The “lactate window” hypothesis: exercise-induced lactate dynamics in neurometabolic remodeling and symptom-dimensional exercise prescription for depression

Abstract

Exercise is an effective non-pharmacological intervention for depressive symptoms, but the biological mechanisms underlying its intensity-dependent and symptom-specific effects remain incompletely defined. This review proposes the “lactate window” hypothesis as a testable mechanistic model, not as an established clinical prescription strategy. Lactate is a plausible candidate link because it is tightly related to exercise intensity, functions as an oxidative substrate and signaling molecule, and participates in brain energy metabolism, astrocyte-neuron metabolic coupling, neuroplasticity, neurovascular signaling, and glial-immunometabolic regulation. Major depressive disorder (MDD) is associated with altered brain energy metabolism, mitochondrial dysfunction, pH abnormalities, and disrupted glial-neuronal support, which may be particularly relevant to fatigue, anhedonia, low motivation, psychomotor slowing, and impaired effort-based decision-making. However, lactate should not be interpreted as uniformly beneficial. Preclinical work suggests that acute L-lactate can produce antidepressant-like effects, whereas human neuroimaging findings indicate that regional lactate in motivation-related cortical circuits may be associated with reduced willingness to exert physical effort. We therefore distinguish three evidence levels: established physiological findings, plausible mechanistic pathways, and hypothesis-generating clinical applications. The proposed lactate window is operationally defined by dynamic features of the response, including blood lactate peak, area under the curve (AUC), time-to-peak, clearance, recovery kinetics, an exploratory lactate-to-rating of perceived exertion (RPE) index, affective response, next-day fatigue, sleep, and adherence. The clinical goal is not to maximize lactate, but to identify a tolerable, recoverable metabolic challenge that may support adaptive brain remodeling. Future trials should test whether lactate kinetics predict antidepressant response beyond conventional exercise dose and whether such effects are strongest for energy-, motivation-, and effort-related symptom dimensions. Because direct clinical evidence in MDD remains limited, lactate-informed exercise prescription should currently be framed as a research agenda requiring prospective validation.

Keywords

major depressive disorder / exercise / lactate / neurometabolism / astrocyte-neuron lactate shuttle / monocarboxylate transporters / fatigue / anhedonia / effort-based decision-making

References

[1] GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022; 9:137-50.

[2] Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al.Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. Am J Psychiatry. 2006; 163:1905-17.

[3] Noetel M, Sanders T, Gallardo-Gómez D, Taylor P, Del Pozo Cruz B, van den Hoek D, et al.Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2024; 384:e075847.

[4] Brooks GA. The lactate shuttle during exercise and recovery. Med Sci Sports Exerc. 1986; 18:360-8.

[5] Brooks GA. The Science and Translation of Lactate Shuttle Theory. Cell Metab. 2018; 27:757-85.

[6] Brooks GA. Lactate as a fulcrum of metabolism. Redox Biol. 2020; 35:101454.

[7] Goodwin ML, Harris JE, Hernández A, Gladden LB. Blood Lactate Measurements and Analysis during Exercise: A Guide for Clinicians. J Diabetes Sci Technol. 2007; 1:558-69.

[8] Billat LV. Use of Blood Lactate Measurements for Prediction of Exercise Performance and for Control of Training. Sports Med. 1996; 22:157-75.

[9] MacInnis MJ, Gibala MJ. Physiological adaptations to interval training and the role of exercise intensity. J Physiol. 2016; 595:2915-30.

[10] Buchheit M, Laursen PB. High-Intensity Interval Training, Solutions to the Programming Puzzle. Sports Med. 2013; 43:313-38.

[11] Laursen PB, Jenkins DG. The Scientific Basis for High-Intensity Interval Training. Sports Med. 2002; 32:53-73.

[12] Jacob N, So I, Sharma B, Marzolini S, Tartaglia MC, Oh P, et al.Effects of High-Intensity Interval Training Protocols on Blood Lactate Levels and Cognition in Healthy Adults: Systematic Review and Meta-Regression. Sports Med. 2023; 53:977-91.

[13] Hagihara H, Miyakawa T. Postmortem evidence of decreased brain pH in major depressive disorder: a systematic review and meta-analysis. Transl Psychiatry. 2024; 14:460.

[14] Meng F, Wang J, Wang L, Zou W. Glucose metabolism impairment in major depressive disorder. Brain Res Bull. 2025; 221:111191.

