the striatum as a major feature, which contributes to cognitive and motor manifestations. Reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in striatal afferents may play a role in neuronal loss. How progressive loss of BDNF expression in different cortical or subcortical afferents contributes to striatal atrophy and behavioral dysfunction in HD is not known, and may best be determined in animal models. We compared age-dependent alterations of BDNF mRNA expression in major striatal afferents from the cerebral cortex, thalamus and midbrain in the R6/2 transgenic mouse model of HD. Corresponding changes in striatal morphology were quantified using unbiased stereology. Changes in motor behavior were measured using an open field, grip strength monitor, limb clasping and a rotarod apparatus. BDNF expression in cortical limbic and midbrain striatal afferents is reduced by age 4 weeks, prior to onset of motor abnormalities. BDNF expression in motor cortex and thalamic afferents is reduced by 6 weeks, coinciding with early motor dysfunction and reduced striatum volume. BDNF loss in afferents progresses until death at 13-15 weeks, correlating with progressive striatal neuronal loss and motor abnormalities. Mutant huntingtin protein expression in R6/2 mice results in progressive loss of BDNF in both cortical and subcortical striatal afferents. BDNF loss in limbic and dopaminergic striatal inputs may contribute to cognitive/psychiatric dysfunction in HD. Subsequent BDNF loss in cortical motor and thalamic afferents may accelerate striatal degeneration, resulting in progressive involuntary movements.

Normalization of the metabolic profile in obese women by exercise and a low fat diet.

This study was performed to evaluate the additive effect of exercise and a low fat diet on body weight, body composition, and the metabolic profile in four obese women who were previously exercise-trained for 15 months. This study therefore included regular aerobic exercise for 15 months and a low fat diet plus exercise for an additional period of 14 months. After 15 months, mean body weight and fat losses corresponded to 6.4 and 8.4 kg, respectively. Significant reductions (P less than 0.05) in plasma insulin, cholesterol, apo B, and LDL-C were also observed. Following the second part of the study, mean cumulative body weight and fat losses were 11.0 and 11.3 kg, respectively. At this time, the subjects were still overweight, but their plasma glucose and insulin during an oral glucose tolerance test were essentially similar to values obtained in a sample of 22 nonobese women. With the exception of plasma apo B and HDL-C levels, plasma lipid and lipoprotein levels were also comparable to those observed in nonobese controls. These results thus indicate that aerobic exercise-training and a low fat diet can normalize the metabolic profile of obese women, even if their adiposity remains higher than that of lean women.