 |
The Journal of Neuroscience, July 30, 2003, 23(17):6690-6694
 Previous Article | Next Article 
BRIEF COMMUNICATION
Brain-Derived Neurotrophic Factor val66met Polymorphism Affects Human Memory-Related Hippocampal Activity and Predicts Memory Performance
Ahmad R. Hariri,
Terry E. Goldberg, *
Venkata S. Mattay, *
Bhaskar S. Kolachana,
Joseph H. Callicott,
Michael F. Egan, and
Daniel R. Weinberger
Clinical Brain Disorders Branch, Intramural Research Program, National
Institute of Mental Health, National Institutes of Health, United States
Department of Health and Human Services, Bethesda, Maryland 20892
 |
Abstract
|
|---|
BDNF plays a critical role in activity-dependent neuroplasticity underlying
learning and memory in the hippocampus. A frequent single nucleotide
polymorphism in the targeting region of the human BDNF gene
(val66met) has been associated with abnormal intracellular
trafficking and regulated secretion of BDNF in cultured hippocampal neurons
transfected with the met allele. In addition, the met allele has been
associated with abnormal hippocampal neuronal function as well as impaired
episodic memory in human subjects, but a direct effect of BDNF alleles on
hippocampal processing of memory has not been demonstrated. We studied the
relationship of the BDNF val66met genotype and hippocampal activity
during episodic memory processing using blood oxygenation level-dependent
functional magnetic resonance imaging and a declarative memory task in healthy
individuals. Met carriers exhibited relatively diminished hippocampal
engagement in comparison with val homozygotes during both encoding and
retrieval processes. Remarkably, the interaction between the BDNF
val66met genotype and the hippocampal response during encoding
accounted for 25% of the total variation in recognition memory performance.
These data implicate a specific genetic mechanism for substantial normal
variation in human declarative memory and suggest that the basic effects of
BDNF signaling on hippocampal function in experimental animals are important
in humans.
Key words: BDNF; hippocampus; human memory; gene; polymorphism; BOLD fMRI
|
Introduction
|
|---|
The molecular cascades governing the development and maturation of the CNS
are highly conserved in adult organisms and contribute to complex experiential
phenomena such as activity-dependent synaptic plasticity. A notable example is
the neurotrophin BDNF, which not only regulates cell survival, proliferation,
and synaptic growth in the developing CNS but also is a critical element in
modulating synaptic changes, such as hippocampal long-term potentiation (LTP),
associated with learning and adaptive behaviors in adult animals
(Poo, 2001 ;
Tyler et al., 2002). Thus,
genetic and environmental influences on BDNF activity may contribute to
alterations in hippocampal function and, subsequently, hippocampal-dependent
learning and memory.
A frequent polymorphism producing a nonconservative amino acid substitution
(valine to methionine) at codon 66 (val66met) has recently been
identified in the human BDNF gene (dbSNP number rs6265). This sequence variant
is located in the 5' pro-BDNF sequence, which encodes the precursor
peptide (pro-BDNF) that is proteolytically cleaved to form the mature protein
(Seidah et al., 1996). Whereas
this BDNF polymorphism does not affect mature BDNF protein function, it has
recently been shown to dramatically alter the intracellular trafficking and
packaging of pro-BDNF and, thus, the regulated secretion of the mature
peptide. Specifically, rat hippocampal neurons transfected with the met allele
exhibit abnormal intracellular trafficking and regulated secretion of BDNF in
comparison with those transfected with the val allele
(Egan et al., 2003). In healthy
human subjects, the met allele is linked with diminished levels of hippocampal
N-acetyl aspartate, a putative marker of neuronal integrity and
synaptic abundance, and deficits in episodic memory
(Egan et al., 2003). These
findings suggest that genetically driven variation in BDNF secretion may
significantly impact human hippocampal function and memory. However, the
impact of this BDNF polymorphism on memory-related hippocampal activity has
not been determined.
To directly assay the contribution of the BDNF val66met
polymorphism to memory-related hippocampal activity, we studied healthy
volunteers with blood oxygenation level-dependent functional magnetic
resonance imaging (BOLD fMRI) while they performed a simple declarative memory
task known to be dependent on the hippocampal formation
(Gabrieli et al., 1998;
Schacter and Wagner, 1999).
The memory task involved the encoding and subsequent retrieval of complex,
novel scenes. On the basis of the basic evidence that BDNF is important for
memory-related hippocampal processes and the effect of the val66met
polymorphism on BDNF secretion, we hypothesized that individuals homozygous
for the val allele (val/val genotype), the variant associated with normal
intracellular trafficking of BDNF and better episodic memory, would exhibit
greater memory-related hippocampal activity than those carrying the met allele
(val/met, met/met genotypes). We also predicted that these genotype-based
differences would impact memory performance, with val homozygote individuals
demonstrating better recognition accuracy than met carriers.
|
Materials and Methods
|
|---|
Subjects. Sixty-four right-handed healthy subjects participated in
this study according to the guidelines of the National Institute of Mental
Health Institutional Review Board. Subjects were recruited from local
advertisements and underwent extensive clinical examinations involving
structured medical and psychiatric history questionnaires, neurocognitive test
batteries, and diagnostic MRI scanning to rule out structural brain
disease.
