The brain-derived neurotrophic factor Val66Met polymorphism affects memory formation and retrieval of biologically salient stimuli

NeuroImage 50 (2010) 1212–1218

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The brain-derived neurotrophic factor Val66Met polymorphism affects memory formation and retrieval of biologically salient stimuli Guido van Wingen a,b,c,⁎, Mark Rijpkema a, Barbara Franke a,b,d, Philip van Eijndhoven b, Indira Tendolkar a,b, Robbert Jan Verkes a,b, Jan Buitelaar a,b, Guillén Fernández a,c a

Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Kapittelweg 29, 6525 EN Nijmegen, The Netherlands Radboud University Nijmegen Medical Centre, Department of Psychiatry, Reinier Postlaan 10, 6525 GC Nijmegen, The Netherlands Radboud University Nijmegen Medical Centre, Department of Neurology, Reinier Postlaan 4, 6525 GC Nijmegen, The Netherlands d Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Department of Human Genetics, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands b c

a r t i c l e

i n f o

Article history: Received 17 August 2009 Revised 12 January 2010 Accepted 15 January 2010 Available online 22 January 2010

a b s t r a c t Brain-derived neurotrophic factor (BDNF) is involved in memory and the pathophysiology of various neuropsychiatric disorders. A single nucleotide polymorphism in the human BDNF gene (Val66Met) affects memory, and influences Alzheimer's disease and depression vulnerability in a sex-specific manner. Recent animal studies suggest that BDNF mediates memory for emotional experiences in the amygdala, but it is currently unknown whether BDNF Val66Met influences memory processing in the amygdala. Here, we investigated its effect on the successful encoding and recognition of biologically salient stimuli. Forty-seven healthy volunteers memorized and recognized faces while their brain activity was measured with eventrelated functional MRI. No significant differences in memory performance were observed between Val homozygotes and Met allele carriers. The imaging results demonstrated BDNF genotype × sex interactions in the amygdala during memory formation, and in the prefrontal cortex and posterior cingulate cortex during memory retrieval. Subsequent tests showed a larger contribution of these brain regions to successful encoding and retrieval in male Met allele carriers than male Val homozygotes, whereas no significant differences were observed in females. These results provide preliminary evidence that the BDNF Val66Met polymorphism influences specific mnemonic operations underlying encoding and retrieval of salient stimuli, and suggest less efficient memory processing in male Met allele carriers. Furthermore, the sex-specific genotype effects may contribute to sex-specific effects of BDNF Val66Met on depression vulnerability. © 2010 Elsevier Inc. All rights reserved.

Introduction Brain-derived neurotrophic factor (BDNF) has an important role in learning and memory (Bekinschtein et al., 2008a; Lu et al., 2008). It regulates activity-dependent synaptic plasticity and appears necessary for short- and long-term memory storage (Alonso et al., 2002; Bekinschtein et al., 2008b). A common single nucleotide polymorphism (SNP) in the human BDNF gene (Val66Met; rs6265), leading to a valine (Val) to methionine (Met) substitution in the prodomain of the encoded protein, decreases its activity-dependent secretion (Chen et al., 2004; Egan et al., 2003). Consistent with the key roles of BDNF and the hippocampus in long-term memory, healthy human carriers of the Met allele have smaller hippocampal volumes (Bueller et al., 2006; Pezawas et al., 2004; Szeszko et al., 2005) (but see Joffe et al., ⁎ Corresponding author. Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Fax: +31 24 3610989. E-mail address: [email protected] (G. van Wingen). 1053-8119/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2010.01.058

