Treadmill exercise delays the onset of non-motor behaviors and striatal pathology in the CAG140 knock-in mouse model of Huntington's disease

- Mouse models with a long prodromal period can test interventions of lifestyle.
- The CAG140 KI model shows early decline in cognition and depression-like behavior.
- CAG140 KI mice can exercise for long periods over their life time.
- Exercise on a motorized treadmill delays onset of depression and improves cognition.
- Exercise results in a reduction in HTT protein aggregate formation.
- Exercise may alter disease progression in HD.

Depression, cognitive impairments, and other neuropsychiatric disturbances are common during the prodromal phase of Huntington's disease (HD) well before the onset of classical motor symptoms of this degenerative disorder. The purpose of this study was to examine the potential impact of physical activity in the form of exercise on a motorized treadmill on non-motor behavioral features including depression-like behavior and cognition in the CAG140 knock-in (KI) mouse model of HD. The CAG140 KI mouse model has a long lifespan compared to other HD rodent models with HD motor deficits emerging after 12 months of age and thus provides the opportunity to investigate early life interventions such as exercise on disease progression. Motorized treadmill running was initiated at 4 weeks of age (1 h per session, 3 times per week) and continued for 6 months. Non-motor behaviors were assessed up to 6 months of age and included analysis of depression-like behavior (using the tail-suspension and forced-swim tests) and cognition (using the T-maze and object recognition tests). At both 4 and 6 months of age, CAG140 KI mice displayed significant depression-like behavior in the forced swim and tail suspension tests and cognitive impairment by deficits in reversal relearning in the T-maze test. These deficits were not evident in mice engaged in treadmill running. In addition, exercise restored striatal dopamine D2 receptor expression and dopamine neurotransmitter levels both reduced in sedentary HD mice. Finally, we examined the pattern of striatal expression of mutant huntingtin (mHTT) protein and showed that the number and intensity of immunohistochemical staining patterns of intranuclear aggregates were significantly reduced with exercise. Altogether these findings begin to address the potential impact of lifestyle and early intervention such as exercise on modifying HD progression.