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Next Article 
The Journal of Neuroscience, December 1, 2002, 22(23):10067-10071
BRIEF COMMUNICATION
Experience-Dependent Coincident Expression of the Effector
Immediate-Early Genes Arc and Homer 1a in
Hippocampal and Neocortical Neuronal Networks
Almira
Vazdarjanova1,
Bruce L.
McNaughton1, 2,
Carol A.
Barnes1, 2,
Paul F.
Worley3, and
John F.
Guzowski1
1 Arizona Research Laboratories, Division of Neural
Systems, Memory and Aging, and 2 Departments of Psychology
and Neurology, University of Arizona, Tucson, Arizona 85724-5115, and
3 Departments of Neuroscience and Neurology, John Hopkins
University, Baltimore, Maryland 21218
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ABSTRACT |
The transcription of the immediate-early genes Arc
and Homer 1a (H1a) is dynamically
regulated in response to synaptic activity; their protein products
function at the postsynaptic sites of excitatory synapses. Previous
studies demonstrate a role for Arc in the maintenance of
long-term potentiation and in memory consolidation processes and
indicate a role for H1a in modifying glutamatergic
signaling pathways. Using double-label fluorescence in
situ hybridization, we demonstrate that Arc and
H1a RNA expression is induced strongly in the same
neurons of rat hippocampus and neocortex after exploration of a novel
environment. These findings support the view that novel experience
activates a cell-specific genomic program and that Arc
and H1a may function in concert in the structural and
functional modifications of dendrites that lead to long-term changes in
synaptic efficacy.
Key words:
memory; learning; transcription; hippocampus; cortex; immediate-early; gene; Arc; Homer 1; dendrite; plasticity
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INTRODUCTION |
Research over the past few years has
identified several proteins localized to the neuronal soma and
dendrites that are rapidly and dynamically regulated by synaptic
activity. These "effector" immediate-early genes (IEGs) have a
number of cellular functions capable of modifying synaptic function
(Lanahan and Worley, 1998 ). Two such effector IEGs are Arc
(activity regulated cytoskeletal-associated protein, also known as
Arg3.1) (Link et al., 1995; Lyford et al., 1995) and
Homer 1a (H1a) (Brakeman et al., 1997).
Arc mRNA and protein can be selectively targeted to active
regions of the dendritic arbor (Steward and Worley, 2001). Moreover,
disrupting Arc protein expression in the hippocampus impairs
the maintenance of long-term potentiation (LTP) and the consolidation
of memory for spatial experience (Guzowski et al., 2000).
H1a interacts with several proteins within the postsynaptic
density (PSD) and may play an important role in modifying glutamatergic
signaling pathways (Xiao et al., 2000).
As more is learned about the individual functions of different IEGs, it
is becoming increasingly important to determine which genes function in
concert, as part of the same plasticity mechanisms, within the same
neurons. Here, we use fluorescence in situ hybridization (FISH) to demonstrate that the transcription of Arc and
H1a is dramatically upregulated in the same hippocampal and
neocortical neurons of rats after exploration of a novel environment.
These findings raise the possibility that Arc and
H1a might function in concert as part of an
activity-dependent genomic program to induce and stabilize long-term
changes in synaptic efficacy in neural networks encoding memory for
specific experiences.
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MATERIALS AND METHODS |
Subjects, apparatus, and behavior. The subjects were
male Sprague Dawley rats (Harlan Sprague Dawley, Indianapolis,
IN), weighing 250-275 gm at arrival. Maximal electroconvulsive
shock (MECS) was induced using a constant-current generator (ECT unit;
Ugo Basile, Comerio, Italy) (Cole et al., 1990). For behavioral
experiments, the rats were handled daily for 1 week before training to
habituate them to the handling procedures. For the Arc/H1a
behavioral time course experiment (see Figs. 2, 3), each rat
(n = 3 per time point) sampled a novel environment for
5 min. The environment was a box divided into nine 400 cm2 grids surrounded by 30-cm-high walls.
