Variant Brain-Derived Neurotrophic Factor (Valine66Methionine) Polymorphism Contributes to Developmental and Estrous Stage-Specific Expression of Anxiety-Like Behavior in Female Mice

Abstract

Background Most anxiety and depressive disorders are twice as common in women compared to men and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and peri-menopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Val66Met), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question. Approach As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle specific expression of anxiety-like behaviors. Results Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxiety-like behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and as adults differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle, specifically more anxiety-like behaviors during the estrus phase. Conclusions These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans.

Neuroimaging the Menstrual Cycle and Premenstrual Dysphoric Disorder

“…Moreover, one study of emotion processing in PMDD provided preliminary evidence of an interaction between the less functional variant of the brain-derived neurotrophic factor polymorphism brain-derived neurotrophic factor (BDNF) Val66Met and decreased frontocingulate activity in PMDD patients during the luteal phase in response to emotional stimuli [64•]. This pattern of association is consistent with findings from a preclinical model on the role of this polymorphism in the developmental and estrous stagespecific expression of anxiety-like behavior in female mice [97]. However, other candidate functional genotypes (e.g., 5-HTTLPR and MAOA-uVNTR polymorphisms) are also likely to modulate the association between neural, behavioral, and hormonal correlates, and should be investigated.…”

Serotonin deficiency alters susceptibility to the long-term consequences of adverse early life experience

“…Indeed, estrous cycle is known to have significant effects on anxiety-like behavior in mice (Maguire et al, 2005, Walf et al, 2009, Bath et al, 2012). It is possible that some additional phenotypes would have been revealed had we controlled for estrous cycle, but future research will be required to evaluate this possibility.…”

Involvement of pregnane xenobiotic receptor in mating-induced allopregnanolone formation in the midbrain and hippocampus and brain-derived neurotrophic factor in the hippocampus among female rats

“…The role of BDNF for behavioral plasticity measures, such as changes in affective or cognitive responding, has been demonstrated in recent reports For example, in an study of anxiety behaviors among female mice over the estrous cycle, genetically manipulated to overexpress a human single nucleotide polymorphism of the BDNF gene associated with anxiety and depression disorders among people, increased anxiety responding over the estrous cycle (Bath et al, 2012). The roles of ovarian steroids, such as estradiol and progesterone, across endogenous cycles, aging, and in animal models of neurodegeneration, for BDNF expression have been described (Bimonte-Nelson et al, 2008; Gibbs, 1998; Meyer et al, 2012); albeit, there is some controversy as to whether progesterone promotes or inhibits estradiol-induced BDNF expression (Aguirre et al, 2010; Aguirre and Baudry, 2009; Bimonte-Nelson et al, 2004; Lorenz et al, 2009; Nilsen and Brinton, 2002; Yao et al, 2011).…”