Lactate is an antidepressant that mediates resilience to stress by modulating the hippocampal levels and activity of histone deacetylases
| Autor: | Maria Bilen, Rajiv R. Ratan, Vanessa Jabre, Nour Barmo, Edward B. Holson, Pascale Ibrahim, Patrick Nasrallah, Rim El-Ghandour, Lauretta El Hayek, Mohamad Khalifeh, Sama F. Sleiman, Joseph S. Stephan, Nabil Karnib |
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| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Histone Deacetylase 2 Anxiety Phenylenediamines Hippocampal formation Hippocampus Article Histone Deacetylases Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Avoidance Learning Animals Medicine Chronic stress Lactic Acid Social Behavior Pharmacology Histone deacetylase 5 Behavior Animal biology Depression business.industry Histone deacetylase 2 Resilience Psychological Antidepressive Agents 030227 psychiatry Histone Deacetylase Inhibitors Mice Inbred C57BL Disease Models Animal Psychiatry and Mental health Histone Endocrinology Benzamides biology.protein Antidepressant Disease Susceptibility Histone deacetylase medicine.symptom business Stress Psychological 030217 neurology & neurosurgery |
| Zdroj: | Neuropsychopharmacology |
| ISSN: | 1740-634X 0893-133X |
| DOI: | 10.1038/s41386-019-0313-z |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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