From this initial cohort, 28 subjects were selected who comprised two equal
groups based on BDNF val 66met genotype (Val group, 14 val/val
individuals; Met group, 12 val/met and two met/met individuals). Because of
the population frequency of the met allele ( 0.19 in subjects of European
ancestry), few met/met individuals are available (i.e., <4%) and, thus, we
combined val/met and met/met genotypes. All subjects, except for one val/val
homozygote (an African-American female) and two met carriers (an
Asian-American female and male), were of European ancestry.
Importantly, the genotype groups were carefully matched for gender (six
females and eight males in each group), age (mean ± SEM; Val group,
30.9 ± 1.3 years; Met group, 30.3 ± 1.6 years;
F(1,26) = 0.09; p = 0.76), and mean intelligence
quotient (IQ) (mean ± SEM; Val group, 110.7 ± 1.5; Met group,
108.1 ± 2.1; F(1,26) = 1.04; p = 0.32).
All 28 subjects were also cleared of neurological, psychiatric, or substance
abuse problems and had no history of other medical problems or medical
treatment relevant to cerebral metabolism and blood flow. Thus, the potential
for these various confounding factors to obscure the contribution of BDNF
genetic variation to memory performance and hippocampal activity was
minimized.
Furthermore, all subjects underwent genotyping of the apolipoprotein (APO)
E gene  alleles, because the 4 allele has a dose-dependent effect
on risk and age of onset for Alzheimer's disease
(Corder et al., 1993) as well
as an impact on memory-related brain activity in healthy, elderly subjects
(Bookheimer et al., 2000).
There was no significant difference in 4 allele frequency between our
two BDNF groups (Val group, four 4 allele carriers; Met group, three
4 allele carriers).
Genotyping. DNA was extracted using standard methods. BDNF val
66met and APO genotypes were determined using the Taqman
5'-exonuclease allelic discrimination assay
(Corder et al., 1993). Data
from a larger sample of subjects (Egan et
al., 2003) has revealed that the frequencies of the BDNF val
allele is 0.81 and that the genotype frequencies (val/val, 0.67; val/met,
0.28; met/met, 0.05) are in Hardy-Weinberg equilibrium.
Declarative memory paradigm. The fMRI paradigm consisted of the
encoding and subsequent retrieval of novel, complex scenes, a task that has
consistently been shown to produce activation of the hippocampal formation in
human neuroimaging experiments (Stern et
al., 1996; Gabrieli et al.,
1997; Zeineh et al.,
2000). Stimuli were presented in a blocked paradigm to maximize
power and sensitivity for BOLD signal change in the hippocampal region
(Birn et al., 2002). Four
encoding blocks were followed by four retrieval blocks in an interleaved
design with a passive rest condition, resulting in a total of 17 blocks. Each
block was 20 sec long, producing a total scan time of 5 hr, 40 min. During
encoding blocks, subjects viewed six images, presented serially for 3 sec
each, and determined whether each image represented an "indoor" or
"outdoor" scene. An equal number of "indoor" and
"outdoor" scenes were presented in each encoding block. All scenes
were of neutral emotional valence and were derived from the International
Affective Picture System (Lang et al.,
1997). During subsequent retrieval blocks, subjects again viewed
six images, presented serially for 3 sec each, and determined whether each
scene was "new" or "old." In each retrieval block,
half the scenes were "old" (i.e., presented during the encoding
blocks) and half were "new" (i.e., not presented during the
encoding blocks). The order of "indoor" and "outdoor"
scenes as well as "new" and "old" scenes were randomly
distributed throughout the encoding and retrieval blocks, respectively. During
the interleaved rest blocks, subjects were instructed to fixate on a centrally
presented cross-hair. Before the beginning of each block, subjects viewed a
brief (2 sec) instruction: "Indoor or Outdoor?," "New or
Old?," or "Rest." During scanning, all subjects responded by
button presses with their dominant hand, allowing for the determination of
accuracy and reaction time.
fMRI acquisition parameters. Each subject was scanned using a GE
Signa 3T scanner with a real-time functional imaging upgrade (General
Electric, Milwaukee, WI). An automated shim procedure was applied to minimize
possible magnetic field inhomogeneities. BOLD functional images were acquired
with a gradient echo planar imaging (EPI) sequence and covered 24 axial slices
(4 mm thick, 1 mm gap) that began at the cerebral vertex and encompassed the
entire cerebrum and the majority of the cerebellum (repetition time/echo time,
2000/28 msec; field of view, 24 cm; matrix, 64 x 64). All scanning
parameters were selected to optimize the quality of the BOLD signal while
maintaining a sufficient number of slices to acquire whole-brain data. Before
the collection of fMRI data for each subject, we acquired a reference EPI scan
and visually inspected it for artifacts (i.e., ghosting) as well as for good
signal across the entire volume of acquisition, including the medial temporal
lobes. The fMRI data from all 28 subjects included in this study were cleared
of such problems.
Image analysis. Analysis of the fMRI data were completed using
statistical parametric mapping (SPM99;
http://www.fil.ion.ucl.ac.uk/spm).
Images for each subject were realigned to the first volume in the time series
to correct for head motion, spatially normalized into a standard stereotactic
space (Montreal Neurological Institute template) using a 12 parameter affine
model and smoothed to minimize noise and residual differences in gyral anatomy
with a Gaussian filter, set at 8 mm full-width at half-maximum. Voxel-wise
signal intensities were ratio normalized to the whole-brain global mean.