The box was positioned on a table in a room with ambient lighting, thus
allowing the rats access to both local and distant visual cues. Each
rat was picked up and released into the center of a different grid
square every 15 sec, on a semirandom schedule. This procedure was used to ensure that the rats sampled the entire environment. At the end of
the 5 min session, the rat was returned to its home cage until it was
killed at the assigned time after exploration. Because rats have a
strong tendency to explore novel environments, the rats
(n = 6) used to establish the correlation between
Arc cytoplasmic and H1a intranuclear foci (INF)
staining (see Fig. 4) were allowed to explore freely for 6 min a novel
open box (61 × 61 cm with 24-cm-high sides), returned to their
cages in the colony room, and killed 26 min later. All rats explored
the novel environment completely, as evidenced by their multiple
crossings of each floor grid (data not shown).
FISH. After decapitation with a rodent guillotine, the
brains were removed rapidly, quick-frozen in isopentane (approximately  50°C), and then stored at 70°C until being sectioned on a
cryostat. Twenty-micrometer-thick sections were mounted on slides such
that all groups were represented on each slide. Digoxigenin- or
fluorescein-labeled riboprobes were generated using commercial
transcription kits (MaxiScript; Ambion, Austin, TX) and RNA labeling
mixes (Roche Products, Hertforshire, UK). The plasmid used to generate
the Arc antisense and sense riboprobes contained a
full-length cDNA (3.0 kbp) of the Arc transcript (Lyford et
al., 1995). The H1a antisense riboprobe was generated using
an H1a cDNA clone and was directed to the 4.4 kb 3'
untranslated region (UTR) of the H1a mRNA (Brakeman
et al., 1997). Single- or double-label FISH was performed as described
in detail previously (Guzowski et al., 1999; Guzowski and Worley, 2001;
Bottai et al., 2002). In Arc/H1a double-labeling studies,
digoxigenin-labeled Arc riboprobe was detected with
anti-digoxigenin-HRP (Roche Products) and a cyanine-3 substrate kit
(CY3 DirectFISH; PerkinElmer Life Sciences, Emeryville, CA).
After detection of the Arc riboprobe, the slides were
treated with 2% H2O2 to
quench residual HRP activity. Fluorescein-labeled H1a probe
was then detected with anti-fluorescein HRP (Roche Products) and a
cyanine-5 substrate kit (CY5 DirectFISH; PerkinElmer Life Sciences).
Nuclei were counterstained with either
4',6'-diamidino-2-phenylindole (DAPI; Vector Laboratories,
Burlingame, CA) (see Fig. 1) or YOYO-1 (quinolinium,1,1'-[1,3-propanediylbis [(dimethyliminio)-3,1-propanediyl]]bis[4-[(3-methyl-2(3H)-benzoxazolylidene)methyl]]-tetraiodide; Molecular Probes, Eugene, OR). The specificity of the labeling was
confirmed by two control conditions. Some slides were hybridized with
Arc and H1a sense riboprobes; on other slides the
riboprobe was omitted. For both control conditions, the remaining
detection steps were performed without modification from the standard procedure.
Image acquisition and analysis. Images were acquired using a
Leica (Nussloch, Germany) TCS-4D confocal microscope equipped with a
krypton-argon laser. Photomultiplier tube (PMT) assignments, pinhole size, and contrast values were kept constant for each brain
region within a slide. Depending on the required analysis, the settings
were adjusted to optimize either the appearance of cytoplasmic labeling
or that of INF (see Fig. 2a). Optimizing for INF was
achieved by increasing the offset of the PMT. Figure 2a,
iii, shows an image optimized for the appearance of
Arc cytoplasmic signal and H1a INF. Z-stacks of
either 1- or 2-µm-thick optical sections were acquired with either a
40× oil or 20× objective lens, respectively. Images for the
behavioral time course analysis of Arc and H1a
INF were collected at 20× magnification (one Z-stack per slide
in two different slides, totaling 104-170 cells per area per slide).
For the Arc/H1a correlation study (see Fig. 4), cell counts
for each rat varied between 79 and 124 for CA1, 43 and 54 for CA3, and
73 and 127 for the parietal cortex.
Only putative neurons were included in the analyses. Putative
glial-cell nuclei were identified based on their small size (~5 µm
in diameter) and bright, uniform nuclear counterstaining (see Fig.
