ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2019
Lactate is an antidepressant that mediates resilience to stress by modulating the hippocampal levels and activity of histone deacetylases.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers, 3 of them syntheses that pooled it.
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Who cites it
80 citing papers in PubMed, 3 syntheses or guidelines pooled it, 136 citations in OpenAlex.
- Lactate Changes Quantified by fMRS: A Meta-Analysis.NMR in biomedicine · 2026Pooled it
- Research trend of epigenetics and depression: adolescents' research needs to strengthen.Frontiers in neuroscience · 2023Pooled it
- Multi-cohort analysis of depression-associated gut bacteria sheds insight on bacterial biomarkers across populations.Cellular and molecular life sciences : CMLS · 2022Pooled it
- Vicarious defeat stress (VDS) is not a simple substitute for chronic social defeat stress (CSDS): a comparative study on behavioral and molecular mechanisms in both stress-induced anxiety- and depression-like behaviors.Behavioral and brain functions : BBF · 2026Article
- Epigenetic Control of Stress-Induced Depression: Emerging Roles of HDAC3 and HDAC6.International journal of molecular sciences · 2026Review
- Integrated multi-omics analysis of gut microbiome and serum metabolome in unipolar and bipolar depression.European archives of psychiatry and clinical neuroscience · 2026Article
- Limited Contribution of the Lactate Receptor HCAR1 to Exercise-Induced Behavioral and Hippocampal Adaptations.eNeuro · 2026Article
- GR/HDAC2/synaptic complexes in hippocampal CA1 mediate the antidepressant effects of magnolol.Biomedical journal · 2026Article
- Hepatic Gluconeogenesis and the Antidepressant Effects of Exercise: A Narrative Review.Metabolites · 2026Review
- From energy metabolism to mood regulation: The rise of lactate as a therapeutic target.Journal of advanced research · 2026Review
- Metabolic profiling in major depressive disorder with high psychological resilience: changes in amino acid and carbohydrate metabolism.BMC psychiatry · 2026Article
- TLR4 and RB1 as the Identified Lactate-Related Genes to Predict the Diagnostic Performance, Gene Regulatory Network, and Targeting Drugs in Depression.Human mutation · 2026Article
- Protein Lactylation in Central Nervous System Diseases: Molecular Mechanisms and Targeted Therapeutic Strategies.International journal of nanomedicine · 2026Review
- Noncanonical role of astrocytic mitochondrial Cx43: suppressing IDH3α to sustain glycolytic homeostasis against depression.Cell death & disease · 2025Article
- Investigations on the Prospects of Using Lactiplantibacillus plantarum to Combat Depression through Gut Microbiota-Brain Axis.Molecular neurobiology · 2025Review
- Crosstalk between skeletal muscle and the brain during physical activity - in search of epigenetic mechanisms.Epigenetics · 2025Review
- Exercise and its beneficial impacts on mood disorders and neurodegeneration: a novel mechanistic perspective of the exosomes involvement.Molecular and cellular biochemistry · 2025Review
- Synaptic Protein Lactylation: A Novel Mechanism Underlying Physical Exercise-mediated Stress Resilience.Neuroscience bulletin · 2025Article
- Role of Histone Lactylation in Neurological Disorders.International journal of molecular sciences · 2025Review
- Histone Acetylation Modifications and HDACs are Associated with Resilience or Susceptibility to Stress in a Rat Model of Major Depressive Disorder.Neurochemical research · 2025Article
20 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chronic stress promotes depression in some individuals, but has no effect in others. Susceptible individuals exhibit social avoidance and anxious behavior and ultimately develop depression, whereas resilient individuals live normally. Exercise counteracts the effects of stress. Our objective was to examine whether lactate, a metabolite produced during exercise and known to reproduce specific brain exercise-related changes, promotes resilience to stress and acts as an antidepressant. To determine whether lactate promotes resilience to stress, male C57BL/6 mice experienced daily defeat by a CD-1 aggressor, for 10 days. On the 11th day, mice were subjected to behavioral tests. Mice received lactate before each defeat session. When compared with control mice, mice exposed to stress displayed increased susceptibility, social avoidance and anxiety. Lactate promoted resilience to stress and rescued social avoidance and anxiety by restoring hippocampal class I histone deacetylase (HDAC) levels and activity, specifically HDAC2/3. To determine whether lactate is an antidepressant, mice only received lactate from days 12-25 and a second set of behavioral tests was conducted on day 26. In this paradigm, we examined whether lactate functions by regulating HDACs using co-treatment with CI-994, a brain-permeable class I HDAC inhibitor. When administered after the establishment of depression, lactate behaved as antidepressant. In this paradigm, lactate regulated HDAC5 and not HDAC2/3 levels. On the contrary, HDAC2/3 inhibition was antidepressant-like. This indicates that lactate mimics exercise's effects and rescues susceptibility to stress by modulating HDAC2/3 activity and suggests that HDAC2/3 play opposite roles before and after establishment of susceptibility to stress.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.