2009), show reduced hippocampal activity during memory encoding and retrieval (Hariri et al., 2003; Hashimoto et al., 2008), and demonstrate poorer memory performance (Dempster et al., 2005; Egan et al., 2003; Goldberg et al., 2008; Hariri et al., 2003). Besides the role of BDNF in memory, this neurotrophin and its Val66Met polymorphism are also implicated in various neuropsychiatric disorders (Angelucci et al., 2005; Duman et al., 1997; Hwang et al., 2006; Momose et al., 2002; Murer et al., 2001; Neves-Pereira et al., 2005; Neves-Pereira et al., 2002; Phillips et al., 1991; Thome et al., 1998; Ventriglia et al., 2002). Although genetic association studies with the Val66Met polymorphism have produced inconsistent results, recent meta-analyses have demonstrated significant associations. However, the risk allele is not the same for all disorders (Gratacos et al., 2007), and may appear different from the risk allele as identified by animal models. For example, BDNF Met mutant mice demonstrate increased anxiety behaviors, whereas humans homozygous for the Val allele have higher neuroticism scores which is an anxiety-related personality trait (Chen et al., 2006; Frustaci et al., 2008). Furthermore, BDNF Val66Met appears to have sex-specific effects in Alzheimer's

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disease (AD) and depression. Whereas the Met allele increases the risk for AD in women, it increases the risk for depression in males (Fukumoto et al., 2010; Verhagen et al., in press). Although BDNF Val66Met has been associated with both memory and neuropsychiatric disorders, the relation between its influence on memory and those disorders remains unclear. One underlying neural mechanism could be its effect on the hippocampus. However, this polymorphism affects hippocampal volume in depressed and schizophrenic patients to a similar extent as in healthy individuals (Frodl et al., 2007; Ho et al., 2006). Another potential link is the amygdala, a brain structure important for emotional memory (LaBar and Cabeza, 2006). Whereas most BDNF studies have focused on the hippocampus, recent animal studies have shown that BDNF also mediates amygdaladependent fear conditioning (Ou and Gean, 2006; Rattiner et al., 2004). Functioning of the amygdala and its structure is altered in several psychiatric disorders and AD (Cuenod et al., 1993; Mori et al., 1999; Phillips et al., 2003; Rauch et al., 2003), and it is more engaged in the successful encoding of faces in depressed patients than in healthy individuals (Roberson-Nay et al., 2006). Taken together, these studies suggest that the BDNF Val66Met polymorphism may affect memory processing in the amygdala, which could represent a vulnerability factor for disorders that include amygdala dysfunction. In the current study, we used face stimuli and event-related functional magnetic resonance imaging (fMRI) to investigate whether the BDNF Val66Met polymorphism influences memory processing in the amygdala in healthy volunteers. Faces are biologically salient stimuli, and the perception of faces with negative, neutral, as well as positive expressions elicits amygdala activity (Fitzgerald et al., 2006). Importantly, the amygdala is involved in the successful encoding and retrieval of faces (Sergerie et al., 2006; van Wingen et al., 2007). By using event-related fMRI, neural responses to specific stimuli can be sorted post hoc according to whether they are remembered or not, and can thereby reveal specific successful encoding and retrieval processes. Materials and methods Participants Genetic and neuroimaging data of 47 right-handed volunteers of self-reported Dutch Caucasian ancestry were obtained (mean age 38 years; range: 18–53). The participants were screened using a self-report questionnaire for the following exclusion criteria: a history of somatic disease potentially affecting the brain, current or past psychiatric or neurological disorder, medication (except hormonal contraceptives) or illicit drug use during the past 6 months, history of substance abuse, current or past alcohol dependence, pregnancy, lactation, menopause, and MRI contraindications. They were recruited for two independent studies (van Wingen et al., 2008a; van Wingen et al., in press), in which the same stimuli and experimental design were used. Twenty-five women and 7 men were homozygous for the Val allele (68%), and 9 women and 6 men were carrier of at least one Met allele (32%; one woman was homozygous for the Met allele). There were no significant differences in age or educational level between the four sex-specific genotype groups (Fs b 1). Furthermore, because the 5-HTTLPR polymorphism is associated with individual differences in amygdala reactivity (Munafò et al., 2008), we tested whether there was an incidental unequal distribution of short allele carriers among the sex-specific genotype groups, but no significant difference was observed (χ(3) = 4.1, p = 0.25). All procedures were approved by the local ethics committee (CMO Regio Arnhem-Nijmegen, The Netherlands), and the volunteers gave written informed consent prior to participation. Face memory paradigm The experiment consisted of study-test cycles during which the participants were requested to memorize and subsequently recognize

