The impact of environmental enrichment on sex-specific neurochemical circuitries - effects on brain-derived neurotrophic factor and the serotonergic system.

Experimental evidence in mice indicates that environmental conditions affect females and males differently. However, in a recent study analyzing the heterozygous mutation of brain-derived neurotrophic factor (BDNF), both sexes presented a similar emotional phenotype, which became obvious only under impoverished, but not in enriched conditions suggesting an "enrichment-induced" rescue. To investigate the basis of this behavioral "rescue" effect, we analyzed neurochemical changes (BDNF expression, serotonergic changes, and corticosterone) in the hippocampus, frontal cortex and hypothalamus of animals housed under respective conditions. In male mice, enrichment induced an increase of BDNF expression in the hippocampus of both BDNF heterozygous (BDNF(+/-)) and wild-types. Notably, in enriched-reared BDNF(+/-) mice BDNF mRNA and protein increased to levels comparable to those of wild-types in impoverished environment. In the frontal cortex of males, only wild-types presented an enrichment-induced increase of BDNF mRNA, while no effect of environment could be detected in BDNF protein levels of the male hypothalamus. A further male-specific effect of "environment" is the significant reduction of hypothalamic 5-hydroxyindoleacetic acid in enriched-housed wild-types. In female mice, environmental enrichment did not affect BDNF expression in the hippocampus and hypothalamus. However, comparable to males, an enrichment-induced increase of BDNF mRNA was detected in the frontal cortex of wild-types only. In contrast to males, no influence of environment on serotonergic parameters was observed. Male and female corticosterone levels were neither affected by "genotype" nor by "environment". In conclusion, we propose that the rescue of the emotional phenotype by environmental enrichment in BDNF(+/-) mice is directed by distinct mechanisms in males and females. Only in male BDNF(+/-) mice the rescue is related to an increase in hippocampal BDNF expression suggesting that enrichment triggers different neuronal systems in a gender-specific manner.