Predetermined condition effects at each voxel within an anatomically
defined region of interest that included the bilateral hippocampi and
parahippocampal cortices (Giedd et al.,
1996) were calculated using a t-statistic, producing a statistical
image for the contrasts of encoding versus rest and retrieval versus rest for
each subject. These individual contrast images were then used in second-level
random effects models, which account for both scan-to-scan and
subject-to-subject variability, to determine task-specific regional responses
at the group level for the entire sample (main effects of task) and paired
t tests (direct comparisons between groups). Because of our strong
a priori hypothesis regarding the differential response of the
hippocampus and our use of a rigorous random effects statistical model, a
statistical threshold of p < 0.05, with a small volume correction
for multiple comparisons, was used to identify significant responses for all
comparisons.
Whole-brain image analyses for all predetermined condition effects were
also calculated using second-level random effects models. Because we did not
have a priori hypotheses regarding the activity of brain regions
outside of the hippocampal formation, we used a statistical threshold of
p < 0.05, corrected for multiple comparisons across all
supra-threshold voxels, for these whole-brain comparisons.
Regression analysis. We examined the relationship between BDNF
genotype, mean BOLD responses in the hippocampus, and memory performance
(i.e., recognition accuracy) using a hierarchical multiple regression in which
variables are entered (or removed) from the linear equation on the basis of
their ability to improve R2 at each successive step in the
model (PROC REG MAXR; SAS Institute, Inc., Cary, NC). Mean BOLD percentage
signal change for all 28 subjects was extracted from both the left and right
hippocampal clusters that demonstrated a significant main effect for encoding
and for retrieval (Fig. 1).
Importantly, these clusters were selected in an unbiased manner (i.e., they
were not chosen on the basis of their sensitivity to either BDNF genotype or
a priori correlation with performance). In addition to BDNF genotype
and mean BOLD signal changes, we created interaction terms representing the
potential contribution of BDNF genotype to left and right hippocampal activity
during both encoding and retrieval (e.g., BDNF genotype x left hippocampal
encoding activity). Gender and IQ were also entered as variables.
View larger version (60K):
[in this window]
[in a new window]
|
Figure 1. Statistical parametric maps showing significant engagement of the
hippocampal formation (hippocampus and parahippocampal gyrus) during encoding
and retrieval. BOLD fMRI responses in the posterior hippocampal formation are
shown overlaid onto averaged structural MRIs in the axial, coronal, and
sagittal plane. Blue cross-hairs are centered on the left hippocampal
formation clusters during encoding and retrieval that contributed maximally to
the observed variance in memory performance (see Regression analysis in
Materials and Methods). a, Talairach coordinates and voxel-level
statistics for the maximal voxel in the left and right hippocampal formation
during encoding are x =-25 mm; y =-44 mm; z = -10 mm; cluster size = 42
voxels; voxel-level corrected p < 0.001; Z score = 5.59;
and x = 22 mm; y = -48 mm; z = -10 mm; cluster size = 60 voxels; voxel-level
corrected p < 0.001; Z score = 7.24, respectively.
b, Talairach coordinates and voxel-level statistics for the maximal
voxel in the left and right HF during retrieval are x = -25 mm; y = -44 mm; z
= -10 mm; cluster size = 36 voxels; voxel-level corrected p <
0.001; Z score = 6.32; and x = 22 mm; y =-48 mm; z = -10 mm; cluster
size = 64 voxels; voxel-level corrected p < 0.001; Z
score = 7.08, respectively.
|
|
|
Results
|
|---|
Consistent with prior reports (Gabrieli
et al., 1998; Schacter and
Wagner, 1999), we found significant bilateral activation of the
posterior hippocampal formation (hippocampus and parahippocampal gyrus) during
both encoding and retrieval in all subjects
(Fig. 1). In addition, both
encoding and retrieval were associated with significant bilateral activations
in the inferotemporal, parietal, and frontal cortices, a distributed network
critical for visuospatial information processing
(Ungerleider and Haxby, 1994).
A conjunction analysis revealed a significant degree of overlap in both
hippocampal and cortical clusters during encoding and retrieval, a finding
consistent with a conservancy of circuits underlying the initial formation and
subsequent recall of specific episodic information
(Persson and Nyberg, 2000).
The posterior localization of the observed hippocampal activity may reflect
the visual nature of the stimuli used and the processing of this information
within object-sensitive fusiform and parahippocampal regions
(Ungerleider and Haxby, 1994)
and adjacent, interconnected hippocampal structures
(Small et al., 2001).
As hypothesized, direct group comparisons revealed that memory-related
hippocampal activity was greater, during both encoding and retrieval, in
subjects homozygous for the BDNF val allele, the relatively normal functional
variant (Fig. 2). The BDNF
val66met polymorphism, however, had no impact on activity within
the distributed cortical network (e.g., inferotemporal, parietal and frontal
locales) involved with general visuospatial information processing. The
specificity of this BDNF effect on hippocampal activity is consistent with the
expression pattern of BDNF in the brain, which is highest in the hippocampus
(Murer et al., 2001), as well
as the critical role of BDNF in hippocampal processes, particularly
activity-dependent synaptic plasticity, mediating learning and memory
(Poo, 2001;
Tyler et al., 2002).
