Fig. 6. Exercise rescued spine density caused by VD. A). Representative hippocampus microphotographs of the spines on secondary dendrites of neurons in each group. B). Number of spine per 10μm in each group.#P<0.05 vs. C group;*P<0.05 vs. VD group.
Discussion
Our study aimed at understanding the link between exercise and AD have focused on structural synaptic plasticity. In this study, we used recognition memory test coupled with transmission electron microscope and golgi staining methods to track dynamics of structural synaptic in the hippocampus after treadmill exercise on VD rat. We found that the restore of synaptic ultrastructure and spine density in the hippocampus with exercise, in additional to improved recognition memory in VD model. Our findings suggest that strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents impairment of recognition memory in VD model.
In our study, we first found that the discrimination index in VD rats was significantly lesser than control rats when exposed to the novel object 5 minutes and 24 hours after they were familiarized with an identical set of objects. As the disease progresses, patients experience progressive memory loss and emotional disorder in daily life, including communication disorder and anxiety[28-29]. In vivo study also confirms impaired discrimination index in recognition memory test[30], which is one of the most common paradigms to assess hippocampal-dependent memory, including short-term recognition memory and long-term recognition memory[31]. In general, short-term memory only refers to the short-term storage of information, whereas long-term memories are required for remembering information[32]. In addition, we also provided vivo evidence that VD rats have a mild anxiety in open field test. It was consisted with clinical investigations. Thus, we demonstrated that the impairment of recognition memory and anxiety-like behavior in VD progression. Furthermore, our study also revealed that treadmill exercise rescued recognition memory impairment and anxiety-like behavior in VD model in the recognition memory test. This result was consisted with previous studies[33-34]. Taken together, VD rats exhibited impairment recognition memory, and the robust decrease of recognition memory errors under the recognition memory test indicate that treadmill exercise pretreatments prevent decline in recognition memory in the VD rat model.
Next, we examined the potential mechanisms that might underline the treadmill exercise-induced improvement of recognition memory function in VD rats. It has been suggested that hippocampal structural synaptic plasticity constitutes the cellular basis of learning and memory, which requires the connections of synapses[35]. Our results showed decreased synapse numbers in the hippocamps of VD rats. In normal state, presynaptic terminal secretes memory-related substances via a canonical release machinery, while postsynaptic specialization senses substances via diverse receptors[36]. Therefore, the changes of synapse of synapse number are bound to affect synaptic structural plasticity. The study performed by Huang Y et al. on a murine model of vascular dementia by HE staining further indicate that significantly neuronal damage in the hippocampal of VD rat[37]. In this study, we also found that treadmill exercise led to an increase in the hippocampal synapse numbers of VD rats. Meanwhile, treadmill exercise increased the synapse numbers in the hippocampus in control group. The form and rearrange synapses under exercise is associated with enhancement of structural synaptic plasticity. Animal studies showed that exercise-induced enhancement of structural synaptic plasticity by regulating synaptic formation and rearrangement in normal states[38-39]. Thus, our study shed some light on the increase of synapse number by exercise that could be effective in exerting beneficial effects in VD rats.
Axons, dendrites, and dendritic spines constitute the structural basis of synaptic plasticity. The axon is functionally specialized to transmit signals, whereas the dendrites are specialized to receive signals[40]. In vivo imaging by FJB staining revealed that impaired of axonal and dendritic in the hippocampus after vascular dementia[41]. Dendritic spines are specialized postsynaptic structures that transduce presynaptic signals, are regulated by neural activity and correlated with learning and memory[42]. Our findings supported that the spine numbers of hippocampus were significantly decreased in the VD group compared to the control group. A review by Frankfurt M et al. reported that strong relationship between dendritic spine in the hippocampus and memory has been demonstrated in different spatial memory tasks[43]. Our study further revealed that treadmill exercise increased the spine numbers of hippocampus in VD rats.
It is likely that treadmill exercise pretreatment potentiates synaptic connections via an increase in dendritic spines under normal and dementia conditions[35, 44]. Such mechanisms might explain why treadmill exercise ameliorates the impairment of recognition memory in VD rat model.
In summary, treadmill exercise improved recognition memory, which can be contributed to the enhancement of hippocampal synapses number and dendritic spine density in VD rats. Our results collectively establish the central role of structural synaptic plasticity for neural network adaptations to exercises and provide more evidence for clinical intervention of memory deficits using exercise interventions.
Conclusions
Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in recognition memory and synapse loss in 2-VO induced VD rat model.