Unraveling the Molecular Underpinnings: The Therapeutic Impact of Aerobic Exercise on Anxiety Disorders

Abstract

Anxiety disorders, characterized by persistent apprehension, somatic symptoms and fatigue, are leading causes of disability worldwide. The burgeoning therapeutic potential of aerobic exercise has gained prominence as a leading non-pharmacological strategy, with evidence supporting its effectiveness in alleviating anxiety across diverse conditions. This review synthesizes current research to clarify the molecular mechanisms through which aerobic exercise ameliorates anxiety in terms of the effects of exercise on the hypothalamic–pituitary–adrenal (HPA) axis, the hepatic-brain axis and epigenetics; electroencephalographic alterations; inflammatory pathways; the balance between oxidative and nitrogenous stress; various substances, such as brain-derived neurotrophic factor (BDNF), atrial natriuretic peptide (ANP), and opioid peptides; and the 5-HT2C receptor and cannabinoid receptor type-1 (CB1R), among others, reflecting the positive modulatory effects of aerobic exercise on anxiety. As a non-pharmacological intervention, aerobic exercise has been demonstrated to be useful in a variety of medical applications and has considerable potential for ameliorating symptoms of anxiety.

Yi-qing ao and Zi-yu Zhou are co-first authors.

Keywords

Aerobic exercise / Anxiety disorders / Molecular mechanisms / Therapeutic interventions

References

[1] NuttDJ. Overview of diagnosis and drug treatments of anxiety disorders. CNS Spectr., 2005, 10(1): 49-56.

[2] ChellappaSL, AeschbachD. Sleep and anxiety: from mechanisms to interventions. Sleep Med Rev., 2022, 61. 101583

[3] BaxterAJ, VosT, ScottKM, et al.. The global burden of anxiety disorders in 2010. Psychol Med., 2014, 44(11): 2363-2374.

[4] KesslerRC, GruberM, HettemaJM, et al.. Co-morbid major depression and generalized anxiety disorders in the national comorbidity survey follow-up. Psychol Med., 2008, 38(3): 365-374.

[5] Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet. 2021;398(10312):1700–1712.

[6] BandelowB, MichaelisS, WedekindD. Treatment of anxiety disorders. Dialogues Clin Neurosci., 2017, 19(2): 93-107.

[7] IsathA, KoziolKJ, MartinezMW, et al.. Exercise and cardiovascular health: a state-of-the-art review. Prog Cardiovasc Dis., 2023, 79: 44-52.

[8] XuS, BakerJS, RenF. The Positive Role of Tai Chi in Responding to the COVID-19 Pandemic. Int J Environ Res Public Health., 2021, 18147479.

[9] ColcombeSJ, KramerAF, EricksonKI, et al.. Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U S A., 2004, 101(9): 3316-3321.

[10] BoaSSN, BarhaCK, EricksonKI, et al.. Physical exercise, cognition, and brain health in aging. Trends Neurosci., 2024, 47(6): 402-417

[11] Liu TT, Pascal LE, Bauer SR, et al. Age-dependent effects of voluntary wheel running exercise on voiding behavior and potential age-related molecular mechanisms in mice. J Gerontol A Biol Sci Med Sci. 2024,79(6):glae007.

[12] Takemura N, Cheung D, Fong D, et al. Effectiveness of aerobic exercise and Tai Chi interventions on sleep quality in patients with advanced lung cancer: a randomized clinical trial. JAMA Oncol. 2024.

[13] GrasserLR, MarusakH. Strong mind, strong body: the promise of mind-body interventions to address growing mental health needs among youth. Mental Health Sci., 2023, 1(2): 58-66.

[14] BaglanYS, ErcanZ, DenizG, et al.. Effects of acute aerobic exercise on brain-derived neurotrophic factor level in rheumatoid arthritis patients. Arch Rheumatol., 2023, 38(2): 209-216.

[15] HeawYC, SinghD, TanMP, et al.. Bidirectional association between executive and physical functions among older adults: a systematic review. Australas J Ageing., 2022, 41(1): 20-41.

[16] De MelloMT, LemosVA, AntunesHK, et al.. Relationship between physical activity and depression and anxiety symptoms: a population study. J Affect Disord., 2013, 149(1–3): 241-246.

[17] LindwallM, GerberM, JonsdottirIH, et al.. The relationships of change in physical activity with change in depression, anxiety, and burnout: a longitudinal study of Swedish healthcare workers. Health Psychol., 2014, 33(11): 1309-1318.