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face pictures (van Wingen et al., 2007). During the study phase, the participants were instructed to memorize pictures of male and female faces, while indicating the gender of the stimulus by a button press. During the subsequent test phase, they were instructed to recognize these pictures among randomly intermixed new pictures, and made an old, new, or unsure decision which they indicated by a button press. The participants completed two (N = 11), three (N = 21), or four (N = 15) study-test cycles during scanning. Within each study-test cycle, each study phase was immediately followed by the respective test phase. There was no significant difference in the number of cycles between the four sex-specific genotype groups (F(3,43) = 1.6, NS). The stimuli consisted of faces with a neutral to mildly happy emotional expression and with direct gaze direction. They were derived from different stimulus sets (Ekman and Friesen, 1976) (The Karolinska directed emotional faces, D. Lundqvist, A. Flykt, and A. Öhman, 1998, Department of Clinical Neuroscience, Karolinska Institute, Sweden; The AR face database, A. Martinez and R. Benavente, 1998, Computer Vision Center, Purdue University, IN) and the Internet. All photos were edited to produce oval grayscale pictures that showed the face from chin to forehead and excluded the ears. The 960 stimuli were divided over eight study-test blocks of 120 faces each, that did not differ in the amount of features (50% male, 24% wearing glasses, 6% with facial hair, and 4% non-Caucasian; χ2(21) = 1.5, NS). Only two to four of the eight blocks were used per participant. In addition, half of the stimuli per block were used as study items, and half as distractors during test. The allocation of specific stimulus blocks and whether the stimuli were used as study or distractor items was counterbalanced across participants. The stimuli were pseudo-randomly intermixed with 10 null events (2 s) per study phase and per test phase, such that there were no more than four consecutive presentations per gender or old/new status of the stimulus. The faces were presented for 0.8 s with an interstimulus interval of 3.3–4.3 s, during both the study and test phase. Recognition memory performance was assessed using signal detection theory (Snodgrass and Corwin, 1988). The discrimination index d′ was calculated as measure for the classification accuracy of old/new decisions, and was based on hit and false alarm rates after exclusion of unsure responses. Behavioral data were analyzed with BDNF genotype (ValVal vs. Met carrier) and sex (male vs. female) as factors and age as covariate. MRI data acquisition Magnetic resonance imaging (MRI) data were acquired with a 1.5 T Siemens (Erlangen, Germany) Sonata MR scanner, equipped with a standard head coil. T2⁎-weighted blood oxygenation leveldependent (BOLD) images were acquired using echo-planar imaging (EPI) in ascending order, with each image volume consisting of 33 axial slices (3 mm, 0.5 mm slice-gap, TR = 2.290 s, TE = 30 ms, 64 × 64 matrix, FOV = 224 mm, FA = 90°). In addition, a high resolution T1weighted structural MR image was acquired for spatial normalization procedures (3D MP-RAGE, TR = 2250 ms, TE = 3.93 ms, TI = 850 ms, 176 contiguous 1 mm slices, 256 × 256 matrix, FOV = 256 mm, FA = 15°). fMRI data analysis Image analysis was performed with SPM5 (Wellcome Department of Imaging Neuroscience, London, UK). The first five EPI-volumes were discarded to allow for T1 equilibration, and the remaining images were realigned to the first volume. Images were then coregistered to the anatomical scan, corrected for differences in slice acquisition time, spatially normalized to the Montreal Neurological Institute (MNI) T1 template, resampled into 2 × 2 × 2 mm3 voxels, and spatially smoothed with a Gaussian kernel of 8 mm FWHM.

