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Branched-chain amino acids govern the high learning ability phenotype in Tokai high avoider (THA) rats.

ABSTRACT: To fully understand the mechanisms governing learning and memory, animal models with minor interindividual variability and higher cognitive function are required. THA rats established by crossing those with high learning capacity exhibit excellent learning and memory abilities, but the factors underlying their phenotype are completely unknown. In the current study, we compare the hippocampi of parental strain Wistar rats to those of THA rats via metabolomic analysis in order to identify molecules specific to the THA rat hippocampus. Higher branched-chain amino acid (BCAA) levels and enhanced activation of BCAA metabolism-associated enzymes were observed in THA rats, suggesting that acetyl-CoA and acetylcholine are synthesized through BCAA catabolism. THA rats maintained high blood BCAA levels via uptake of BCAAs in the small intestine and suppression of BCAA catabolism in the liver. Feeding THA rats with a BCAA-reduced diet decreased acetylcholine levels and learning ability, thus, maintaining high BCAA levels while their proper metabolism in the hippocampus is the mechanisms underlying the high learning ability in THA rats. Identifying appropriate BCAA nutritional supplements and activation methods may thus hold potential for the prevention and amelioration of higher brain dysfunction, including learning disabilities and dementia.

SUBMITTER: Shida Y

PROVIDER: S-EPMC8630195 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCirculating branched-chain amino acid (BCAA) levels reflect metabolic health and dietary intake. However, associations with breast cancer are unclear.MethodsWe evaluated circulating BCAA levels and breast cancer risk within the Nurses' Health Study (NHS) and NHSII (1997 cases and 1997 controls). A total of 592 NHS women donated 2 blood samples 10 years apart. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer risk in multivariable logistic regression models. We conducted an external validation in 1765 cases in the Women's Health Study (WHS). All statistical tests were 2-sided.ResultsAmong NHSII participants (predominantly premenopausal at blood collection), elevated circulating BCAA levels were associated with lower breast cancer risk (eg, isoleucine highest vs lowest quartile, multivariable OR = 0.86, 95% CI = 0.65 to 1.13, P trend = .20), with statistically significant linear trends among fasting samples (eg, isoleucine OR = 0.74, 95% CI = 0.53 to 1.05, P trend = .05). In contrast, among postmenopausal women, proximate measures (<10 years from blood draw) were associated with increased breast cancer risk (eg, isoleucine OR = 1.63, 95% CI = 1.12 to 2.39, P trend = .01), with stronger associations among fasting samples (OR = 1.73, 95% CI = 1.15 to 2.61, P trend = .01). Distant measures (10-20 years since blood draw) were not associated with risk. In the WHS, a positive association was observed for distant measures of leucine among postmenopausal women (OR = 1.23, 95% CI = 0.96 to 1.58, P trend = .04).ConclusionsNo statistically significant associations between BCAA levels and breast cancer risk were consistent across NHS and WHS or NHSII and WHS. Elevated circulating BCAA levels were associated with lower breast cancer risk among predominantly premenopausal NHSII women and higher risk among postmenopausal women in NHS but not in the WHS. Additional studies are needed to understand this complex relationship.

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Branched-chain amino acids govern the high learning ability phenotype in Tokai high avoider (THA) rats.

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