2a, iii). Furthermore, these cells did not
express Arc or H1a, consistent with a previous
report that Arc was expressed predominantly, if not
exclusively, in excitatory neurons (Cirelli and Tononi, 2000). Z-stacks
were analyzed using MetaMorph software (Universal Imaging Corporation,
West Chester, PA). First, neuronal nuclei present in the median planes
(representing 20% of the stack thickness) were identified and
outlined. Then nuclei were characterized for the presence of
Arc and H1a INF (see Fig. 3) or Arc
cytoplasmic labeling and H1a INF (see Fig. 4). The results
were expressed as a percentage of the total neuronal nuclei analyzed
per stack. To prevent bias, the experimenter was unaware of the
relationship between the images and the behavioral conditions they
represented. The median planes criterion reduced the likelihood of
analyzing partial nuclei, which could yield false negative results.
This approach is essentially an optical dissector technique that
minimizes sampling errors attributable to partial cells and
stereological concerns, because variations in cell volumes do not
influence sampling frequencies (West, 1993).
Statistical analyses. The main effect of treatment (e.g.,
caged/exploration or time after the end of behavioral testing) was evaluated by ANOVA. When the main effect was significant at the  = 0.05 level, additional comparisons between groups were
conducted with Fisher post hoc tests (Statview software;
Statview, Berkeley, CA).
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RESULTS |
Previous characterization of Homer 1 transcriptional
regulation in mice demonstrated that the appearance of the Homer
1 RNA signal after MECS was dependent on the location of the
riboprobe along the primary transcript (Bottai et al., 2002). Here, we
examined the time course of the appearance of the signal from an
antisense riboprobe specific to the 3'UTR of rat H1a. This
probe distinguishes synaptic activity-dependent H1a
transcripts from the constitutive Homer 1 forms (Xiao et
al., 2000). These results were compared with those obtained using an
antisense riboprobe generated from the entire Arc cDNA. Rats
received MECS to activate IEG expression in the hippocampus and cortex.
As reported previously (Guzowski et al., 1999), the Arc RNA
signal was detected in INF in ~95% of the neurons (see Materials and
Methods) in the hippocampus (Fig. 1,
left) and the parietal cortex within 5 min of MECS. IEG INF
appear as either one or two (usually two) distinct areas of intense
fluorescent staining within neuronal nuclei (Fig. 1). INF indicate the
genomic sites of IEG RNA synthesis (Guzowski et al., 1999; Bottai et
al., 2002). By 30 min, the Arc signal was prominent in the
cytoplasm, and the proportion of INF-positive cells was similar to
baseline (Fig. 1, left). H1a RNA was also detected in most hippocampal (Fig. 1, right) and parietal
cortical neurons. However, H1a INF did not appear until 30 min after MECS (Fig. 1, right). The delayed appearance of
the H1a INF is explained by the relative position of the
3'UTR riboprobe along the primary transcript (~40 kb from the
transcript start site) (Bottai et al., 2002) and the limited elongation
rate of RNA polymerase II (~1.4 kb/min) (Femino et al., 1998). These
data show that with a strong stimulus, both Arc and
H1a can be induced in the majority of the hippocampal and
cortical neurons.
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Figure 1.
Distinct temporal profiles of Arc
and H1a RNA appearance in CA1 neurons after MECS. Rats
were killed at the indicated time (in minutes) after MECS.
Arc and H1a RNAs were detected with
digoxigenin-label antisense riboprobes as described in Materials and
Methods. IEG RNAs were detected with CY3 (red), and
nuclei were counterstained with DAPI (blue). Scale bar,
20 µm.
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Next, we examined the kinetics of Arc and H1a RNA
appearance after open field exploration (a behavior that induces
place-cell activity in hippocampal neurons). Rats were exposed to a
novel environment for 5 min and then killed at 0, 8, 16, 25, or 35 min after exploration (n = 3/group). Rats that were killed
after a delay were returned to their home cage in the colony room
between exploration and being killed. The brains were processed for
Arc and H1a double-label FISH, and confocal
images were acquired for qualitative (Fig.
2) or quantitative (Fig.
3) analysis. The dynamics of
Arc and H1a transcription were similar in the
hippocampal CA1 and CA3 regions and in the parietal cortex (Fig.
2b). In each region, the greatest proportion of
Arc INF-positive cells was seen in the group killed
immediately after exploration. Furthermore, the proportion of
Arc INF-positive cells returned to control levels within 16 min after exploration. In contrast, an increase in the proportion of
H1a INF-positive cells above control levels was not seen
until 25 min after exploration.
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Figure 2.