[15] Larrea A, Sánchez-Sánchez L, Diez-Martin E, Elexpe A, Torrecilla M, Astigarraga E, et al.Mitochondrial Metabolism in Major Depressive Disorder: From Early Diagnosis to Emerging Treatment Options. J Clin Med. 2024; 13:1727.

[16] Zuccoli GS, Saia-Cereda VM, Nascimento JM, Martins-de-Souza D. The Energy Metabolism Dysfunction in Psychiatric Disorders Postmortem Brains: Focus on Proteomic Evidence. Front Neurosci. 2017; 11:493.

[17] Hurwitz TA, Clark C, Murphy E, Klonoff H, Martin WR, Pate BD. Regional Cerebral Glucose Metabolism in Major Depressive Disorder. Can J Psychiatry. 1990; 35:684-8.

[18] Kennedy SH, Evans KR, Krüger S, Mayberg HS, Meyer JH, McCann S, et al.Changes in Regional Brain Glucose Metabolism Measured With Positron Emission Tomography After Paroxetine Treatment of Major Depression. Am J Psychiatry. 2001; 158:899-905.

[19] Hagihara H, Shoji H, Hattori S, Sala G, Takamiya Y, Tanaka M, et al.Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment. eLife. 2024; 12

[20] Bélanger M, Allaman I, Magistretti PJ. Brain Energy Metabolism: Focus on Astrocyte-Neuron Metabolic Cooperation. Cell Metab. 2011; 14:724-38.

[21] Beard E, Lengacher S, Dias S, Magistretti PJ, Finsterwald C. Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives. Front Physiol. 2022; 12:825816.

[22] Rajkowska G, Stockmeier CA. Astrocyte Pathology in Major Depressive Disorder: Insights from Human Postmortem Brain Tissue. Curr Drug Targets. 2013; 14:1225-36.

[23] Banasr M, Duman RS. Glial Loss in the Prefrontal Cortex Is Sufficient to Induce Depressive-like Behaviors. Biol Psychiatry. 2008; 64:863-70.

[24] Cobb JA, O'Neill K, Milner J, Mahajan GJ, Lawrence TJ, May WL, et al.Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder. Neuroscience. 2016; 316:209-20.

[25] Rial D, Lemos C, Pinheiro H, Duarte JM, Gonçalves FQ, Real JI, et al.Depression as a Glial-Based Synaptic Dysfunction. Front Cell Neurosci. 2016; 9:521.

[26] Wu A, Lee D, Xiong WC. Lactate Metabolism, Signaling, and Function in Brain Development, Synaptic Plasticity, Angiogenesis, and Neurodegenerative Diseases. Int J Mol Sci. 2023; 24:13398.

[27] Pellerin L, Pellegri G, Bittar PG, Charnay Y, Bouras C, Martin JL, et al.Evidence Supporting the Existence of an Activity-Dependent Astrocyte-Neuron Lactate Shuttle. Dev Neurosci. 1998; 20:291-9.

[28] Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, et al.Astrocyte-Neuron Lactate Transport Is Required for Long-Term Memory Formation. Cell. 2011; 144:810-23.

[29] Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem. 2005; 94:1-14.

[30] Bergersen LH. Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle. Neuroscience. 2007; 145:11-9.

[31] Dienel GA. Brain Lactate Metabolism: The Discoveries and the Controversies. J Cereb Blood Flow Metab. 2011; 32:1107-38.

[32] Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci. 1994; 91:10625-9.

[33] Bouzier-Sore AK, Voisin P, Canioni P, Magistretti PJ, Pellerin L. Lactate is a Preferential Oxidative Energy Substrate over Glucose for Neurons in Culture. J Cereb Blood Flow Metab. 2003; 23:1298-306.

[34] Descalzi G, Gao V, Steinman MQ, Suzuki A, Alberini CM. Lactate from astrocytes fuels learning-induced mRNA translation in excitatory and inhibitory neurons. Commun Biol. 2019; 2:247.

[35] El Hayek L, Khalifeh M, Zibara V, Abi Assaad R, Emmanuel N, Karnib N, et al.Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF). J Neurosci. 2019; 39:2369-82.

[36] Margineanu MB, Mahmood H, Fiumelli H, Magistretti PJ. L-Lactate Regulates the Expression of Synaptic Plasticity and Neuroprotection Genes in Cortical Neurons: A Transcriptome Analysis. Front Mol Neurosci. 2018; 11:375.

[37] Yang J, Ruchti E, Petit JM, Jourdain P, Grenningloh G, Allaman I, et al.Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc Natl Acad Sci. 2014; 111:12228-33.

