Fig. 5. Effect of treadmill exercise on hippocampal spine density in
stress model. (A) Representative Golgi staining images of the secondary
dendrites in the hippocampus. (B) The spines numbers of hippocampus in
each group. #p<0.05 vs. control;*p<0.05 vs. stress.
Treadmill exercise prevented stress-induced dopamine loss
To further investigate the changes of dopamine in each group, ELISA
method was used to detected dopamine. In stress rats, the hippocampal
concentrations of dopamine significantly decreased when compared with
control rats (Fig. 6, p <0.05). But in Exe-stress group, the
level of dopamine was significantly higher than that in stress group
(Fig. 6, p <0.05). Thus, we concluded that stress-induced
hippocampal dopamine loss can be rescued by treadmill exercise.
Fig. 6. Effect of treadmill exercise on hippocampal dopamine in stress
model. ##p<0.01 vs. control;**p<0.01 vs. stress.
Discussion
In this study, we found stress-induced working memory deficit and
anxiety-like behavior, which is associated with hippocampal neuron
impairment and dopamine loss. Furthermore, we also found healthier
neuronal and dendritic spine as well as increased
dopamine of hippocampus after treadmill exercise in stress rat, in
addition to improved working memory.
Repeated stress may lead to the development of various somatic,
cognitive and mental disorders[25]. And those
phenomenon was observed in human studies. A
follow-up study in clinical subjects demonstrated that even very low
levels of stress exposure can have negative effects on
cognition[26]. And chronic stress early in life
can influence working memory in adulthood[27].
Alternatively, stress-induced memory deficit and was also observed in
vivo studies, such as spatial memory, recognition
memory[28-29]. Passive avoid test were used to
evaluated working memory in this study, which revealed that
significantly working memory deficit in stress rat. In addition, consist
with previous study, we also demonstrated that repeated restraint stress
rats also exposed anxiety-like behavior in open filed
test[30]. but the mechanism of stress-induced
memory deficit need to be further studies.
The hippocampus has long been considered critical for encoding
memories[31]. Furthermore, the hippocampus is
implicated in disease states that result in cognitive dysfunction and
synaptic function. Chronic stress has frequently been shown to impair
the structure and function of the hippocampus, in associated with memory
deficit[32-33]. Our research showed that stress
rats exhibit fewer neurons in the hippocampus. Previous finding revealed
that stress triggers divergent dendritic alterations in immature neurons
of the adult hippocampus[34]. Golgi staining in
our study also found that the dendritic spine numbers of the secondary
dendrites in the hippocampus significantly decreased after stress. This
results are consist with previous study[35]. In
addition, neuromodulator and intracellular signaling events that
underlie memory retrieval mediated by the
hippocampus[36]. As an important neuromodulator,
dopamine is involved in memory formation through information
transmission between neurons[37]. In our study,
significantly decreased of hippocampal dopamine were observed in stress
rats. A review by Holly EN et al. reported that extracellular dopamine
and its metabolites have found a robust variation
during stress. This review further revealed that the nature and degree
of the dopaminergic change vary according to stressor and
intensity[38]. Thus, we concluded that
stress-induced working memory deficit is associated with the loss of
neuron and dopamine in the hippocampus.
Exercise has beneficiary effects on both memory and mental functions.
Exercise effective in enhancing logical memory and motor learning in
humans[39-40]. And animal studies also found that
exercise improves motor skill learning and spatial memory, especially in
stress model[41-43]. In this study, we revealed
that working memory was significantly improved after treadmill exercise
interventions in stress rat. As further evidence, we also revealed that
stress-induced anxiety behavior can be rescued by treadmill exercise.
This results are consist with previous study[44].
Alternatively, a follow-up molecular study demonstrated that increased
in mTOR signaling could contribute to the beneficial effects of exercise
on cognitive function and mental health[45]. The
transmission of neurotransmitter between neurons is the necessary
structure of memory formation, and changes in any of these factors can
lead to memory dysfunction. Thus, we hypothesized that treadmill
exercise improved working memory and mental health via modulating
neurotransmitter and neuron in stress model. The subsequent results in
our study proved that stress-induced hippocampal neuron impairment and
dopamine loss, which can be rescued by treadmill exercise. First,
Immunofluorescence results revealed that a greater NeuN-positive cells
was observed in the hippocampus in stress rat model after treadmill
exercise intervention. Those results suggest that stress-induced
hippocampal neuron loss can be rescued by treadmill exercise. It is
related to exercise followed by stress enhanced the new cells with
mature neuron phenotype[46]. Second, our study
confirmed that there were more spines on the apical dendrites of
pyramidal cells from Exe-Stress rat than on those from stress rat.
Chen’s study directly confirmed that chronic exercise facilitates new
spine formation in the brain[47]. Last, our study
also demonstrated that stress-induced hippocampal dopamine loss can be
rescued by exercise. Similar recent studies showed that moderate
exercise can induce the released of dopamine under normal or disease
status[48-49].
In summary, this study demonstrated that treadmill exercise improved
working memory via ameliorating hippocampal neuron and dopamine loss in
stress rat. This study provided evidences for stress-related memory
deficit, and potential treatment of stress-induced memory deficit by
treadmill exercise, although further studies are required to elucidate
underlying neural circuits and molecular mechanisms.
Conclusion
Treadmill exercise ameliorated stress-induced neuron impairment and
dopamine loss in rat hippocampus and improved working memory.