View larger version (80K):
[in this window]
[in a new window]
|
Figure 2. Genotype-based parametric comparisons showing significantly greater
hippocampal activity in the Val group versus the Met group during both
encoding and retrieval. BOLD fMRI responses in the posterior hippocampal
formation are shown overlaid onto averaged structural MRIs in the coronal and
sagittal plane. a, Talairach coordinates and voxel-level statistics
for the maximal voxels in the right hippocampus and parahippocampal gyrus
exhibiting Val greater than Met activity during encoding: x = 30 mm; y =-19
mm; z = -12 mm; cluster size = 5 voxels; voxel-level corrected p =
0.047; Z score = 1.91; and x = 22 mm; y = -44 mm; z = -6 mm; cluster
size = 6 voxels; voxel-level corrected p = 0.043; Z score =
1.97, respectively. b, Talairach coordinates and voxel-level
statistics for the maximal voxels in the left and right parahippocampal gyrus
exhibiting Val greater than Met activity during retrieval: x = -30 mm; y = -44
mm; z = -2 mm; cluster size = 3 voxels; voxel-level corrected p =
0.046; Z score = 1.87; and x = 22 mm; y =-48 mm; z = -6 mm; cluster
size = 7 voxels; voxel-level corrected p = 0.035; Z score =
2.45, respectively.
|
|
In addition to the effect of the BDNF val66met polymorphism on
memory-related hippocampal activity, and consistent with the prior finding of
impaired episodic memory in met carriers
(Egan et al., 2003), val
homozygotes in the present study were significantly more accurate at
recognizing both "new" and "old" (i.e., encoded)
scenes during retrieval (percentage correct ± SEM; Val group, 91.6
± 1.5; Met group, 84.5 ± 2.6; F(1,26) =
5.69; p = 0.02). The increased number of recognition errors in met
carriers was equally distributed across misses (i.e., not recognizing encoded
scenes as "old") and false alarms (i.e., recognizing novel scenes
as "old"). Importantly, this difference in memory performance did
not simply reflect the differential ability of subjects from each group to
accurately encode these stimuli, because there was no difference in encoding
accuracy between groups (percentage correct ± SEM; Val group, 94.9
± 0.6; Met group, 93.2 ± 1.2; F(1,26) =
1.71; p > 0.20). Furthermore, the absence of systematic group
differences in reaction time during either encoding (msec ± SEM; Val
group, 1316.4 ± 44.9; Met group,1314.5 ± 56.8;
F(1,26) = 0.001; p = 0.98) or retrieval (msec
± SEM; Val group, 1554.1 ± 43.5; Met group, 1613.33 ±
41.5; F(1,26) = 0.97; p = 0.33) suggests that the
observed disparity in memory performance is unlikely to be driven by
differential attention during the tasks.
We used a modified hierarchical stepwise regression analysis to explore the
relationship between the observed influence of the BDNF val66met
polymorphism on memory-related hippocampal activity and recognition accuracy.
This approach allows for the unbiased determination of the contribution of
independent variables as well as the interaction of specific variables to the
observed variation in memory performance. Only two variables entered the model
significantly as determined by scree inspection and "F to enter":
the interaction term of BDNF val66met genotype and mean left
hippocampal activity during encoding (F(1,26) = 9.44;
R2 = 0.25; p = 0.005), and mean left hippocampal
activity during retrieval (F(1,26) = 4.99;
R2 = 0.04; p = 0.035). Together, 30% of the
total variation in recognition memory performance was accounted for by these
two variables. It is striking that an interaction term reflecting BDNF
genotype modulation of hippocampal engagement during the encoding of novel
scenes accounted for the majority of the explained variance (25%), followed
only by simple activation of the hippocampus during recognition itself.
|
Discussion
|
|---|
The results of this study have several important implications. First,
unbiased selection of hippocampal regions engaged during encoding or retrieval
proved to be significant predictors of behavioral variance. Thus, hippocampal
activity across individuals, as measured by BOLD fMRI, could be linked
directly with memory performance, although the magnitude of the effect is
relatively small. This finding is consistent with earlier reports
(Gabrieli et al., 1998;
Schacter and Wagner, 1999).
Second, the finding that the interaction of BDNF genotype and hippocampal
activity during encoding accounts for a substantial proportion of the
behavioral variance during retrieval (25%) suggests that BDNF modulation of
hippocampal engagement is a key process in the initial acquisition of
information and is consistent with the known role of BDNF in
activity-dependent plasticity and hippocampal LTP, processes that are thought
to underlie the formation of new learning and memory
(Poo, 2001;
Tyler et al., 2002). Third,
the contribution of hippocampal activity during retrieval to variation in
memory performance was not modulated by BDNF, suggesting that accurate
judgments about recognition may, in part, reflect the simple engagement of
hippocampal subregions. However, this retrieval-related activity also seems to
be a less robust predictor of performance than BDNF-modulated hippocampal
activity during encoding. Our finding of a preeminent contribution of
BDNF-modulated hippocampal activity during encoding to subsequent memory
performance is consistent with studies indicating that the strength of the
hippocampal trace during encoding is the most robust predictor of subsequent
memory accuracy (Wagner et al.,
1999; Fell et al.,
2001). Finally, our data highlight a laterality effect during the
information processing associated with our paradigm, because hippocampal
activity in the left hemisphere, during both encoding and retrieval, was the
predictor of performance. This effect suggests that scenes from the real world
that undergo further semantic encoding (during "indoor" or
"outdoor" judgments) and that engage the left hippocampal
formation as a consequence are subsequently better remembered.