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Statistical analysis was performed within the framework of the general linear model. Later remembered and later forgotten stimuli were separately modeled for the study phase, as were hits, misses, correct rejections, and false alarms for the test phase. Stimuli with an incorrect gender decision or omission during the study phase, or with an unsure response or omission during test phase, were included in a condition of no interest, to ensure that all stimuli included into the contrasts of interest were attended. The explanatory variables (0.8 s) and null events (2 s) were temporally convolved with the canonical hemodynamic response function of SPM5. In addition, the realignment parameters were included to model potential movement artifacts, as was a high-pass filter (cut-off at 1/128 Hz). The data were proportionally scaled to account for various global effects, and temporal autocorrelation was modeled with an AR(1) process. Parameter images contrasting (subsequent) hit and (subsequent) miss conditions were entered in a BDNF genotype × sex ANOVA with nonsphericity correction. Statistical tests were family-wise error rate corrected for multiple comparisons across the entire brain or for regions of interest using a small volume correction (SVC) (Worsley et al., 1996). Search volumes for the amygdala, hippocampus, and left inferior frontal gyrus (Brodmann area 44) were based on probabilistic cytoarchitectonic maps (Amunts et al., 2005, 1999; Eickhoff et al., 2005). In addition, a search volume for a region involved in face memory retrieval in the posterior cingulate cortex was defined as a sphere with 10 mm radius around a previously reported coordinate (van Wingen et al., 2008a). Genotyping Genetic analyses were carried out at the Department of Human Genetics of the Radboud University Nijmegen Medical Centre, in a laboratory which has a quality certification according to CCKL criteria. High molecular weight DNA was isolated from saliva using Oragene containers (DNA Genotek, Ottawa, Ontario, Canada) according to the protocol supplied by the manufacturer. The BDNF 198-GNA (rs6265) polymorphism (Val66Met) was genotyped using Taqman® analysis (assay ID: Taqman assay: C_11592758_10; reporter 1: VIC-C-allele, reverse assay; Applied Biosystems, Nieuwerkerk a/d IJssel, The Netherlands). Genotyping was carried out in a volume of 10 μl containing 10 ng of genomic DNA, 5 μl of Taqman Mastermix (2×; Applied Biosytems), 0.375 μl of the Taqman assay and 3.625 μl of H2O. Genotyping was performed on a 7500 Fast Real-Time PCR System and genotypes were scored using the algorithm and software supplied by the manufacturer (Applied Biosystems). The genotyping assay had been validated before use and 5% duplicates and blanks were taken along as quality controls during genotyping. Testing for Hardy– Weinberg equilibrium did not show deviations from the expected distribution.

Table 1 Behavioral performance for BDNF Val homozygotes and BDNF Met allele carriers. BDNF ValVal Male

BDNF Met Female

Male

Female

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Encoding Accuracy (%) RT

93.8 1051

2.5 273

93.9 1091

2.5 235

93.8 1360

2.4 427

93.8 1011

3.2 263

Recognition Accuracy (d′) RT hits RT misses RT correct rejections RT false alarms

0.98 1320 1567 1519 1421

0.40 253 333 336 279

0.80 1363 1580 1503 1430

0.31 232 275 233 256

0.93 1502 1770 1640 1620

0.23 314 364 348 357

0.79 1207 1331 1300 1254

0.32 321 389 338 329

RT = reaction time in milliseconds.

