Physical exercise lowers markers of systemic stress and enhances the function of the neuroendocrine system.

Exercise increases circulating endogenous TLR4 ligands including heat shock proteins, fatty acids, and bacterial endotoxins derived from gut and muscle tissue

Chronic exercise elevates soluble TLR4 in circulation, which binds and neutralizes TLR4 ligands, preventing activation of membrane-bound TLR4 on immune and muscle cells

Reduced TLR4 signaling prevents IκBα degradation and blocks NF-κB nuclear translocation, suppressing transcription of proinflammatory cytokines IL-6, TNF-α, and IL-1β

Exercise increases endothelial shear stress, activating endothelial nitric oxide synthase to produce nitric oxide, which dilates resistance vessels and reduces peripheral vascular resistance

Exercise increases skeletal muscle lactate production, which crosses the blood-brain barrier and activates SIRT1 and PGC-1α to enhance BDNF transcription in the hippocampus and prefrontal cortex

Lactate and β-hydroxybutyrate enter the brain and inhibit histone deacetylases HDAC2 and HDAC3, increasing histone acetylation at the BDNF promoter and enhancing synaptic protein synthesis

Exercise increases irisin and adiponectin secretion from muscle and fat, which cross the blood-brain barrier and suppress microglial activation and neuroinflammation

Exercise upregulates kynurenine aminotransferases in skeletal muscle, converting neurotoxic kynurenine into kynurenic acid, which remains peripheral and prevents neuroinflammation

Exercise increases endocannabinoid levels, which activate CB1 receptors on forebrain GABAergic neurons, reducing GABA release and disinhibiting prefrontal circuits that suppress amygdala activity

Exercise activates proprioceptive afferents from dorsal root ganglia, which relay signals via gracile nucleus and dorsal raphe to increase serotonin release in the medial prefrontal cortex

Exercise increases VEGF-A from muscle and endothelium, which stimulates angiogenesis and neurogenesis in the hippocampus, enhancing structural plasticity and neurovascular coupling

BDNF binding to TrkB receptors activates PI3K-Akt-mTOR signaling in neurons, driving dendritic remodeling, synaptic protein synthesis, and stabilization of prefrontal-amygdala and hippocampal circuits

mTOR complex 1 integrates metabolic signals from lactate, insulin, and IGF-1 to enhance local translation of synaptic proteins in the prefrontal cortex, hypothalamus, and hippocampus

Exercise-induced lactylation of synaptic proteins such as SNAP91 in the medial prefrontal cortex stabilizes synaptic structure and enhances resilience to chronic stress

Exercise restores m6A RNA methylation patterns in the medial prefrontal cortex via liver-derived methyl donors, enhancing translation of synaptic plasticity genes such as Slc1a2/GLT-1

Enhanced prefrontal cortex activity inhibits basolateral amygdala output and reduces hypothalamic corticotropin-releasing hormone release, dampening systemic stress hormone production