These results suggest that the BDNF val66met polymorphism has a
dramatic and regionally specific impact on memory-related brain activity that
may contribute significantly to human variation in normal memory ability
(Wechsler, 1997). This effect
may be mediated through alterations in activity-dependent hippocampal
processes requiring BDNF-regulated secretion. Specifically, it is conceivable
that the abnormal intracellular trafficking and regulated secretion of BDNF in
met carriers may result in impaired hippocampal LTP or analogous synaptic
events that may underlie encoding, reflected in their relatively diminished
hippocampal BOLD fMRI responses, and a subsequently weakened hippocampal
trace. The poorer recall and recognition of previously encoded items in these
same met carriers may, thus, reflect the weakness of this initial trace.
Alternatively, given the importance of BDNF in neuronal survival and synaptic
proliferation, our observed BDNF effect on memory-related hippocampal activity
and recognition accuracy may reflect abnormalities in met carriers in the
development of the extended brain circuitry, centered on the hippocampus,
which is critical for mediating consolidation of episodic information.
Additional studies are needed to determine the contribution of these and
potentially other mechanisms to the observed modulation of memory-related
hippocampal activity and memory performance by the BDNF val66met
polymorphism.
Our data implicate a genetic mechanism for variation in normal human
declarative memory. A common functional polymorphism in the gene encoding
BDNF, a protein critical for hippocampal synaptic plasticity involved in
learning and memory in lower animals, has a significant impact on the activity
of the human hippocampus during declarative memory processing. In turn, this
BDNF-driven variation in hippocampal activity strongly predicts how accurately
information is remembered. The BDNF val66met polymorphism may
impact on the expression of human conditions that affect hippocampal function
(e.g., aging, trauma, degenerative disease), and BDNF signaling may be a
propitious target for interventions to enhance declarative memory. More
generally, our current findings along with those of other recent studies
(Bookheimer et al., 2000;
Egan et al., 2001;
Hariri et al., 2002),
highlight the potential of functional neuroimaging as an approach for
exploring the biological impact of genetic variation on information processing
within distinct brain regions and circuits in relatively small samples of
healthy subjects (Hariri and Weinberger,
2003).
|
Footnotes
|
|---|
Received Apr. 21, 2003;
revised May. 28, 2003;
accepted May. 29, 2003.
This study was supported by the National Institute of Mental Health
Intramural Research Program. We thank A. Gopal, K. Munoz, S. Sust, and D.
Goldsmith for technical assistance.
Correspondence should be addressed to Dr. Daniel R. Weinberger, Clinical
Brain Disorders Branch, National Institute of Mental Health, 10 Center Drive,
Room 4S235, Bethesda, MD 20892-1384. E-mail:
weinberd{at}intra.nimh.nih.gov.
Copyright © 2003 Society for Neuroscience
0270-6474/03/236690-05$15.00/0
* T.E.G. and V.S.M. contributed equally to this work. 
|
References
|
|---|
Birn RM, Cox RW, Bandettini PA (2002) Detection versus
estimation in event-related fMRI: choosing the optimal stimulus timing.
NeuroImage 15:
252-264.[Web of Science][Medline]
Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance
MA, Mazziotta JC, Small GW (2000) Patterns of brain activation in
people at risk for Alzheimer's disease. N Engl J Med
343: 450-456.[Abstract/Free Full Text]
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC,
Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose
of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late
onset families. Science 261:
921-923.[Abstract/Free Full Text]
Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM,
Straub RE, Goldman D, Weinberger DR (2001) Effect of COMT
Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.
Proc Natl Acad Sci USA 98:
6917-6922.[Abstract/Free Full Text]
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS,
Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR
(2003) The BDNF val 66met polymorphism affects
activity-dependent secretion of BDNF and human memory and hippocampal
function. Cell 112:
257-269.[Web of Science][Medline]
Fell J, Klaver P, Lehnertz K, Grunwald T, Schaller C, Elger CE,
Fernandez G (2001) Human memory formation is accompanied by
rhinalhippocampal coupling and decoupling. Nat Neurosci
4: 1259-1264.[Web of Science][Medline]
Gabrieli JD, Brewer JB, Desmond JE, Glover GH (1997)
Separate neural bases of two fundamental memory processes in the human medial
temporal lobe. Science 276:
264-266.[Abstract/Free Full Text]
Gabrieli JDE, Brewer JB, Poldrack RA (1998) Images of
medial temporal lobe functions in human learning and memory. Neurobiol
Learn Mem 70:
275-283.[Web of Science][Medline]
Giedd JN, Vaituzis AC, Hamburger SD, Lange N, Rajapakse JC, Kaysen
D, Vauss YC, Rapoport JL (1996) Quantitative MRI of the temporal
lobe, amygdala, and hippocampus in normal human development: ages 4-18 years.
