Background: Depression is associated with a constellation of cognitive impairments reflecting prefrontal cortex (PFC) dysfunction. The pathogenesis of depressive disorders may
also involve mitochondrial abnormalities in the brain. However, the neurocellular basis of depression-associated PFC dysfunction is not clear. This study examined the mitochondrial dysfunction in the
prefrontal cortex and the possible ameliorative effects of aerobic exercise in the chronic unpredictable mild stress (CUMS) model.
Methods: Adult male Sprague-Dawley rats (300−400 g, four months old) were divided into control (C), CUMS (D), and CUMS plus aerobic exercise (D+E) groups, the latter allowed access
to treadmill running for the last 18 days of the 28-day CUMS protocol. Body weight, sucrose preference, open field (OF) activity, and Morris water-maze (MWM) performance were assessed, followed by
measurements of respiratory control ratio (RCR), ATP synthesis rate, manganese superoxide dismutase (Mn-SOD) and glutathione peroxidase (GSH-Px) activities, and malondialdehyde (MDA) accumulation in
Results: By CUMS day 28, the change in body weight after CUMS differed significantly among groups (F（2, 33）= 215.132, P < 0.001). Positive change in body weight was highest in
group C (P< 0.001), and group D+E also had a positive change (P< 0.01). Similarly, sucrose consumption was significantly different among groups (F（2, 33）= 58.634, P < 0.001), sucrose preference was
highest in group C (P< 0.001), but higher in group D+E than D (P<0.001). In the probe trial, the number of platform site crossings in the MWM were significant differences among groups (F（2, 33）=
9.529, P =0.001), groups C and D+E performed better than D (P < 0.001). Mitochondrial RCR, ATP synthesis, Mn-SOD activity, and GSH-Px activity were higher in group C than D (all P<0.01), while Mn-SOD
and GSH-Px activities were higher in group D+E than D (all P <0.01). In contrast, MDA was ignificantly lower in groups D+E and C than D (all P <0.001) with no significantly difference between groups C
Conclusions: Aerobic exercise partially ameliorated the CUMS-induced depressive phenotype (motor retardation, anhedonia, and cognitive dysfunction). Moreover, exercise suppressed
the associated oxidative damage of PFC mitochondria, possibly accounting for the preservation of cognitive function or other anti-depressive effects.