significant differences in decision latencies were observed across memory categories (main effect of genotype: F b 1; main effect of sex: F(1,42) = 3.4, p = 0.07; genotype × sex interaction: F(1,42) = 3.4, p = 0.07). These results suggest that neural effects of BDNF genotype are unlikely explained by mere differences in memory performance, or other cognitive factors such as attention or effort. Imaging results Memory encoding The brain regions involved in the successful encoding of faces were identified by comparing responses to subsequently remembered and subsequently forgotten items across BDNF genotype and sex groups. This analysis showed that regions in the amygdala, hippocampus, inferior and middle frontal gyri, inferior and superior parietal lobules, insula, and precentral gyrus were generally involved in memory formation (p b 0.001, cluster ≥20 voxels; see Table 2). However, a BDNF genotype × sex interaction demonstrated significant differences in memory formation between groups in the amygdala, indicating a larger BDNF genotype effect in males than females (left: [−22, − 6, − 30], Z = 3.7, p SVC = 0.037; right: [24, − 6, − 28], Z = 3.9, pSVC = 0.018). Subsequent analyses showed a larger contribution of the amygdala to memory formation in male Met allele carriers than male Val homozygotes (left: [−24, − 8, −6], Z = 3.5, pSVC = 0.060; see Fig. 1), whereas no significant difference between genotype groups was observed in women (pSVC = 0.24). Recognition memory The brain regions involved in the successful retrieval of faces were identified by comparing responses to remembered and forgotten items across BDNF genotype and sex groups. This analysis showed that regions in the inferior, middle, and superior frontal gyri, middle

Results Behavioral performance

Table 2 Main effect of successful memory encoding (i.e., subsequent hits − subsequent misses). MNI coordinates

The behavioral data are presented in Table 1. The participants were requested to make a gender decision during memory encoding. No significant differences between BDNF ValVal and Met allele carriers were observed in gender classification accuracy (main effect and interactions: Fs b 1), or response times (main effect of genotype: F (1,42) = 1.7, p = 0.2; main effect of sex: F(1,42) = 3.0, p = 0.1; genotype × sex interaction: F(1,42) = 3.3, p = 0.08). Furthermore, no significant differences in memory performance between groups were observed (recognition accuracy (d′); main effect sex: F(1,42) = 2.1, p = 0.2; other Fs b 1). Response times for memory decisions were fastest for hits and slowest for misses (hits b false alarms b correct rejections b misses; F(3,40) = 4.1, p = 0.01), but no significant interactions with genotype were observed (Fs b 1). Furthermore, no

L superior parietal lobule R inferior frontal gyrus R inferior parietal lobule R middle frontal gyrus L insula L amygdalaa L precentral gyrus L inferior frontal gyrus R amygdalaa R hippocampusa

x

y

z

− 30 54 38 20 − 46 − 22 − 24 −44 16 38

− 66 26 − 42 26 −6 −8 − 26 24 −4 − 18

50 24 48 18 0 − 16 52 22 − 20 − 14

Cluster size

Z

551 45 39 33 26 106 51 49 25 −

5.0 4.8 3.9 3.9 3.8 3.7 3.6 3.6 3.7 3.7

pSVC

0.04

0.04 0.05

Data are reported in MNI coordinates for local maxima of significant clusters at p b 0.001, uncorrected with a cluster size ≥ 20 voxels; cluster size in number of voxels. a Data from the search volume for the region of interest.

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Fig. 1. The BDNF Val66Met polymorphism affects successful memory encoding of faces in the amygdala in a sex-dependent manner. The left panel shows the BDNF genotype × sex interaction, and the middle panel shows the larger contribution to memory formation in male Met allele carriers than male Val homozygotes at the peak of the interaction (y = − 6). No significant genotype differences were observed in females. The statistical comparisons were corrected for multiple comparisons (pSVC b 0.05) and the figures display the effects at p b 0.005, uncorrected, for visualization. The right panel shows the mean (± SEM) difference between subsequent hits and subsequent misses across the region of interest for males (M) and females (F) separately in arbitrary units.