J Comp Neurol 366:
223-230.[Web of Science][Medline]
Hariri AR, Weinberger DR (2003) Imaging genomics.
Br Med Bull 65:
237-248.
Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D,
Egan MF, Weinberger DR (2002) Serotonin transporter genetic
variation and the response of the human amygdala. Science
297: 400-403.[Abstract/Free Full Text]
Lang PJ, Bradley MM, Cuthbert BN (1997)
International Affective Picture System (IAPS): technical manual and
affective ratings. NIMH Center for the Study of Emotion and Attention,
University of Florida, Gainesville, FL.
Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived
neurotrophic factor in the control human brain, and in Alzheimer's disease and
Parkinson's disease. Prog Neurobiol 63:
71-124.[Web of Science][Medline]
Persson J, Nyberg L (2000) Conjunction analysis of
cortical activations common to encoding and retrieval. Microsc Res
Tech 51:
39-44.[Web of Science][Medline]
Poo MM (2001) Neurotrophins as synaptic modulators.
Nat Rev Neurosci 2:
24-32.[Web of Science][Medline]
Schacter DL, Wagner AD (1999) Perspectives:
neuroscience. Remembrance of things past. Science
285: 1503-1504.[Free Full Text]
Seidah NG, Benjannet S, Pareek S, Chretien M, Murphy RA
(1996) Cellular processing of the neurotrophin precursors of NT3
and BDNF by the mammalian proprotein convertases. FEBS Lett
379: 247-250.[Web of Science][Medline]
Small SA, Nava AS, Perera GM, DeLaPaz R, Mayeux R, Stern Y
(2001) Circuit mechanisms underlying memory encoding and
retrieval in the long axis of the hippocampal formation. Nat
Neurosci 4:
442-449.[Web of Science][Medline]
Stern CE, Corkin S, Gonzalez RG, Guimaraes AR, Baker JR, Jennings
PJ, Carr CA, Sugiura RM, Vedantham V, Rosen BR (1996) The
hippocampal formation participates in novel picture encoding: evidence from
functional magnetic resonance imaging. Proc Natl Acad Sci USA
93: 8660-8665.[Abstract/Free Full Text]
Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002)
From acquisition to consolidation: on the role of brain-derived neurotrophic
factor signaling in hippocampal-dependent learning. Learn Mem
9: 224-237.[Abstract/Free Full Text]
Ungerleider LG, Haxby JV (1994) 'What' and 'where' in
the human brain. Curr Opin Neurobiol 4:
157-165.[Medline]
Wagner AD, Koutstaal W, Schacter DL (1999) When
encoding yields remembering: insights from event-related neuroimaging.
Philos Trans R Soc Lond B Biol Sci 354:
1307-1324.[Abstract/Free Full Text]
Wechsler D (1997) Wechsler memory
scale, Ed 3. San Antonio: The Psychological Corporation.
Zeineh MM, Engel SA, Bookheimer SY (2000) Application
of cortical unfolding techniques to functional MRI of the human hippocampal
region. NeuroImage 11:
668-683.[Web of Science][Medline]
This article has been cited by other articles:
|
|
|
|
 
A. C. Need, D. K. Attix, J. M. McEvoy, E. T. Cirulli, K. L. Linney, P. Hunt, D. Ge, E. L. Heinzen, J. M. Maia, K. V. Shianna, et al.
A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB
Hum. Mol. Genet.,
December 1, 2009;
18(23):
4650 - 4661.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. McHughen, P. F. Rodriguez, J. A. Kleim, E. D. Kleim, L. M. Crespo, V. Procaccio, and S. C. Cramer
BDNF Val66Met Polymorphism Influences Motor System Function in the Human Brain
Cereb Cortex,
September 10, 2009;
(2009)
bhp189v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Woollett, H. J. Spiers, and E. A. Maguire
Talent in the taxi: a model system for exploring expertise
Phil Trans R Soc B,
May 27, 2009;
364(1522):
1407 - 1416.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Yu, Y. Wang, S. Pattwell, D. Jing, T. Liu, Y. Zhang, K. G. Bath, F. S. Lee, and Z.-Y. Chen
Variant BDNF Val66Met Polymorphism Affects Extinction of Conditioned Aversive Memory
J. Neurosci.,
April 1, 2009;
29(13):
4056 - 4064.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Greenwood, M.-K. Lin, R. Sundararajan, K. J. Fryxell, and R. Parasuraman
Synergistic effects of genetic variation in nicotinic and muscarinic receptors on visual attention but not working memory
PNAS,
March 3, 2009;
106(9):
3633 - 3638.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Lane, S. R. Waldstein, M. A. Chesney, J. R. Jennings, W. R. Lovallo, P. J. Kozel, R. M. Rose, D. A. Drossman, N. Schneiderman, J. F. Thayer, et al.
The Rebirth of Neuroscience in Psychosomatic Medicine, Part I: Historical Context, Methods, and Relevant Basic Science
Psychosom Med,
February 1, 2009;
71(2):
117 - 134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Bertolino, L. Fazio, A. Di Giorgio, G. Blasi, R. Romano, P. Taurisano, G. Caforio, L. Sinibaldi, G. Ursini, T. Popolizio, et al.
