Abstract
The val66met polymorphism on the BDNF gene has been reported to explain individual differences in hippocampal volume and memory-related activity. These findings, however, have not been replicated consistently and no studies to date controlled for the potentially confounding impact of early life stress, such as childhood abuse, and psychiatric status. Using structural and functional MRI, we therefore investigated in 126 depressed and/or anxious patients and 31 healthy control subjects the effects of val66met on hippocampal volume and encoding activity of neutral, positive and negative words, while taking into account childhood abuse and psychiatric status. Our results show slightly lower hippocampal volumes in carriers of a met allele (n=54) relative to val/val homozygotes (n=103) (P=0.02, effect size (Cohen's d)=0.37), which appeared to be independent of childhood abuse and psychiatric status. For hippocampal encoding activity, we found a val66met–word valence interaction (P=0.02) such that carriers of a met allele showed increased levels of activation in response to negative words relative to activation in the neutral word condition and relative to val/val homozygotes. This, however, was only evident in the absence of childhood abuse, as abused val/val homozygotes showed hippocampal encoding activity for negative words that was comparable to that of carriers of a met allele. Neither psychiatric status nor memory accuracy did account for these associations. In conclusion, BDNF val66met has a significant impact on hippocampal volume independently of childhood abuse and psychiatric status. Furthermore, early adverse experiences such as childhood abuse account for individual differences in hippocampal encoding activity of negative stimuli but this effect manifests differently as a function of val66met.
Highlights
IntroductionBrain-derived neurotrophic factor (BDNF) regulates the sprouting of axons and dendrites in the hippocampus, a key structure for emotion and memory processing.[1,2,3,4] Rodent studies, for example, have shown that BDNF modulates hippocampal neuronal differentiation[5] and hippocampal dependent memory.[6,7,8] human studies have reported a positive relation between BDNF concentration, hippocampal volume and memory performance.[9,10]Studies focusing on a single nucleotide site in the DNA sequence of the BDNF gene; val66met (a valine (val) to methionine (met) insertion at codon 66) have partly confirmed the associations of BDNF protein expression with neurobiological and behavioral abnormalities
We addressed the effects of val66met on hippocampal volume and function while taking into account the possible confounding effects of childhood abuse and psychiatric status
Our data suggest that the association between the met allele and hippocampal volume is independent of childhood abuse
Summary
Brain-derived neurotrophic factor (BDNF) regulates the sprouting of axons and dendrites in the hippocampus, a key structure for emotion and memory processing.[1,2,3,4] Rodent studies, for example, have shown that BDNF modulates hippocampal neuronal differentiation[5] and hippocampal dependent memory.[6,7,8] human studies have reported a positive relation between BDNF concentration, hippocampal volume and memory performance.[9,10]Studies focusing on a single nucleotide site in the DNA sequence of the BDNF gene; val66met (a valine (val) to methionine (met) insertion at codon 66) have partly confirmed the associations of BDNF protein expression with neurobiological and behavioral abnormalities. Egan et al.[11] showed in vitro that the met allele is linked to a reduced activitydependent expression of BDNF in hippocampal neurons of rats, a finding that was replicated by Chen et al.[12] In addition, studies have shown that in the hippocampus the met allele is associated with diminished levels of N-acetyl-aspartate, a putative marker for neuronal integrity.[11,13] In line with these findings, some studies have shown that the met allele is associated with impaired episodic memory[11] and executive functioning.[14,15] Structural and functional magnetic resonance imaging (MRI) studies further suggest that carriers of a met allele have smaller hippocampal volumes relative to val/ val homozygotes[16,17,18,19] and altered hippocampal activity during the encoding of stimuli.[11,20] these findings have not been consistently replicated,[21,22,23,24,25,26] which might be due to the inclusion of small samples and task characteristics such as the emotional valence of the stimuli. Gene–environment interactions have been reported between BDNF val66met and abuse on brain structure and activity.[28,29]
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