BDNF is a key regulator of long-term potentiation and promotes synaptic plasticity and efficacy via excitatory glutamatergic neurotransmission in the hippocampus (Messaoudi et al. 1998
; Drake et al. 1999
; Tartaglia et al. 2001
; Bramham et al. 2005
). The BDNF Val66
Met polymorphism attenuates activity-dependent but not constitutive BDNF signaling in cultured hippocampal neurons (Egan et al. 2003
; Lu 2003
) and has been linked to both hippocampal and prefrontal abnormalities by functional neuroimaging. Previous fMRI experiments, whose measurements inherently depend on computing differences between two brain states and thus provide only relative measures of activation over baseline (Deyoe et al. 1994
), have shown abnormal hippocampal recruitment during memory-related tasks compared to control tasks (Egan et al. 2003
; Hariri et al. 2003
; Hashimoto et al. 2008
). Other fMRI studies have also found activation differences in medial PFC dependent on BDNF genotype where Met carriers showed reduced ventral mPFC activity during memory extinction (Soliman et al. 2010
). However, it has remained unclear until the present work whether this polymorphism has implications for the cerebral metabolic landscape during the so-called basal or resting state. We used a gold-standard PET method that allows task-independent brain function, specifically rCBF, a parameter tightly coupled to cerebral glucose metabolic rate, to be measured and mapped without reference to any other brain state.
Our data demonstrate that even at rest, rCBF in bilateral hippocampal/parahippocampal and medial frontal regions of healthy individuals is affected by the BDNF Val66
Met polymorphism. In addition to providing an important perspective on fMRI activation studies, these data suggest that there exists a potent, genetically mediated bias in the basal activity of frontotemporal circuitry. Because BDNF generally facilitates neural activity in hippocampus and cortex (Henderson 1996
; Benraiss et al. 2001
), this bias in Met carriers – increased regional activity at baseline – could reflect a neural systems level accommodation for the relatively inefficient, activity-dependent BDNF signaling associated with Met alleles at the cellular level (Egan et al. 2003
). Whether this is additionally related to previously reported compensatory increases in peripheral serum concentration of BDNF in healthy Met carriers (Lang et al. 2009
) is unclear, and given BDNF’s broad impact on neuronal development, activity, and plasticity, delineating the precise roots of such speculated accommodation necessarily requires further research. Nonetheless, it is remarkable that even subtle differences in this molecule result in measurable neurofunctional alterations, particularly in key components of the default resting state network (Raichle, MacLeod et al. 2001
), in a cognitively and affectively unchallenged state.
Our finding of increased resting rCBF in women compared to men is consistent with several previous studies (Devous et al. 1986
; Yoshii et al, 1988
; Slosman et al. 2001
) and has been hypothesized to reflect physiologic compensation for the smaller brain size found in women (Ho et al. 1980a
; Ankney et al. 1992
). The observation that sex effects in several regions within frontotemporal structures are interactively modulated by BDNF allelic variation is in line with a substantial body of animal literature demonstrating parallel and interacting actions of estradiol and BDNF in the brain. Not only do estrogen receptors, BDNF, and trkB show regional coexpression in the hippocampus and frontal cortex (Miranda et al. 1993
; Sohrabji et al. 2006
), both BDNF and estradiol increase adult neurogenesis (Ormerod et al. 2004
; Sairanen et al. 2005
), provide neuroprotection (Kiprianova et al. 1999
; Shughrueet al. 2003
), and facilitate memory formation (Mizuno et al. 2000
; Frick et al. 2002
). Additionally, BDNF mRNA levels are reduced in ovariectomized female rats and are rescued by estradiol replacement in the hippocampus and cortex (Singh et al. 1995
; Sohrabji et al. 1995
; Liu et al. 2001
). Despite this ample preclinical evidence for sex-by-genotype interaction, there is a paucity of human data demonstrating true statistical interactions between genotype and sex, though several authors have reported genotype effects occurring only in one sex and not the other (Henningsson et al. 2009
; van Wingen et al. 2010;). The generally greater magnitude of BDNF genotype effects in men than women in these select regions agrees with studies finding genotype effects on frontotemporal measures selectively in men, including those examining serotonin transporter availability (Henningsson et al. 2009
) and activation during memory tasks (van Wingen et al. 2010). However, our findings of reversed sex effects on resting rCBF in Val homozygotes versus Met carriers indicate that the combined effects of sex and BDNF signaling on neurophysiological function are likely to be complex.
