Abstract
Physical activity—a lifestyle factor that is associated with immune function, neuroprotection, and energy metabolism—modulates the cellular and molecular processes in the brain that are vital for emotional and cognitive health, collective mechanisms that can go awry in depression. Physical activity optimizes the stress response, neurotransmitter level and function (e.g., serotonergic, noradrenergic, dopaminergic, and glutamatergic), myokine production (e.g., interleukin-6), transcription factor levels and correlates [e.g., peroxisome proliferator-activated receptor C coactivator-1α [PGC-1α], mitochondrial density, nitric oxide pathway activity, Ca2+ signaling, reactive oxygen specie production, and AMP-activated protein kinase [AMPK] activity], kynurenine metabolites, glucose regulation, astrocytic health, and growth factors (e.g., brain-derived neurotrophic factor). Dysregulation of these interrelated processes can effectuate depression, a chronic mental illness that affects millions of individuals worldwide. Although the biogenic amine model has provided some clinical utility in understanding chronic depression, a need remains to better understand the interrelated mechanisms that contribute to immune dysfunction and the means by which various therapeutics mitigate them. Fortunately, convergent evidence suggests that physical activity improves emotional and cognitive function in persons with depression, particularly in those with comorbid inflammation. Accordingly, the aims of this review are to (1) underscore the link between inflammatory correlates and depression, (2) explicate immuno-neuroendocrine foundations, (3) elucidate evidence of neurotransmitter and cytokine crosstalk in depressive pathobiology, (4) determine the immunomodulatory effects of physical activity in depression, (5) examine protocols used to effectuate the positive effects of physical activity in depression, and (6) highlight implications for clinicians and scientists. It is our contention that a deeper understanding of the mechanisms by which inflammation contributes to the pathobiology of depression will translate to novel and more effective treatments, particularly by identifying relevant patient populations that can benefit from immune-based therapies within the context of personalized medicine.
Highlights
Depression is a pervasive health problem that includes emotional, psychomotor, cognitive, and biorhythmic disturbances (Kessler et al, 2005), symptoms that are associated with a 20-fold increase in the risk of suicide (Lépine and Briley, 2011)
Greenwood et al (2011) demonstrated that young adult male Fischer rats that participated in voluntary wheel—running for 6 weeks exhibited a conditioned place preference for the wheel as well as increased FosB/FosB immunoreactivity in the nucleus accumbens, increased tyrosine hydroxylase mRNA levels in the ventral tegmental area (VTA), and compensatory down-regulation of D2 receptor mRNA in the nucleus accumbens; these findings suggest that (1) long-term voluntary physical activity (PA) is rewarding and alters gene transcription in mesolimbic reward neurocircuitry (Greenwood et al, 2011), (2) post-exercise increases in serum Ca2+ may activate tyrosine hydroxylase enzyme and dopamine synthesis, and (3) PA may reverse inflammation-induced disruptions in dopaminergic transmission in the nucleus accumbens and ventral striatum in models of depression
Psychiatric illness is defined by a constellation of different symptoms that can be influenced by multiple neural processes and circuits
Summary
Depression is a pervasive health problem that includes emotional, psychomotor, cognitive, and biorhythmic disturbances (Kessler et al, 2005), symptoms that are associated with a 20-fold increase in the risk of suicide (Lépine and Briley, 2011). The HPA and sympathetic nervous system function to increase cortisol and catecholamine release during challenge to coordinate the fight-or-flight response These stress hormones inhibit excess production of proinflammatory cytokines (e.g., IL-12, TNF-α, and interferon [IFN]-γ) in healthy individuals with optimal regulatory capacity, while simultaneously increasing production of anti-inflammatory cytokines (e.g., IL-10 and IL4) (Elenkov and Chrousos, 1999). The low-grade inflammation that results in these persons derives in part from macrophages and T-cells infiltration of adipocytes in white adipose tissue, liver, and skeletal muscle This infiltration elicits a state of persistent secretion of proinflammatory cytokines, including TNF-α, IL-1, and IL-6 and a reduction in anti-inflammatory cytokines (e.g., adiponectin) (Hotamisligil, 2006; Kanda et al, 2006; Pedersen, 2009; Ouchi et al, 2011). The presence of pro-inflammatory cytokines markedly affects neurotransmission within regulatory brain circuits related to emotions and induces hormonal changes commensurate with those observed following stress (Gadek-Michalska et al, 2013)
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