[18] McdowellCP, DishmanRK, VancampfortD, et al.. Physical activity and generalized anxiety disorder: results from the Irish longitudinal study on ageing (Tilda). Int J Epidemiol., 2018, 47(5): 1443-1453.

[19] McMahonEM, CorcoranP, O'ReganG, et al.. Physical activity in European adolescents and associations with anxiety, depression and well-being. Eur Child Adolesc Psychiatry., 2017, 26(1): 111-122.

[20] TeychenneM, CostiganSA, ParkerK. The association between sedentary behaviour and risk of anxiety: a systematic review. BMC Public Health., 2015, 15513.

[21] KandolaA, StubbsB. Exercise and anxiety. Adv Exp Med Biol., 2020, 1228: 345-352.

[22] AbelsonJL, KhanS, LiberzonI, et al.. HPA axis activity in patients with panic disorder: review and synthesis of four studies. Depress Anxiety., 2007, 24(1): 66-76.

[23] KallenVL, TulenJH, UtensEM, et al.. Associations between HPA axis functioning and level of anxiety in children and adolescents with an anxiety disorder. Depress Anxiety., 2008, 25(2): 131-141.

[24] SothmannMS, BuckworthJ, ClaytorRP, et al.. Exercise training and the cross-stressor adaptation hypothesis. Exerc Sport Sci Rev., 1996, 24: 267-287.

[25] AthanasiouN, BogdanisGC, MastorakosG. Endocrine responses of the stress system to different types of exercise. Rev Endocr Metab Disord., 2023, 24(2): 251-266.

[26] HackneyAC. Stress and the neuroendocrine system: the role of exercise as a stressor and modifier of stress. Expert Rev Endocrinol Metab., 2006, 1(6): 783-792.

[27] HillEE, ZackE, BattagliniC, et al.. Exercise and circulating cortisol levels: the intensity threshold effect. J Endocrinol Invest., 2008, 31(7): 587-591.

[28] VossMW, VivarC, KramerAF, et al.. Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn Sci., 2013, 17(10): 525-544.

[29] CotmanCW, BerchtoldNC, ChristieLA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci., 2007, 30(9): 464-472.

[30] PruessnerJC, DedovicK, Khalili-MahaniN, et al.. Deactivation of the limbic system during acute psychosocial stress: evidence from positron emission tomography and functional magnetic resonance imaging studies. Biol Psychiatry., 2008, 63(2): 234-240.

[31] BassoJC, SuzukiWA. The effects of acute exercise on mood, cognition, neurophysiology, and neurochemical pathways: a review. Brain Plast., 2017, 2(2): 127-152.

[32] DevilbissDM, Etnoyer-SlaskiJL, DunnE, et al.. Effects of exercise on EEG activity and standard tools used to assess concussion. J Healthc Eng., 2019, 20194794637.

[33] PastalkovaE, ItskovV, AmarasinghamA, et al.. Internally generated cell assembly sequences in the rat hippocampus. Science., 2008, 321(5894): 1322-1327.

[34] SchmidtLA, PooleKL, HassanR, et al.. Frontal EEG alpha-delta ratio and social anxiety across early adolescence. Int J Psychophysiol., 2022, 175: 1-7.

[35] LiuWZ, ZhangWH, ZhengZH, et al.. Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety. Nat Commun., 2020, 1112221.

[36] LanT, LiY, ChenX, et al.. Exercise-activated MPFC tri-synaptic pathway ameliorates depression-like behaviors in mouse. Adv Sci (Weinh)., 2025, 123. e2408618

[37] ChenK, ZhengY, WeiJA, et al.. Exercise training improves motor skill learning via selective activation of mTOR. Sci Adv., 2019, 57. w1888

[38] YanL, WangM, YangF, et al.. Physical exercise mediates a cortical FMRP-mTOR pathway to improve resilience against chronic stress in adolescent mice. Transl Psychiatry., 2023, 13116.

[39] NagaharaAH, TuszynskiMH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov., 2011, 10(3): 209-219.

[40] KaplanGB, VasterlingJJ, VedakPC. Brain-derived neurotrophic factor in traumatic brain injury, post-traumatic stress disorder, and their comorbid conditions: role in pathogenesis and treatment. Behav Pharmacol., 2010, 21(5–6): 427-437.

[41] GoldSM, SchulzKH, HartmannS, et al.. Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls. J Neuroimmunol., 2003, 138(1–2): 99-105.