Because both BDNF and estradiol play important roles in axonal guidance and dendritic arborization (Dominguez et al. 2004
) as well as in synaptogenesis (Tanapat et al. 1999
; Scharfman et al. 2005
), we postulated that BDNF function, as predicted by genotype, both alone and in conjunction with sex, may modulate the functional connectivity of areas impacted by BDNF genotype. In keeping with this hypothesis, significantly greater positive correlations between rCBF in the BA25and that in mPFC, and between hippocampus and parahippocampus were seen in Val homozygotes compared to Met carriers during rest, consistent with prior documentation of greater resting network connectivity in these areas in Val homozygotic children (Thomason et al. 2009
). These findings are complimented by the sex-by-genotype interactions, which demonstrated consistent genotype-determined differences in sexually dimorphic patterns of interregional cooperativity within BA25 and hippocampal/parahippocampal regions. The correlations of rCBF between these regions were modulated differentially by sex, with correlations more robustly positive for Val homozygotic females than males, whereas for met carriers, this pattern was reversed. These results together suggest that when investigating genotypic modulation on neurophysiology, sex difference is an important factor that should be considered in explaining the findings.
Our results are also relevant in considering the neural substrate of neuropsychiatric disorders. For example, the ‘neurotrophin hypothesis’ of depression speculates that incompetent BDNF function is directly related to the pathophysiology of depression. Although previous genetic association studies of BDNF Val66
Met polymorphism in depression have generated inconsistent results (Verhagen et al. 2008; Surtees et al. 2007
; Chen et al. 2008
), our data suggest that several brain regions known to display depression-related abnormalities could also be modulated by the BDNF Val66
Met polymorphism. The hippocampus, BA25, and mPFC have been shown to exhibit abnormal depression-related variations, including hyperperfusion in BA25 in chronic/treatment resistant patients (Mayberg 1994
; Drevets et al. 1997
; Mayberg 2005
), hyperactivation of hippocampus to emotional stimuli (Lau et al. 2010), and hyperrecruitment of PFC when down-regulating amygdala responses to negative stimuli (Johnstone et al. 2007
). Our finding of increased resting regional cerebral blood flow in these same regions in healthy Met carriers without clinical depression mirrors this systems-level pathological phenotype and suggests that inefficient BDNF protein processing may translate to limbic functional changes that could have importance in illness states. On the other hand, abnormally increased subgenual cingulate and default network functional connectivity observed in depressed patients (Greicius et al. 2007
) was manifested differently in Met carriers in our study, suggesting that the confluence of BDNF genotype effects and depression pathophysiology is intricate and requires further investigation.
There are several caveats that warrant mention regarding the present work. First, we were unable to document menstrual cycle phase on all women in the study, which prevents the investigation of the effect of this important variable in our data. Future research including such hormonally-related parameters will provide crucial information. Second, even though our study controlled for age, race, sex and past psychiatric illness, genes interact with many factors including early life stress, hormones, and the environment to influence the underlying neurobiology of the intermediate phenotype. Although our sample size is adequate, these factors could contribute variance to findings in the present study. In addition, resting state by definition implies unrestricted thought process, and variation in the content of the thought process or in the response to the scanning session may be affected by genotype and these effects also may interact with sex and other personality related features. Such experiential variability could be reflected in our rCBF results.
In conclusion, our data identify in healthy individuals BDNF genotype-determined differences in basal resting activity and interregional activity relationships within medial frontotemporal nodes important in neuropsychiatric illnesses such as depression. The fact that sex differences in these measures in these regions are modulated by BDNF genotype serves as an important impetus to further examine BDNF-gonadal hormone interactions on resting network dynamics in both healthy individuals and patients with major depression.