The role of exercise in the treatment of depression: biological underpinnings and clinical outcomes. Molecular psychiatry Globally, depression is a leading cause of disability and has remained so for decades. Antidepressant medications have suboptimal outcomes and are too frequently associated with side effects, highlighting the need for alternative treatment options. Although primarily known for its robust physical health benefits, exercise is increasingly recognized for its mental health and antidepressant benefits. Empirical evidence indicates that exercise is effective in treating individuals with depression; however, the mechanisms by which exercise exerts anti-depressant effects are not fully understood. Acute bouts of exercise have been shown to transiently modulate circulating levels of serotonin and norepinephrine, brain-derived neurotrophic factor, and a variety of immuno-inflammatory mechanisms in clinical cohorts with depression. However, exercise training has not been demonstrated to consistently modulate such mechanisms, and evidence linking these putative mechanisms and reductions in depression is lacking. The complexity of the biological underpinnings of depression coupled with the intricate molecular cascade induced by exercise are significant obstacles in the attempt to disentangle exercise's effects on depression. Notwithstanding our limited understanding of these effects, clinical evidence uniformly argues for the use of exercise to treat depression. Regrettably, exercise remains underutilized despite being an accessible, low-cost alternative/adjunctive intervention that can simultaneously reduce depression and improve overall health. To address the gaps in our understanding of the clinical and molecular effects of exercise on depression, we propose a model that leverages systems biology and multidisciplinary team science with a large-scale public health investment. Until the science matches the scale of complexity and burden posed by depression, our ability to advance knowledge and treatment will continue to be plagued by fragmented, irreproducible mechanistic findings and no guidelines for standards of care. 10.1038/s41380-022-01819-w

Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus, yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise. 10.1038/s41586-021-04183-x