[42] GoekintM, HeymanE, RoelandsB, et al.. No influence of noradrenaline manipulation on acute exercise-induced increase of brain-derived neurotrophic factor. Med Sci Sports Exerc., 2008, 40(11): 1990-1996.

[43] StrohleA, JahnH, MontkowskiA, et al.. Central and peripheral administration of atriopeptin is anxiolytic in rats. Neuroendocrinology., 1997, 65(3): 210-215.

[44] WisenAG, EkbergK, WohlfartB, et al.. Plasma ANP and BNP during exercise in patients with major depressive disorder and in healthy controls. J Affect Disord., 2011, 129(1–3): 371-375.

[45] SkofitschG, JacobowitzDM, EskayRL, et al.. Distribution of atrial natriuretic factor-like immunoreactive neurons in the rat brain. Neuroscience., 1985, 16(4): 917-948.

[46] BergeyJL, MuchDR, KratunisV, et al.. Effects of human ANF-(99–126) on sympathetic nerve function, hemodynamic parameters and plasma cGMP levels in anesthetized, ganglion-blocked dogs. Eur J Pharmacol., 1989, 159(2): 103-112.

[47] LangCC, StruthersAD. Interactions between atrial natriuretic factor and the autonomic nervous system. Clin Auton Res., 1991, 1(4): 329-336.

[48] HoltzJ, SommerO, BassengeE. Inhibition of sympathoadrenal activity by atrial natriuretic factor in dogs. Hypertension., 1987, 9(4): 350-354.

[49] BoeckerH, SprengerT, SpilkerME, et al.. The runner's high: opioidergic mechanisms in the human brain. Cereb Cortex., 2008, 18(11): 2523-2531.

[50] DalgleishT. The emotional brain. Nat Rev Neurosci., 2004, 5(7): 583-589.

[51] MoylanS, EyreHA, MaesM, et al.. Exercising the worry away: how inflammation, oxidative and nitrogen stress mediates the beneficial effect of physical activity on anxiety disorder symptoms and behaviours. Neurosci Biobehav Rev., 2013, 37(4): 573-584.

[52] O'DonovanA, HughesBM, SlavichGM, et al.. Clinical anxiety, cortisol and interleukin-6: evidence for specificity in emotion-biology relationships. Brain Behav Immun., 2010, 24(7): 1074-1077.

[53] MaesM, GaleckiP, ChangYS, et al.. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry., 2011, 35(3): 676-692.

[54] GleesonM, BishopNC, StenselDJ, et al.. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol., 2011, 11(9): 607-615.

[55] Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol (1985). 2005;98(4):1154–1162.

[56] FebbraioMA, PedersenBK. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. Faseb J., 2002, 16(11): 1335-1347.

[57] KellerC, SteensbergA, PilegaardH, et al.. Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content. Faseb J., 2001, 15(14): 2748-2750.

[58] RasmussenP, VedelJC, OlesenJ, et al.. In humans, IL-6 is released from the brain during and after exercise and paralleled by enhanced IL-6 mRNA expression in the hippocampus of mice. Acta Physiol (Oxf)., 2011, 201(4): 475-482.

[59] SchellerJ, ChalarisA, Schmidt-ArrasD, et al.. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta., 2011, 1813(5): 878-888.

[60] SilvaL, TortelliL, MottaJ, et al.. Effects of aquatic exercise on mental health, functional autonomy and oxidative stress in depressed elderly individuals: a randomized clinical trial. Clinics (Sao Paulo)., 2019, 74. e322

[61] DianoS, MatthewsRT, PatryloP, et al.. Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology., 2003, 144(11): 5014-5021.

[62] VaynmanS, YingZ, WuA, et al.. Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity. Neuroscience., 2006, 139(4): 1221-1234.

[63] DietrichMO, AndrewsZB, HorvathTL. Exercise-induced synaptogenesis in the hippocampus is dependent on UCP2-regulated mitochondrial adaptation. J Neurosci., 2008, 28(42): 10766-10771.

[64] AndrewsZB, DianoS, HorvathTL. Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci., 2005, 6(11): 829-840.

[65] NebukaM, OhmuraY, IzawaS, et al.. Behavioral characteristics of 5-HT(2c) receptor knockout mice: locomotor activity, anxiety-, and fear memory-related behaviors. Behav Brain Res., 2020, 379. 112394

[66] DavisJM, BaileySP, WoodsJA, et al.. Effects of carbohydrate feedings on plasma free tryptophan and branched-chain amino acids during prolonged cycling. Eur J Appl Physiol Occup Physiol., 1992, 65(6): 513-519.