and posterior cingulate cortices, caudate nucleus, putamen, precentral gyurs, cuneus, precuneus, cerebellum, and orbitofrontal cortex were generally involved in memory retrieval (p b 0.001, cluster ≥20 voxels; see Table 3). A BDNF genotype × sex interaction demonstrated significant differences in successful memory retrieval between groups in the left inferior frontal gyrus ([−54, 16, 26], Z = 3.6, pSVC = 0.041) and the posterior cingulate cortex ([− 8, − 42, 38], Z = 3.4, pSVC = 0.042), indicating a larger BDNF genotype effect in males than females. Subsequent analyses showed a larger contribution of the left inferior frontal gyrus ([− 54, 14, 28], Z = 3.9, pSVC = 0.019) and posterior cingulate cortex ([− 8, − 42, 38], Z = 4.4, pSVC = 0.001) to successful memory retrieval in male Met allele carrier than male Val homozygotes (see Fig. 2), but no significant differences between genotype groups in females (left inferior frontal gyrus: pSVC = 0.10; posterior cingulate cortex: pSVC = 0.52). Discussion The results of this study provide preliminary evidence that the BDNF Val66Met polymorphism affects memory formation of biologically salient stimuli in the amygdala and the successful retrieval of those stimuli in the prefrontal cortex and posterior cingulate cortex in a sex-specific manner. Male Met allele carriers showed a larger contribution of these brain regions to successful memory encoding and retrieval than male Val homozygotes, whereas no significant genotype differences were observed in females. These results reveal that a variation in the human BDNF gene that affects its activitydependent secretion (Chen et al., 2004; Egan et al., 2003) modulates

Table 3 Main effect of successful memory retrieval (i.e., hits − misses). MNI coordinates

R precentral gyrus R inferior frontal gyrus R/L caudate nucleus L putamen L cuneus R caudate nucleus Middle cingulate cortex L middle frontal gyrus L superior frontal gyrus L posterior cingulate cortexa R precuneus L cerebellum L orbitofrontal cortex

x

y

z

24 42 6 − 30 − 10 28 0 − 32 − 20 − 10 4 − 14 − 28

− 22 36 6 − 14 − 72 0 − 30 18 22 − 44 − 56 − 42 34

56 14 −2 −2 26 30 28 52 52 38 40 − 32 − 14

Cluster size

Z

170 53 187 33 39 46 39 46 31 63 70 36 32

4.6 4.5 4.2 4.1 4.0 4.0 4.0 4.0 4.0 3.8 3.8 3.8 3.4

pSVC

0.010

Data are reported in MNI coordinates for local maxima of significant clusters at p b 0.001, uncorrected with a cluster size ≥20 voxels; cluster size in number of voxels. a Data from the search volume for the region of interest.

memory formation as well as retrieval in an event-related manner, and support the sex-dependent effects of BDNF Val66Met. The current study should be viewed in the light of some strengths and limitations. The main limitation is the relatively small sample of men and the small sample of BDNF Met allele carriers, which is due to the low minor allele frequency of the BDNF Val66Met polymorphism. However, the unequal group sizes did not bias the results because the used statistics are invariant to the cell frequencies. Nevertheless, our results should be considered preliminary until the results are replicated in an independent study. The main strengths of this study are the first application of event-related fMRI to investigate the effects of BDNF genotype on successful memory encoding and retrieval in humans, and its combination with biologically salient stimuli to reveal its influence on memory processing in the amygdala. The larger effects in male Met allele carriers compared to male Val homozygotes were accompanied by equal memory performance. The larger recruitment of neural resources involved in successful memory encoding and retrieval in male BDNF Met carriers suggests a reduction of neural efficiency, and may reflect a compensatory mechanism to maintain adequate memory performance. Reduced neural efficiency appears in line with the facilitatory role of BDNF in the induction of long-term potentiation (LTP) (Figurov et al., 1996; Patterson et al., 1996). Because the Met allele is associated with reduced activitydependent secretion (Chen et al., 2004; Egan et al., 2003), a larger neuronal population may be required to induce LTP. Moreover, the larger engagement of the prefrontal cortex indicates the recruitment of additional neural resources to exert more top–down control over retrieval processes (Miyashita, 2004; Simons and Spiers, 2003). Whereas our results show a larger increase in neural activity during successful encoding and retrieval in male Met allele carriers, previous human imaging studies reported decreased neural activity in Met allele carriers during memory encoding and retrieval regardless of memory success (Hariri et al., 2003; Hashimoto et al., 2008). Although the stimulus material and recruited brain regions also differed between these studies and ours, these differences are most likely explained by the use of different functional imaging designs. Whereas previous studies used blocked designs that measure a combination of phasic and tonic activity, we used an event-related design to measure phasic responses, which allowed us to dissociate neural responses to (later) remembered and forgotten items. The larger successful encoding and retrieval effects in Met allele carriers suggest that the reduced neural activity as measured with blocked designs may reflect a reduced neural recruitment to maintain an effective encoding or retrieval state (Donaldson et al., 2001; Otten et al., 2002). To investigate whether changes in memory formation and encoding state co-occur, future studies may employ mixed eventrelated and blocked designs enabling dissociation of successful memory formation from an encoding state (e.g., Otten et al., 2002).