Genetically Determined Interaction between the Dopamine Transporter and the D2 Receptor on Prefronto-Striatal Activity and Volume in Humans
J. Neurosci.,
January 28, 2009;
29(4):
1224 - 1234.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Carim-Todd, K. G. Bath, G. Fulgenzi, S. Yanpallewar, D. Jing, C. A. Barrick, J. Becker, H. Buckley, S. G. Dorsey, F. S. Lee, et al.
Endogenous Truncated TrkB.T1 Receptor Regulates Neuronal Complexity and TrkB Kinase Receptor Function In Vivo
J. Neurosci.,
January 21, 2009;
29(3):
678 - 685.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Cramer
A window into the molecular basis of human brain plasticity
J. Physiol.,
December 1, 2008;
586(23):
5601 - 5601.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Cheeran, P. Talelli, F. Mori, G. Koch, A. Suppa, M. Edwards, H. Houlden, K. Bhatia, R. Greenwood, and J. C. Rothwell
A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS
J. Physiol.,
December 1, 2008;
586(23):
5717 - 5725.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Osada, Y. Adachi, H. M Kimura, and Y. Miyashita
Towards understanding of the cortical network underlying associative memory
Phil Trans R Soc B,
June 27, 2008;
363(1500):
2187 - 2199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Nectoux, N. Bahi-Buisson, I. Guellec, J. Coste, N. D. Roux, H. Rosas, M. Tardieu, J. Chelly, and T. Bienvenu
The p.Val66Met polymorphism in the BDNF gene protects against early seizures in Rett syndrome
Neurology,
May 27, 2008;
70(22_Part_2):
2145 - 2151.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Petrella, V. S. Mattay, and P. M. Doraiswamy
Imaging Genetics of Brain Longevity and Mental Wellness: The Next Frontier?
Radiology,
January 1, 2008;
246(1):
20 - 32.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B.-C. Ho, N. C. Andreasen, J. D. Dawson, and T. H. Wassink
Association Between Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism and Progressive Brain Volume Changes in Schizophrenia
Am J Psychiatry,
December 1, 2007;
164(12):
1890 - 1899.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Zivadinov, B. Weinstock-Guttman, R. Benedict, M. Tamano-Blanco, S. Hussein, N. Abdelrahman, J. Durfee, and M. Ramanathan
Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor
Hum. Mol. Genet.,
November 15, 2007;
16(22):
2659 - 2668.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Siironen, S. Juvela, K. Kanarek, J. Vilkki, J. Hernesniemi, and J. Lappalainen
The Met Allele of the BDNF Val66Met Polymorphism Predicts Poor Outcome Among Survivors of Aneurysmal Subarachnoid Hemorrhage
Stroke,
October 1, 2007;
38(10):
2858 - 2860.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. D. Bohbot, J. Lerch, B. Thorndycraft, G. Iaria, and A. P. Zijdenbos
Gray Matter Differences Correlate with Spontaneous Strategies in a Human Virtual Navigation Task
J. Neurosci.,
September 19, 2007;
27(38):
10078 - 10083.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. S. McEwen
Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain
Physiol Rev,
July 1, 2007;
87(3):
873 - 904.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Ize-Ludlow, J. A. Gray, M. A. Sperling, E. M. Berry-Kravis, J. M. Milunsky, I. S. Farooqi, C. M. Rand, and D. E. Weese-Mayer
Rapid-Onset Obesity With Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Presenting in Childhood
Pediatrics,
July 1, 2007;
120(1):
e179 - e188.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Frodl, C. Schule, G. Schmitt, C. Born, T. Baghai, P. Zill, R. Bottlender, R. Rupprecht, B. Bondy, M. Reiser, et al.
Association of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism With Reduced Hippocampal Volumes in Major Depression
Arch Gen Psychiatry,
April 1, 2007;
64(4):
410 - 416.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Miskowiak, U. O'Sullivan, and C. J. Harmer
Erythropoietin Enhances Hippocampal Response during Memory Retrieval in Humans
J. Neurosci.,
March 14, 2007;
27(11):
2788 - 2792.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R Huang, J Huang, H Cathcart, S Smith, and S E Poduslo
Genetic variants in brain-derived neurotrophic factor associated with Alzheimer's disease
J. Med. Genet.,
February 1, 2007;
44(2):
e66 - e66.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Magby, C. Bi, Z.-Y. Chen, F. S. Lee, and M. R. Plummer
Single-Cell Characterization of Retrograde Signaling by Brain-Derived Neurotrophic Factor
J. Neurosci.,
December 27, 2006;
26(52):
13531 - 13536.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. del Toro, J. M. Canals, S. Gines, M. Kojima, G. Egea, and J. Alberch
Mutant huntingtin Impairs the Post-Golgi Trafficking of Brain-Derived Neurotrophic Factor But Not Its Val66Met Polymorphism
J. Neurosci.,
December 6, 2006;
26(49):
12748 - 12757.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-Y. Chen, D. Jing, K. G. Bath, A. Ieraci, T. Khan, C.-J. Siao, D. G. Herrera, M. Toth, C. Yang, B. S. McEwen, et al.
Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior.
Science,
October 6, 2006;
314(5796):
140 - 143.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G Oroszi, L Lapteva, E Davis, C H Yarboro, T Weickert, T Roebuck-Spencer, J Bleiberg, D Rosenstein, M Pao, P E Lipsky, et al.
