The role of branched chain amino acid and tryptophan metabolism in rat's behavioral diversity: Intertwined peripheral and brain effects.
Previously, we showed that a transient early-in-life interference with the expression of multiple genes by mithramycin (MTR) followed by later-in-life exposure to chronic stress, leads to a "daring" and novelty seeking behavior in rats. In this study we searched for molecular changes that contribute to this behavioral alteration. We applied a non-hypothesis driven strategy using whole genome cDNA array analysis (WGA) followed by Genome Scale Metabolic modeling analysis (GSMM). Gene expression validation was performed by qRT-PCR and immunoblotting. Brain and serum amino acids levels were measured by HPLC. WGA data directed us towards metabolic pathways and GSMM pointed at branched chain amino acids (BCAA) pathway. Out of 21 amino acids analyzed in the prefrontal cortex of MTR+Stress rats only tryptophan, whose brain levels depend on serum BCAA levels, showed a significant decrease. No change was observed in serotonin or kynurenine levels. However, a significant reduction in mRNA and protein levels of the large neutral amino acid transporter (LAT1), which transports BCAA and tryptophan into the brain, as well as in serum levels of tryptophan/BCAA ratio were observed. The latter may be attributed to the failure to increase serum insulin, following stress, in rats pre-exposed to mithramycin. Finally, significant correlations were observed between the anxiety index and tryptophan and between T-maze errors and LAT1. This study shows a specific behavioral pattern, which is linked to modulations in fluxes of amino acids both peripheral and central, which converge and reciprocally interact, and may thus be equally important targets for therapeutic intervention.
Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center, Tel Aviv University, Tel Aviv, Israel; B. Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
Eyal
E
Asor
The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Shiri
S
Stempler
Behavioral Neuroscience Lab, The Emek Medical Center Afula, Technion-IIT, Haifa, Israel; B. Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
Avi
A
Avital
Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center, Tel Aviv University, Tel Aviv, Israel; B. Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
Ehud
E
Klein
The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
Eytan
E
Ruppin
Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center, Tel Aviv University, Tel Aviv, Israel; B. Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel. Electronic address: shachar@tx.technion.ac.il.
Dorit
D
Ben-Shachar
D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D007328:Insulin / Q000097:blood; D007737:Kynurenine / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008926:Plicamycin / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*
D000597:Amino Acids, Branched-Chain; D001786:Blood Glucose; D007328:Insulin; D027283:Large Neutral Amino Acid-Transporter 1; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D012701:Serotonin; D007737:Kynurenine; D014364:Tryptophan; D008926:Plicamycin
Essential amino acids; Gene–environmental interaction; Insulin; Mithramycin; Stress; Tryptophan