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Fig. 2. The BDNF Val66Met polymorphism affects successful memory retrieval of faces in the left inferior frontal gyrus (A; z = 26) and posterior cingulate cortex (B; x = − 8) in a sexdependent manner. The left panels show the BDNF genotype × sex interaction, and the middle panels show the larger contribution to memory formation in male Met allele carriers than male Val homozygotes at the peak of the interaction. No significant genotype differences were observed in females. The statistical comparisons were corrected for multiple comparisons (pSVC b 0.05) and the figures display the effects at p b 0.005, uncorrected, for visualization. The right panels show the mean (± SEM) difference between hits and misses across the regions of interest for males (M) and females (F) separately in arbitrary units.

Another possibility is that Met allele carriers have a higher baseline activity during the control task or during rest, which could be investigated with an absolute measure of brain perfusion like arterial spin labeling or positron emission tomography (cf., Canli et al., 2005, 2006; Heinz et al., 2007; Rao et al., 2007). The results showed BDNF genotype effects during memory formation in the amygdala. This brain structure is mainly implicated in the relatively automatic facilitation of memory processes in other brain regions during memory encoding (Kensinger and Corkin, 2004; Kilpatrick and Cahill, 2003; McGaugh, 2004). During memory retrieval, BDNF genotype effects were observed in the prefrontal cortex and posterior cingulate cortex. The prefrontal cortex is thought support memory retrieval by exerting executive control over retrieval processes (Miyashita, 2004; Simons and Spiers, 2003). The posterior cingulate cortex is part of the default mode network that shows decreased activity when individuals focus on the external environment (Gusnard et al., 2001). However, it is recruited when individuals are engaged in internally focused tasks (Buckner et al., 2008), suggesting that the posterior cingulate cortex may shift attention to internally generated memory representations (Daselaar et al., 2009; Wagner et al., 2005). Surprisingly, no significant BDNF Val66Met effects were observed in the hippocampus, even though the hippocampus was involved in memory formation. In addition, no significant involvement of the hippocampus was observed during memory retrieval. Both negative effects may be explained by the used stimulus material and the recognition memory test procedure. Memory for faces is relatively preserved in patients with selective hippocampal lesions (Carlesimo et al., 2001), and we used a familiarity judgment during the recognition memory test which appears to be independent of the hippocampus (Yonelinas et al., 2002). This suggests that our experimental procedure was not optimal to detect hippocampal differences. Future studies may use more complex scenes or associative memory tasks and memory tests that target recollection rather than familiarity (Eichenbaum et al., 2007) to investigate the influence of BDNF Val66Met on successful memory encoding and retrieval in the hippocampus. The effects of BDNF Val66Met on memory processing were larger in men than women. Whereas the results showed significant genotype effects in males, we did not observe significant genotype

