学位論文内容の要旨（Summary of dissertation ）博士の専攻分野の名称
博士（医 学）（Degree conferred: Doctor of Philosophy）

氏名 陳 冲（Name of recipient: CHONG CHEN ）学 位 論 文 題 名（Title of dissertation）
The neurobiological basis of the antidepressant-like effect of exercise(運動の抗うつ様効果の神経生物学的基盤に関する研究)
Introduction
Exercise, or physical activity, improves stress coping and reduces depression in humans and rodents.
However, the underlying neurobiological mechanism remains unclear. Rarely has any research examinedthe causality between the observed neurobiological changes and the beneficial outcomes by exercise.
This is further complicated by a ‘side effect’ of exercise: it increases basal glucocorticoid (CORT), thestress hormone, which has been shown to be a mediator linking stress to depressive disorders. For
instance, basal CORT is typically elevated by chronic stress and in depression, and elevated basal CORT
has been shown to predict the onset of depression. Here we aimed to explore the effects of exercise on
CORT and various neurotransmitters in the medial prefrontal cortex (mPFC) and identify how exercise
exerts antidepressant-like effect despite potentially increasing CORT, employing in vivo microdialysis
and microinjection.
Methods and results
Experiment 1 The behavioral and neurobiological effects of exercise
Rats were randomly allocated to exercise (EX) or control (CON) group, both raised in the same cagebox while only EX rats had free access to a running wheel attached on the side of the box. Three weeks
later, one subset of rats was subjected to the forced swim test (FST), while another subset was subjectedto the FST under microdialysis. We found that three weeks of voluntary wheel running reducedimmobility time in the FST, an antidepressant-like effect. Monitoring extracellular fluids in the mPFC
we found that, compared to CON, EX rats had significantly higher bassal CORT, but lower CORT
overall-exposure after FST. Further, exercise rats had higher DA both at baseline and after FST. There
was no significant effect of wheel running on other neurotransmitters measured, including NA, 5-HT,alanine, glycine, taurine, glutamine, and glutamate. Nor was there significant effect of wheel running on
the protein expression density of glucocorticoid receptor (GR), DA D1R, D2R, or 5-HT1AR.
Experiment 2 The role of medial prefrontal DA in the antidepressant-like effect of exercise
This experiment aimed to examine whether the upregulated DA observed in experiment 1 plays acausal role in the antidepressant-like effect of wheel running, by intra-mPFC pre-microinjection of a
D1R or D2R antagonist. 25-30 min (27.23±0.33) before the FST, EX rats were injected a D1R or D2R
antagonist while CON rats received only the vehicle. In the meantime, we monitored the general motoractivity of a subset of EX and CON rats using an apparatus with an infrared sensor that detects thermalradiation from animals. We observed that, the antidepressant-like effect of wheel running in the FST wascompletely abolished by intra-mPFC pre-microinjection of a D2R but not D1R antagonist, at a dose that
does not affect normal rats’ performance in the FST. Further, wheel running did not affect the generalmotor activity of rats.
Experiment 3 The role of elevated medial prefrontal CORT in the antidepressant-like effect of exercise
Experiment 3 was designed to test the hypothesis that the elevated basal CORT in the mPFC isresponsible for the upregulated DA and thus plays a causal role in the antidepressant-like effect of wheelrunning. A GR antagonist was injected into the mPFC of EX rats 30 min before the FST, while CON rats
only received the vehicle. One subset of rats underwent the FST only, while another subset of rats
underwent the FST under microdialysis. We found that the antidepressant-like effect of three weeks ofwheel running in the FST was abolished by intra-mPFC pre-microinjection of a GR antagonist. In themeantime, intra-mPFC pre-microinjection of the GR antagonist also downregulated the basal DA as wellas the FST-responsive DA in the mPFC of exercise rats, without any effect on the 5-HT in the mPFC.
Discussion
Consistent with previous reports that exercise reduces depression and improves stress coping, we
observed that wheel running reduced immobility in the FST, without affecting general motor activity.
This antidepressant-like effect was accompanied by overall upregulated DA in the mPFC. Moreinterestingly, intra-mPFC pre-microinjection of a D2R but not D1R receptor antagonist completely
abolished the antidepressant-like effect of wheel running. These results suggest that exercise exerts
antidepressant-like effect through upregulating DA in the mPFC and in a D2R-dependent way. It has
been shown that chronic stress reduces while antidepressants increase DA in the mPFC and that DA in
the mPFC is associated with animal’s performance in the FST and effortful behavior. Our research, forthe first time, provides causal support for the essential role of DA in the mPFC for active coping andantidepressant-like effect.
In the meantime, we observed that EX rats also showed higher basal CORT but overall lower FSTresponsive CORT. Further, intra-mPFC pre-microinjection of a GR antagonist abolished theantidepressant-like effect of wheel running and blocked the originally upregulated basal and FSTresponsive DA by wheel running. This suggests that the elevated basal CORT may be responsible for theupregulated DA. This is consistent with recent evidence that CORT increases DA efflux in the mPFC
through activating GR but that DA in the mPFC acts to suppress stress-responsive CORT.
These results suggest a causal pathway linking CORT, GR, DA, and D2R, to the antidepressant-like
effect of exercise. Returning to the CORT paradox we discussed in the introduction, a second
comparison of chronic stress and exercise reveals fundamental differences. Although both elevate basal
CORT, chronic stress reduces while exercise increases DA in the mPFC. This might be the key why theformer is detrimental while the latter is beneficial to stress coping and depression.
Conclusion
Exercise achieves antidepressant-like effect through the CORT-GR-DA-D2R pathway and that theincreased CORT by exercise itself is beneficial rather than detrimental.