[38] Müller P, Duderstadt Y, Lessmann V, Müller NG. Lactate and BDNF: Key Mediators of Exercise Induced Neuroplasticity?. J Clin Med. 2020; 9:1136.

[39] Morland C, Andersson KA, Haugen ØP, Hadzic A, Kleppa L, Gille A, et al.Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat Commun. 2017; 8:15557.

[40] Zhang L, Zheng J, Liu SY, Hou LL, Zhang B, Tian SW. Acute Administration of Lactate Exerts Antidepressant-like Effect Through cAMP-dependent Protein Synthesis. Neuroscience. 2024; 542:11-20.

[41] Knudsen GM, Paulson OB, Hertz MM. Kinetic Analysis of the Human Blood-Brain Barrier Transport of Lactate and its Influence by Hypercapnia. J Cereb Blood Flow Metab. 1991; 11:581-6.

[42] Kennedy L, Glesaaen ER, Palibrk V, Pannone M, Wang W, Al-Jabri A, et al.Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia. eLife. 2022; 11

[43] Han H, Zhao Y, Du J, Wang S, Yang X, Li W, et al.Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia. Immun Ageing. 2023; 20:63.

[44] Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al.Metabolic regulation of gene expression by histone lactylation. Nature. 2019; 574:575-80.

[45] Nicola R, Madar R, Okun E. HCAR1-Mediated l-Lactate Signaling Suppresses Microglial Phagocytosis. NeuroMolecular Med. 2022; 24:399-404.

[46] Yang H, Mo N, Tong L, Dong J, Fan Z, Jia M, et al.Microglia lactylation in relation to central nervous system diseases. Neural Regen Res. 2024; 20:29-40.

[47] Treadway MT, Bossaller NA, Shelton RC, Zald DH. Effort-based decision-making in major depressive disorder: A translational model of motivational anhedonia. J Abnorm Psychol. 2012; 121:553-8.

[48] Treadway MT, Buckholtz JW, Schwartzman AN, Lambert WE, Zald DH. Worth the ‘EEfRT’? The Effort Expenditure for Rewards Task as an Objective Measure of Motivation and Anhedonia. PLoS ONE. 2009; 4:e6598.

[49] Yang XH, Huang J, Zhu CY, Wang YF, Cheung EF, Chan RC, et al.Motivational deficits in effort-based decision making in individuals with subsyndromal depression, first-episode and remitted depression patients. Psychiatry Res. 2014; 220:874-82.

[50] Salamone JD, Correa M, Farrar AM, Nunes EJ, Pardo M. Dopamine, Behavioral Economics, and Effort. Front Behav Neurosci. 2009; 3:13.

[51] Salamone JD, Yohn SE, López-Cruz L, San Miguel N, Correa M. Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology. Brain. 2016; 139:1325-47.

[52] Buyukdura JS, McClintock SM, Croarkin PE. Psychomotor retardation in depression: Biological underpinnings, measurement, and treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35:395-409.

[53] Liberg B, Rahm C. The Functional Anatomy of Psychomotor Disturbances in Major Depressive Disorder. Front Psychiatry. 2015; 6:34.

[54] Cooper JA, Arulpragasam AR, Treadway MT. Anhedonia in depression: biological mechanisms and computational models. Curr Opin Behav Sci. 2018; 22:128-35.

[55] Rizvi SJ, Pizzagalli DA, Sproule BA, Kennedy SH. Assessing anhedonia in depression: Potentials and pitfalls. Neurosci Biobehav Rev. 2016; 65:21-35.

[56] Brydges CR, Bhattacharyya S, Dehkordi SM, Milaneschi Y, Penninx B, Jansen R, et al.Metabolomic and inflammatory signatures of symptom dimensions in major depression. Brain Behav Immun. 2022; 102:42-52.

[57] Goldsmith DR, Haroon E, Woolwine BJ, Jung MY, Wommack EC, Harvey PD, et al.Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder. Brain Behav Immun. 2016; 56:281-8.

[58] Hird EJ, Slanina-Davies A, Lewis G, Hamer M, Roiser JP. From movement to motivation: a proposed framework to understand the antidepressant effect of exercise. Transl Psychiatry. 2024; 14:273.

[59] Dennis A, Thomas AG, Rawlings NB, Near J, Nichols TE, Clare S, et al.An Ultra-High Field Magnetic Resonance Spectroscopy Study of Post Exercise Lactate, Glutamate and Glutamine Change in the Human Brain. Front Physiol. 2015; 6:351.

