Abstract:
In vascular dementia (VD), memory impairment caused by the damage of synaptic plasticity is the most prominent feature that afflicts patients and their families. Treadmill exercise has proven beneficial for memory by enhancing synaptic plasticity in animal models including stroke, dementia, and mental disorders. The aim of this study was to examine the effects of treadmill exercise on recognition memory, and structural synaptic plasticity in VD rat model. Here, our study demonstrated that VD rat exhibited significantly recognition impairment, while treadmill exercise improved recognition memory in VD rat. To further investigate potential mechanisms for the treadmill exercise-induced improvement of recognition memory, we examined hippocampal structural synaptic plasticity by means of transmission electron microscopy and golgi staining in VD rat that had undergone 4 weeks of treadmill exercise. The results demonstrated that VD rat causes the damage of structural synaptic plasticity. However, treadmill exercise led to increases in synapse numbers and the number of dendritic spines in VD rat. Together, the improvement of VD-associated recognition memory by treadmill exercises is associated with enhanced structural synaptic plasticity in VD rat model.
Keywords: Treadmill exercise; VD; Recognition memory; Structural synaptic plasticity.
Introduction
Vascular dementia (VD) is considered to be the second most common form of dementia after alzheimer’s disease (AD) and accounts for at least 20% of dementia cases[1-2]. VD may be caused by cerebrovascular disease, including ischemic or hemorrhagic stroke, and hypoperfusion ischemic brain injury due to cardiovascular and circulatory disorders[3]. The persistent and irreversible memory impairment in VD patients leads to a serious deterioration in quality of life and places a heavy economic burden on the families of patients[4-5]. Together with the increasing age of the population and improved survival rates from cardiovascular diseases, VD may affect more individuals in the future[6]. Therefore, prevention and treatment of VD is increasingly important at home and abroad, especially in countries with aging populations. It was mentioned as early as 1980’s that VD at present may be more amenable to prevention and treatment than AD[7]. Until now, many more drugs exerts memory protective effects in VD patients, including donepezil and tanzhi granules, targeted the amelioration of cognitive impairment by inhibiting neuroinflammation and acetylcholinesterase[8]. But the drug’s side effects can include drug dependence and depression.
As a non-pharmacological treatment, physical exercise has proven beneficial for support brain health and function, including but not limited to dampen brain inflammation[9], reducing neuroinflammation[10], and the redistribution of blood flow and neural activity[11]. Among new therapeutic strategies being pursued to minimize cognitive damage, clinical studies have confirmed that physical exercise is associated with lower incidence of vascular dementia[12]. Moreover, various animal models have demonstrated that regular volunteer running or treadmill exercise all can improve memory function in VD rats, in association with protected the function of astrocytes[13-14]. However, the molecular mechanism for exercise-improved memory in VD model remains poorly understood and still need for further study.
The brain changes throughout life at synaptic levels, including morphological and physiological changes. Structural synaptic plasticity is relative with synaptic morphology, which is thought to underlie higher cognitive processes such as memory storage and recall[15]. The role of structural synaptic plasticity between physical exercise and memory function has been recognized on both animal models and humans. Strong clinical and experimental evidence support that during exercise, modifications in the morphology of synaptic generate structural synaptic plasticity changes that is assumed to underlie enhanced cognitive processes such as memory function[16-17]. Furthermore, in vivo evidence has been provided to illustrate the molecular mechanisms of exercise on memory function possibly via regulating dendritic spine formation[18] and the ultrastructural morphology of synapses[19], in addition to memory recovery in VD[20] and other mental disease[21]. These findings suggest an important role for structural synaptic plasticity in the pathogenesis of VD and it has become an interesting target for therapeutic intervention. However, whether exercise improve memory function is related with structural synaptic plasticity still needs to be further explored. Here, the aim of our present study is to determine the regulatory paradigm of physical exercise on memory function and structural synaptic plasticity in the hippocampus under VD model.
Methods
Experimental animals and grouping
Male Sprague-Dawley rats (8 weeks of age) were purchased from Shanghai SLAC Laboratory Animal Co., Ltd and housed three per cage under normal light-dark cycle with food and water (Temperature: 22 ± 3°C; Humidity: 40 to 70%). All rats were randomly assigned into four groups (n = 6 each): Control group (C group), vascular dementia group (VD group), treadmill exercise and vascular dementia group (Exe-VD group), treadmill exercise and black group (Exe group). Body weight was measured every three days, and other treatments were performed at designated times according to the experimental timeline (Fig. 1).