PMID- 31193350 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 2352-2895 (Print) IS - 2352-2895 (Electronic) IS - 2352-2895 (Linking) VI - 11 DP - 2019 Nov TI - Branched-chain amino acids mediate resilience to chronic social defeat stress by activating BDNF/TRKB signaling. PG - 100170 LID - 10.1016/j.ynstr.2019.100170 [doi] LID - 100170 AB - 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. FAU - Nasrallah, Patrick AU - Nasrallah P AD - Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Haidar, Edwina Abou AU - Haidar EA AD - Molecular Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Stephan, Joseph S AU - Stephan JS AD - School of Medicine, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - El Hayek, Lauretta AU - El Hayek L AD - Molecular Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Karnib, Nabil AU - Karnib N AD - Molecular Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Khalifeh, Mohamad AU - Khalifeh M AD - Molecular Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Barmo, Nour AU - Barmo N AD - Molecular Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Jabre, Vanessa AU - Jabre V AD - Molecular Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Houbeika, Rouba AU - Houbeika R AD - Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Ghanem, Anthony AU - Ghanem A AD - Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Nasser, Jason AU - Nasser J AD - Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Zeeni, Nadine AU - Zeeni N AD - Nutrition Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Bassil, Maya AU - Bassil M AD - Nutrition Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. FAU - Sleiman, Sama F AU - Sleiman SF AD - Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. AD - Molecular Biology Program, Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon. LA - eng PT - Journal Article DEP - 20190514 PL - United States TA - Neurobiol Stress JT - Neurobiology of stress JID - 101643409 PMC - PMC6526306 OTO - NOTNLM OT - BDNF OT - Branched chain amino acids OT - Chronic social defeat stress OT - Exercise OT - FNDC5 OT - High protein diet EDAT- 2019/06/14 06:00 MHDA- 2019/06/14 06:01 PMCR- 2019/05/14 CRDT- 2019/06/14 06:00 PHST- 2019/02/27 00:00 [received] PHST- 2019/05/10 00:00 [revised] PHST- 2019/05/11 00:00 [accepted] PHST- 2019/06/14 06:00 [entrez] PHST- 2019/06/14 06:00 [pubmed] PHST- 2019/06/14 06:01 [medline] PHST- 2019/05/14 00:00 [pmc-release] AID - S2352-2895(19)30015-3 [pii] AID - 100170 [pii] AID - 10.1016/j.ynstr.2019.100170 [doi] PST - epublish SO - Neurobiol Stress. 2019 May 14;11:100170. doi: 10.1016/j.ynstr.2019.100170. eCollection 2019 Nov.