[67] FischerHG, HollmannW, De MeirleirK. Exercise changes in plasma tryptophan fractions and relationship with prolactin. Int J Sports Med., 1991, 12(5): 487-489.

[68] ChaouloffF, LaudeD, GuezennecY, et al.. Motor activity increases tryptophan, 5-hydroxyindoleacetic acid, and homovanillic acid in ventricular cerebrospinal fluid of the conscious rat. J Neurochem., 1986, 46(4): 1313-1316.

[69] ChaouloffF, LaudeD, ElghoziJL. Physical exercise: evidence for differential consequences of tryptophan on 5-HT synthesis and metabolism in central serotonergic cell bodies and terminals. J Neural Transm., 1989, 78(2): 121-130.

[70] FernstromJD, WurtmanRJ. Brain serotonin content: physiological dependence on plasma tryptophan levels. Science., 1971, 173(3992): 149-152.

[71] WurtmanRJ, FernstromJD. Control of brain neurotransmitter synthesis by precursor availability and nutritional state. Biochem Pharmacol., 1976, 25(15): 1691-1696.

[72] ChaouloffF. Effects of acute physical exercise on central serotonergic systems. Med Sci Sports Exerc., 1997, 29(1): 58-62.

[73] BroocksA, MeyerT, GeorgeA, et al.. Decreased neuroendocrine responses to meta-chlorophenylpiperazine (m-CPP) but normal responses to ipsapirone in marathon runners. Neuropsychopharmacol., 1999, 20(2): 150-161.

[74] XuJY, ChenC. Endocannabinoids in synaptic plasticity and neuroprotection. Neuroscientist., 2015, 21(2): 152-168.

[75] CastilloPE, YountsTJ, ChavezAE, et al.. Endocannabinoid signaling and synaptic function. Neuron., 2012, 76(1): 70-81.

[76] LigrestiA, De PetrocellisL, Di MarzoV. From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology. Physiol Rev., 2016, 96(4): 1593-1659.

[77] SorianoD, VacottoM, BruscoA, et al.. Neuronal and synaptic morphological alterations in the hippocampus of cannabinoid receptor type 1 knockout mice. J Neurosci Res., 2020, 98(11): 2245-2262.

[78] MarsicanoG, LafenetreP. Roles of the endocannabinoid system in learning and memory. Curr Top Behav Neurosci., 2009, 1: 201-230.

[79] GuzmanAS, AvalosMP, De GiovanniLN, et al.. CB1R activation in nucleus accumbens core promotes stress-induced reinstatement of cocaine seeking by elevating extracellular glutamate in a drug-paired context. Sci Rep., 2021, 11112964.

[80] RenardJ, KrebsMO, Le PenG, et al.. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology. Front Neurosci., 2014, 8361.

[81] ImperatoreR, MorelloG, LuongoL, et al.. Genetic deletion of monoacylglycerol lipase leads to impaired cannabinoid receptor CB(1)R signaling and anxiety-like behavior. J Neurochem., 2015, 135(4): 799-813.

[82] SegevA, RubinAS, AbushH, et al.. Cannabinoid receptor activation prevents the effects of chronic mild stress on emotional learning and LTP in a rat model of depression. Neuropsychopharmacol., 2014, 39(4): 919-933.

[83] HillMN, TitternessAK, MorrishAC, et al.. Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus., 2010, 20(4): 513-523.

[84] DeboerLB, PowersMB, UtschigAC, et al.. Exploring exercise as an avenue for the treatment of anxiety disorders. Expert Rev Neurother., 2012, 12(8): 1011-1022.

[85] HenrikssonM, WallA, NybergJ, et al.. Effects of exercise on symptoms of anxiety in primary care patients: a randomized controlled trial. J Affect Disord., 2022, 297: 26-34.

[86] PattenRK, McilvennaLC, Moreno-AssoA, et al.. Efficacy of high-intensity interval training for improving mental health and health-related quality of life in women with polycystic ovary syndrome. Sci Rep., 2023, 1313025.

[87] WallA, HenrikssonM, NybergJ, et al.. Exercise and health-related quality of life and work-related outcomes in primary care patients with anxiety disorders - a randomized controlled study. J Affect Disord., 2024, 360: 5-14.

Funding

National Natural Science Foundation of China(82405550)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to Huazhong University of Science and Technology