The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus
Ann Rheum Dis,
October 1, 2006;
65(10):
1330 - 1335.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. F Reichardt
Neurotrophin-regulated signalling pathways
Phil Trans R Soc B,
September 29, 2006;
361(1473):
1545 - 1564.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Meyer-Lindenberg, J. W. Buckholtz, B. Kolachana, A. R. Hariri, L. Pezawas, G. Blasi, A. Wabnitz, R. Honea, B. Verchinski, J. H. Callicott, et al.
Neural Mechanisms of Genetic Risk for Impulsivity and Violence in Humans
Focus,
August 1, 2006;
4(3):
360.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B.-C. Ho, P. Milev, D. S. O'Leary, A. Librant, N. C. Andreasen, and T. H. Wassink
Cognitive and Magnetic Resonance Imaging Brain Morphometric Correlates of Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism in Patients With Schizophrenia and Healthy Volunteers.
Arch Gen Psychiatry,
July 1, 2006;
63(7):
731 - 740.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lind, J. Persson, M. Ingvar, A. Larsson, M. Cruts, C. Van Broeckhoven, R. Adolfsson, L. Backman, L.-G. Nilsson, K. M. Petersson, et al.
Reduced functional brain activity response in cognitively intact apolipoprotein E {varepsilon}4 carriers
Brain,
May 1, 2006;
129(5):
1240 - 1248.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Meyer-Lindenberg, J. W. Buckholtz, B. Kolachana, A. R. Hariri, L. Pezawas, G. Blasi, A. Wabnitz, R. Honea, B. Verchinski, J. H. Callicott, et al.
From the Cover: Neural mechanisms of genetic risk for impulsivity and violence in humans
PNAS,
April 18, 2006;
103(16):
6269 - 6274.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Vaynman and F. Gomez-Pinilla
License to Run: Exercise Impacts Functional Plasticity in the Intact and Injured Central Nervous System by Using Neurotrophins
Neurorehabil Neural Repair,
December 1, 2005;
19(4):
283 - 295.
[Abstract]
[PDF]
|
|
|
|
|
|
|
L. M. Rattiner, M. Davis, and K. J. Ressler
Brain-Derived Neurotrophic Factor in Amygdala-Dependent Learning
Neuroscientist,
August 1, 2005;
11(4):
323 - 333.
[Abstract]
[PDF]
|
|
|
|
|
|
|
Z.-Y. Chen, A. Ieraci, H. Teng, H. Dall, C.-X. Meng, D. G. Herrera, A. Nykjaer, B. L. Hempstead, and F. S. Lee
Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway
J. Neurosci.,
June 29, 2005;
25(26):
6156 - 6166.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Callicott, R. E. Straub, L. Pezawas, M. F. Egan, V. S. Mattay, A. R. Hariri, B. A. Verchinski, A. Meyer-Lindenberg, R. Balkissoon, B. Kolachana, et al.
Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia
PNAS,
June 14, 2005;
102(24):
8627 - 8632.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. K. Teng, K. K. Teng, R. Lee, S. Wright, S. Tevar, R. D. Almeida, P. Kermani, R. Torkin, Z.-Y. Chen, F. S. Lee, et al.
ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin
J. Neurosci.,
June 1, 2005;
25(22):
5455 - 5463.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Pezawas, B. A. Verchinski, V. S. Mattay, J. H. Callicott, B. S. Kolachana, R. E. Straub, M. F. Egan, A. Meyer-Lindenberg, and D. R. Weinberger
The Brain-Derived Neurotrophic Factor val66met Polymorphism and Variation in Human Cortical Morphology
J. Neurosci.,
November 10, 2004;
24(45):
10099 - 10102.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. J. Heyer, D. Echeverria, A. C. Bittner Jr., F. M. Farin, C. C. Garabedian, and J. S. Woods
Chronic Low-Level Mercury Exposure, BDNF Polymorphism, and Associations with Self-Reported Symptoms and Mood
Toxicol. Sci.,
October 1, 2004;
81(2):
354 - 363.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. F. Egan, R. E. Straub, T. E. Goldberg, I. Yakub, J. H. Callicott, A. R. Hariri, V. S. Mattay, A. Bertolino, T. M. Hyde, C. Shannon-Weickert, et al.
Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia
PNAS,
August 24, 2004;
101(34):
12604 - 12609.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-Y. Chen, P. D. Patel, G. Sant, C.-X. Meng, K. K. Teng, B. L. Hempstead, and F. S. Lee
Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons
J. Neurosci.,
May 5, 2004;
24(18):
4401 - 4411.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
The Neuroscientist Comments
Neuroscientist,
February 1, 2004;
10(1):
7 - 9.
[PDF]
|
|
|
|
|
|
|
P. M. Greenwood and R. Parasuraman
Normal Genetic Variation, Cognition, and Aging
Behav Cogn Neurosci Rev,
December 1, 2003;
2(4):
278 - 306.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. Alder, S. Thakker-Varia, D. A. Bangasser, M. Kuroiwa, M. R. Plummer, T. J. Shors, and I. B. Black
Brain-Derived Neurotrophic Factor-Induced Gene Expression Reveals Novel Actions of VGF in Hippocampal Synaptic Plasticity
J. Neurosci.,
November 26, 2003;
23(34):
10800 - 10808.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction
