It is clear that genetic predisposition, aberrant changes in gene expression and environmental factors such as chronic stress are involved. Interestingly, some individuals are more susceptible to depression, and the molecular mechanisms underlying this vulnerability are poorly understood. Because of the limited efficacy of traditional antidepressants, there is an urgent need to identify novel cellular pathways involved in regulating susceptibility and resilience to stress. Antidepressants that target neurotransmitter systems are currently prescribed however, less than half of the depressed patients achieve complete remission upon treatment. The World Health Organization estimates that 320 million people suffer from this disease. Major depressive disorder or depression is the leading cause of disability worldwide. 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. On the contrary, HDAC2/3 inhibition was antidepressant-like. In this paradigm, lactate regulated HDAC5 and not HDAC2/3 levels. When administered after the establishment of depression, lactate behaved as antidepressant. In this paradigm, we examined whether lactate functions by regulating HDACs using co-treatment with CI-994, a brain-permeable class I HDAC inhibitor. 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. 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. When compared with control mice, mice exposed to stress displayed increased susceptibility, social avoidance and anxiety. Mice received lactate before each defeat session. On the 11th day, mice were subjected to behavioral tests. To determine whether lactate promotes resilience to stress, male C57BL/6 mice experienced daily defeat by a CD-1 aggressor, for 10 days. 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. Exercise counteracts the effects of stress. Susceptible individuals exhibit social avoidance and anxious behavior and ultimately develop depression, whereas resilient individuals live normally. Chronic stress promotes depression in some individuals, but has no effect in others.
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