Peripheral tissue BDNF expression is affected by promoter IV defect and enriched environments in mice: negative hippocampus-intestine and positive thymus-serum-muscle correlations.

Abstract

BACKGROUND: Brain-derived neurotrophic factor (BDNF) expression is reduced in the brain of various central nervous system (CNS) disorders, but its relation to peripheral expression remains unclear. This study aimed to determine peripheral BDNF expression affected by BDNF promoter IV defect and enriched environment treatment (EET). Promoter IV defect is associated with CNS disorders and chronic stress, whereas EET increases hippocampal BDNF expression and ameliorates CNS dysfunctions. METHODS: Enzyme-linked immunosorbent assay measured BDNF protein levels in eleven regions (hippocampus, frontal cortex, heart, lung, liver, spleen, intestine, kidney, intestine, thymus, muscle, serum) in wild-type and knock-in promoter IV (KIV) mice with or without 3 weeks of EET provided after weaning. RESULTS: Knock-in promoter IV resulted in BDNF levels significantly decreased in muscle, but significantly increased in intestine, liver, thymus, and serum, which suggests compensatory upregulation of other promoters in those tissues. EET increased BDNF levels in muscle and serum of KIV mice and thymus of wild-type mice, suggesting EET's beneficial effects in muscle motor and adaptive immune regulation. EET increased hippocampal BDNF levels in both genotypes, which significantly negatively correlated with intestine BDNF levels, suggesting its role in the brain-gut axis. EET reduced wild-type heart BDNF levels, possibly through parasympathetic regulation. Significant positive BDNF correlations were observed among serum-muscle, serum-thymus, lung-spleen, and intestine-liver, suggesting inter-organ interaction and regulation of BDNF. Partial Least Squares discriminant analyses (PLS-DA) identified that variations in BDNF levels in intestine, liver, frontal cortex, and serum contribute most to classify promoter IV defect, and those in hippocampus, serum, heart, thymus, and liver contribute most to classify EET effects. CONCLUSION: This is the first study to demonstrate how genetic and environmental factors affect BDNF expression in peripheral tissues, highlighting the complex BDNF correlations across organ systems and suggesting usefulness of multivariate BDNF analyses for detecting promoter IV defect and enriched environment effects. Elucidation of BDNF's role and regulatory mechanisms in peripheral organ systems may help better our understanding of its connection to CNS disorders and their treatments.