Branched-chain amino acids mediate resilience to chronic social defeat stress by activating BDNF/TRKB signaling

Abstract

How individuals respond to chronic stress varies. Susceptible individuals ultimately develop depression; whereas resilient individuals live normally. In this study, our objective was to examine the effect of branched-chain amino acids (BCAA), commonly used by athletes, on susceptibility to stress. Male C57BL/6 mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day11, the behavior of mice was assessed using the social interaction test, elevated plus maze and open field. Mice received the BCAA leucine, isoleucine or valine before each defeat session. Furthermore, we examined whether BCAA regulate brain derived neurotrophic factor (BDNF) signaling by using a brain-permeable tropomyosin receptor kinase B (TRKB) inhibitor, ANA-12. We also tested the effect of voluntary exercise and high protein diets on susceptibility to stress. Mice exposed to chronic stress displayed increased susceptibility and social avoidance. BCAA promoted resilience to chronic stress, rescued social avoidance behaviors and increased hippocampal BDNF levels and TRKB activation. Inhibition of TRKB signaling abolished the ability of BCAA to promote resilience to stress and to rescue social avoidance. Interestingly, we found that BCAA activate the exercise-regulated PGC1a/FNDC5 pathway known to induce hippocampal BDNF signaling. Although both voluntary exercise and BCAA promoted resilience to stress, combining them did not yield synergistic effects confirming that they affect similar pathways. We also discovered that high protein diets mimic the effect of BCAA by rescuing social deficits induced by chronic stress and increase Bdnf expression in the hippocampus. Our data indicate that BCAA, exercise and high protein diets rescue susceptibility to stress by activating the hippocampal BDNF/TRKB signaling.

Stress-Related Dysfunction of Adult Hippocampal Neurogenesis—An Attempt for Understanding Resilience?

“…BDNF-mediated stress resilience to learned helplessness (LH) was also demonstrated by individually higher expression in the hippocampus of resilient than in susceptible rats [ 215 ]. Interestingly, also acute effects of amino acid metabolites-induced BDNF/TrkB signaling led to stress resilience in a mouse model of CSDS [ 216 ]. Vice versa, mice deficient in BDNF or with decreased BDNF/TrkB signaling are more susceptible to acute mild stress, subchronic mild stress and CSDS, by displaying increased plasma corticosterone levels [ 217 , 218 , 219 , 220 ].…”

Antidepressant‐like Effects of Degraded Porphyran Isolated fromPorphyra haitanensis

“…In the present study, CUMS inhibited BDNF/TrkB/ERK/CREB signaling pathway, which was in accordance with the previous studies. [ 35–37 ] In contrast, chronic porphyran administration for 4 weeks reversed the inhibition of BDNF/TrkB/ERK/CREB pathway. Besides the neurotrophic signaling, we also evaluated the effects of porphyran on neurogenesis and spinogenesis.…”

Evaluation of a TrkB agonist on spatial and motor learning in the Ube3a mouse model of Angelman syndrome

“…Beginning a neurotrophic drug intervention early in life, during a critical period of brain development, may be essential for neurodevelopmental disorders such as Angelman syndrome (Sonzogni et al 2019). Although TrkB agonists have been shown to improve components of social and motor behaviors in adult mice (Simmons et al 2013;Kang et al 2017;Li et al 2017;Nasrallah et al 2019;Rhine et al 2019), brain disorders with structural neuroanatomical abnormalities established during early development, such as reductions in myelination which have been reported for Angelman syndrome (Harting et al 2009;Peters et al 2011;Tiwari et al 2012;Grier et al 2015), may require that neurotrophic interventions begin at a very young age (Silva-Santos et al 2015;Sonzogni et al 2019).…”