Reports of beneficial effects of exercise on psychological health in humans are increasingly supported by basic research studies. Exercise is hypothesized to regulate antidepressant-related mechanisms and we therefore characterized the effects of chronic exercise in mouse behavioral paradigms relevant to antidepressant actions. Mice given free access to running wheels showed antidepressant-like behavior in learned helplessness, forced-swim (FST) and tail suspension paradigms. These responses were similar to responses of antidepressant drug-treated animals. When tested under conditions where locomotor activity was not altered, exercising mice also showed reduced anxiety compared to sedentary control mice. In situ hybridization analysis showed that BDNF mRNA was increased in specific subfields of hippocampus after wheel running. We chose one paradigm, the FST, in which to investigate a functional role for brain-derived neurotrophic factor (BDNF) in the behavioral response to exercise. We tested mice heterozygous for a deletion of the BDNF gene in the FST after wheel-running. Exercising wild-type mice showed the expected antidepressant-like behavioral response in the FST but exercise was ineffective in improving FST performance in heterozygous BDNF knockout mice. A possible functional contribution of a BDNF signaling pathway to FST performance in exercising mice was investigated using the specific MEK inhibitor PD184161 to block the MAPK signaling pathway. Subchronic administration of PD184161 to exercising mice blocked the antidepressant-like behavioral response seen in vehicle-treated exercising mice in the FST. In summary, chronic wheel-running exercise in mice results in antidepressant-like behavioral changes that may involve a BDNF related mechanism similar to that hypothesized for antidepressant drug treatment.

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Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss (1). Clinical and pre-clinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions (2-9), but the molecular mechanisms underlying these morphological alterations have not yet been identified. Here, we show that stress increases levels of REDD1 (regulated in development and DNA damage responses 1), an inhibitor of mTORC1 (mammalian/mechanistic target of rapamycin complex 1) (10), in rat prefrontal cortex (PFC). This is concurrent with a decrease in phosphorylation of signaling targets of mTORC1, which is implicated in protein synthesis-dependent synaptic plasticity. We also found that REDD1 levels are increased in the postmortem PFC of human subjects with MDD relative to matched controls. Mutant mice with a deletion of REDD1 are resilient to the behavioral, synaptic, and mTORC1 signaling deficits caused by chronic unpredictable stress (CUS), while viral-mediated over expression of REDD1 in the rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and pre-clinical findings identify REDD1 as a critical mediator underlying the atrophy of neurons and depressive behavior caused by chronic stress exposure.

Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.

Clinical brain imaging and postmortem studies provide evidence of structural and functional abnormalities of key limbic and cortical structures in depressed patients, suggesting that spine synapse connectivity is altered in depression. Characterization of the cellular determinants underlying these changes in patients are limited, but studies in rodent models demonstrate alterations of dendrite complexity and spine density and function that could contribute to the morphological and functional alterations observed in humans. Rodent studies demonstrate region specific effects in chronic stress models of depression, including reductions in dendrite complexity and spine density in the hippocampus and prefrontal cortex (PFC) but increases in the basolateral amygdala and nucleus accumbens. Alterations of spine synapse connectivity in these regions are thought to contribute to the behavioral symptoms of depression, including disruption of cognition, mood, emotion, motivation, and reward. Studies of the mechanisms underlying these effects demonstrate a role for altered brain derived neurotrophic factor (BDNF) signaling that regulates synaptic protein synthesis. In contrast, there is evidence that chronic antidepressant treatment can block or reverse the spine synapse alterations caused by stress. Notably, the new fast acting antidepressant ketamine, which produces rapid therapeutic actions in treatment resistant MDD patients, rapidly increases spine synapse number in the PFC of rodents and reverses the effects of chronic stress. The rapid synaptic and behavioral actions of ketamine occur via increased BDNF regulation of synaptic protein synthesis. Together these studies provide evidence for a neurotophic and synaptogenic hypothesis of depression and treatment response and indicate that spine synapse connectivity in key cortical and limbic brain regions is critical for control of mood and emotion.