differences in females. One potential explanation is the lack of sufficient power to detect differences in women. However, it may also be explained by sex differences in the relative volumes of these brain structures (Goldstein et al., 2001), or by fluctuating gonadal steroid hormone levels during the female menstrual cycle (Berman et al., 1997; Goldstein et al., 2005; van Wingen et al., 2007, 2008b). In support of the latter possibility, BDNF plasma levels change across the menstrual cycle in humans (Begliuomini et al., 2007), and hippocampal BDNF mRNA levels change across the estrous cycle in rats (Gibbs, 1998). Moreover, BDNF appears to mediate estradiol's regulation of dendritic spine density in the hippocampus (Murphy et al., 1998). This regulation of BDNF action by cyclical hormone changes may reduce the effect of BDNF genotype in women. Alternatively, the effect of BDNF may be menstrual cycle phase dependent, or modulated by hormonal contraceptive use. However, these hormonal factors were not controlled in the current study. Future studies may investigate these possibilities, for example by investigating women during specific phases of the menstrual cycle. Polymorphisms in other genes have also been linked to amygdala activity and several neuropsychiatric disorders, in particular a polymorphism in the serotonin transporter linked polymorphic region (5-HTTLPR) that influences serotonin transporter expression and function (Caspi et al., 2003; Hariri et al., 2002; Munafò et al., 2008). Although this polymorphism affects amygdala reactivity, it does not appear to influence emotional memory (Strange et al., 2008). Nevertheless, we investigated whether variability in this gene influenced our results. We did not observe an incidental unequal distribution of short allele carriers among the sex-specific genotype groups. Furthermore, we corrected our results for the 5-HTTLPR genotype by including it in the statistical models as covariate, and observed a similar pattern of results as without the covariate (data not shown). Thus, our results are not influenced by variation in the serotonin transporter gene. The BDNF Val66Met polymorphism is associated with various neuropsychiatric disorders (Hwang et al., 2006; Neves-Pereira et al., 2005, 2002; Ventriglia et al., 2002). Analogous to the observations in the current study, this genotype also has sex-specific effects on the vulnerability to AD and depression. In contrast to our findings that the BDNF genotype mainly affects males, the Met allele increases the risk

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for AD in women (Fukumoto et al., 2010). This suggests that altered amygdala functioning is not strongly related to AD risk, but more studies are warranted to investigate this possibility further. In addition, future studies may investigate whether BDNF Val66Met influences hippocampal memory processes in women to a larger extent than in men. In line with our results, the Met allele increases the risk for depression sex-specifically in males (Verhagen et al., in press). Interestingly, depressed patients also show increased amygdala activity during the successful encoding of faces (Roberson-Nay et al., 2006). However, other research suggests that the Val allele may enhance the vulnerability to depression. For example, the Val allele appears to increase neuroticism (Frustaci et al., 2008), a personality trait that increases the risk for depression (Kendler et al., 2004; Ormel et al., 2004). Thus, further research is needed to clarify this apparent contradiction. Nevertheless, the parallel sex effect in our results and the risk for depression suggest that altered memory processing in the amygdala in male Met carriers may represent a vulnerability factor to depression. Acknowledgments This work was supported by a grant (918.66.613) from the Netherlands Organization for Scientific Research (NWO). We thank Sabine Kooijman, Sara Pieters and Staś Zylicz for assistance with data collection, Marlies Naber and Angelien Heister for genotyping, and Paul Gaalman for technical support. References Alonso, M., Vianna, M.R., Depino, A.M., Mello e Souza, T., Pereira, P., Szapiro, G., Viola, H., Pitossi, F., Izquierdo, I., Medina, J.H., 2002. BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation. Hippocampus 12, 551–560. Amunts, K., Kedo, O., Kindler, M., Pieperhoff, P., Mohlberg, H., Shah, N.J., Habel, U., Schneider, F., Zilles, K., 2005. 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