[60] Quistorff B, Secher NH, Van Lieshout JJ. Lactate fuels the human brain during exercise. FASEB J. 2008; 22:3443-9.

[61] Dalsgaard MK, Quistorff B, Danielsen ER, Selmer C, Vogelsang T, Secher NH. A reduced cerebral metabolic ratio in exercise reflects metabolism and not accumulation of lactate within the human brain. J Physiol. 2004; 554:571-8.

[62] Maddock RJ, Casazza GA, Buonocore MH, Tanase C. Vigorous exercise increases brain lactate and Glx (glutamate+glutamine): A dynamic 1H-MRS study. NeuroImage. 2011; 57:1324-30.

[63] Boumezbeur F, Petersen KF, Cline GW, Mason GF, Behar KL, Shulman GI, et al.The Contribution of Blood Lactate to Brain Energy Metabolism in Humans Measured by Dynamic¹³C Nuclear Magnetic Resonance Spectroscopy. J Neurosci. 2010; 30:13983-91.

[64] Siebenmann C, Sørensen H, Bonne TC, Zaar M, Aachmann-Andersen NJ, Nordsborg NB, et al.Cerebral lactate uptake during exercise is driven by the increased arterial lactate concentration. J Appl Physiol. 2021; 131:1824-30.

[65] Aveseh M, Nikooie R, Sheibani V, Esmaeili-Mahani S. Endurance training increases brain lactate uptake during hypoglycemia by up regulation of brain lactate transporters. Mol Cell Endocrinol. 2014; 394:29-36.

[66] Singh B, Olds T, Curtis R, Dumuid D, Virgara R, Watson A, et al.Effectiveness of physical activity interventions for improving depression, anxiety and distress: an overview of systematic reviews. Br J Sports Med. 2023; 57:1203-9.

[67] Ross RE, VanDerwerker CJ, Saladin ME, Gregory CM. The role of exercise in the treatment of depression: biological underpinnings and clinical outcomes. Mol Psychiatry. 2022; 28:298-328.

[68] Zeng J, Wang H. The impact of high-intensity exercise on patients with depression: a systematic review and meta-analysis of randomized controlled trials. Front Public Health. 2025; 13:1616925.

[69] Ribeiro JA, Schuch FB, Vargas KFM, Müller PT, Boullosa D. A Rapid Review of Randomized Trials Assessing the Effects of High-Intensity Interval Training on Depressive Symptoms in People with Mental Illness. Int J Environ Res Public Health. 2022; 19:10581.

[70] Yao S, Xu MD, Wang Y, Zhao ST, Wang J, Chen GF, et al.Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice. Nat Commun. 2023; 14:729.

[71] Yin YN, Hu J, Wei YL, Li ZL, Luo ZC, Wang RQ, et al.Astrocyte-Derived Lactate Modulates the Passive Coping Response to Behavioral Challenge in Male Mice. Neurosci Bull. 2020; 37:1-14.

[72] Jouroukhin Y, Kageyama Y, Misheneva V, Shevelkin A, Andrabi S, Prandovszky E, et al.DISC1 regulates lactate metabolism in astrocytes: implications for psychiatric disorders. Transl Psychiatry. 2018; 8:76.

[73] Clairis N, Barakat A, Brochard J, Xin L, Sandi C. A neurometabolic mechanism involving dmPFC/dACC lactate in physical effort-based decision-making. Mol Psychiatry. 2024; 30:899-913.

[74] Carrard A, Elsayed M, Margineanu M, Boury-Jamot B, Fragnière L, Meylan EM, et al.Peripheral administration of lactate produces antidepressant-like effects. Mol Psychiatry. 2016; 23:392-9.

[75] Firth J, Rosenbaum S, Stubbs B, Gorczynski P, Yung AR, Vancampfort D. Motivating factors and barriers towards exercise in severe mental illness: a systematic review and meta-analysis. Psychol Med. 2016; 46:2869-81.

[76] Castro Monteiro F, Barreto Schuch F, Camaz Deslandes A, Paz Mosqueiro B, Caldieraro MA, Pio de Almeida Fleck M. Factors associated with adherence to sports and exercise among outpatients with major depressive disorder. Trends Psychiatry Psychother. 2021

[77] Mohammadi Jouabadi S, Mokhtari S. Mechanistic Clinical Pharmacology: Bridging PK–PD Modeling, Biomarkers, and Translational Therapeutics. Nexus Pathophysiol Ther. 2026; 1:1-5.