Long‐Term Treadmill Exercise and Voluntary Running Pre‐Training Attenuates Vascular Dementia‐Related Pathology by Regulating Hippocampal Structural Synaptic Plasticity in a Rat Model

ABSTRACT

Background
Clinical and basic research suggests that exercise is a safe behavioral intervention and effective in improving cognition in vascular dementia (VD). However, despite global efforts, there is still no effective method to completely cure VD. This study aimed to investigate the effects of long‐term exercise pretreatment on typical VD pathology in a rat model, and further compare the neuroprotective impacts of different exercise modalities on VD rats.


Methods
Forty‐eight SD adult male rats (200–240 g) were randomly allocated to a control group (Con, n = 12), a vascular dementia group (VD, n = 12), and a treadmill exercise and vascular dementia group (Tre‐VD, n = 12), a voluntary running and vascular dementia group (Vol‐VD, n = 12). Aerobic exercise training included treadmill exercise in the Tre‐VD rats, and voluntary running in the Vol‐VD rats, respectively. The bilateral common carotid artery occlusion operation was performed to induce the VD rat model in all groups except the Con group. Rat behavior, anxious‐depressive‐like behavior and cognition, was tested by the sucrose preference test, the open field test, the novel object recognition test, and the Y‐maze and passive avoidance test. Brain microdialysis combined with a high‐performance liquid chromatography (HPLC) system was applied to measure neurotransmitter concentrations in hippocampal extracellular fluid, including epinephrine (E), norepinephrine (NE), and dopamine (DA). Immunofluorescent staining was conducted to measure neuronal apoptosis. Transmission electron microscope was carried out to analyze hippocampal synaptic ultrastructure.


Results

The behavioral results also showed that long‐term treatment and voluntary pretreatment significantly alleviated cognitive impairment and anxious‐depressive‐like behaviors in VD rats (
p
< 0.05). Meanwhile, compared to the Con rat, VD rats had significantly decreased E NE, DA, and 5‐HT (
p
< 0.05), while exercise significantly increased those neurotransmitter levels in the hippocampus (
p
< 0.05). Moreover, neuronal apoptosis was found in the VD rat when comparing with the Con group (
p
< 0.05), conversely, exercise pretreatment effectively alleviated VD‐induced neuronal apoptosis (
p
< 0.05). In addition, the results of TEM revealed a significant reduction in hippocampal synapse numbers and postsynaptic density as well as the width of the synaptic cleft in VD rats compared to the Con (
p
< 0.05), which was reversed by eight weeks of exercise pretreatment (
p
< 0.05). Intriguingly, overall speaking, the neuroprotective hippocampal structural synaptic plasticity effect of voluntary running on VD rats is better than treadmill exercise.



Conclusion
Both treadmill exercise and voluntary running improve cognitive function and ameliorate anxious‐depressive‐like behaviors in VD rat models. These therapeutic effects are mediated through enhanced synaptic structural plasticity in the hippocampal region of VD rats.