Dynamic appearance of Arc and
H1a INF in CA1, CA3, and parietal cortical neurons after
behavioral experience. a, Optimizing confocal microscope
settings for the detection of either Arc cytoplasmic RNA
labeling or Arc INF. i and
ii represent the same field imaged with different
confocal settings: i, Clear Arc
cytoplasmic RNA labeling is achieved when the PMT offset is low;
ii, unobstructed image of Arc INF is
achieved by increasing the PMT offset; iii, an image
optimized for detection of both Arc cytoplasmic labeling
(red) and H1a INF
(green). The white arrow points to
a putative glial cell nuclei. b, Rats were exposed to a
novel environment for 5 min and killed at the indicated time (in
minutes) after removal (n = 3/group). Double-label
FISH for Arc and H1a was performed on
coronal brain sections as described in Materials and Methods. In these
images, the confocal microscope settings were optimized for the
detection of INF; the Arc signal is indicated in
red, the H1a signal is indicated in
green, and nuclei are indicated in blue.
Note the predominance of the Arc INF at 0 min and
H1a INF at 25 min in each brain region. Par.
Cx, Parietal cortex. Scale bar, 50 µm.
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Figure 3.
Experience-dependent appearance of
Arc INF in CA1 neurons is rapid, transient, and does not
coincide in time with the delayed appearance of H1a INF.
Confocal Z-stacks of the CA1 region were collected from
Arc/H1a double-label slides from rats killed at
different delays after behavioral exploration (see Results and Fig. 2).
The percentage of counted nuclei positive for Arc
(a) or H1a
(b) INF is indicated for each time point. Note
that compared with the caged control group, the percentage of neurons
with Arc INF was significantly higher only in the 0 and
8 min groups, whereas the percentage of neurons with H1a
INF was significantly higher only in the 25 and 35 min groups.
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Quantitative analysis of Z-stacks from CA1 confirmed the above
observations for both Arc (Fig. 3a) and
H1a (Fig. 3b). For Arc cell counts,
there was a significant effect of time of death (overall ANOVA;
F(5,12) = 51.34; p < 0.0001), and post hoc comparisons revealed significant
differences between the caged and 0 min groups, caged and 8 min
groups, and 8 min and 16 min groups (p < 0.0001 for all three comparisons). The proportions of Arc
INF-positive cells in the 16, 25, and 35 min groups were not
statistically different from the caged group. In contrast, the
percentage of H1a INF-positive CA1 neurons was comparable
with that of caged controls until 25 min after exploration (Fig.
3b) (overall ANOVA; F(5,12) = 26.97; p < 0.0001). Post hoc comparisons
revealed significant differences between the caged and 25 min
groups and the caged and 35 min groups (p < 0.0001), whereas those between the caged and 0, 8, and 16 min groups
did not reveal a significant effect. In addition, the percentage of
H1a INF-positive neurons in the 25 min postexploration group
was significantly higher than that of the 16 min group
(p < 0.0001).
The finding that Arc and H1a were expressed in a
similar proportion of hippocampal and parietal cortical neurons of rats
that had explored a novel environment is consistent with the
idea that these genes might be dynamically regulated in the same
neurons. To test this possibility directly, the correspondence of
neurons containing Arc cytoplasmic labeling and
H1a INF in the hippocampus and cortex of caged control rats
was compared with rats that had explored a novel environment 30 min
before being killed. Neurons were scored as containing Arc
cytoplasmic labeling only, H1a INF only, or both
Arc cytoplasmic labeling and H1a INF (Fig.
2a, iii). In the hippocampus (CA1 and CA3
regions) and the parietal cortex of the rats from the exploration
group, the correspondence of Arc cytoplasmic labeling and
H1a INF was >90% (Fig. 4)
(95% for CA1, 94% for CA3, and 93% for the parietal cortex).
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Figure 4.
Exploration of a novel environment induces the
coincident expression of Arc and H1a in
single neurons of the rat hippocampus and parietal cortex. One group of
rats was exposed to a novel environment for 6 min, returned to their
home cages in the colony room for 26 min, and then killed (exploration
group; n = 6). A separate group of rats was killed
directly from their home cages (caged control group;
n = 3). Double-label FISH for Arc
and H1a was performed on coronal brain sections, and
image stacks were collected and analyzed from CA1, CA3, and parietal
cortical regions. The percentage of neurons in a respective brain
region expressing Arc cytoplasmic RNA staining only
(white bars), H1a INF only
(gray bars), or both (black bars)
is shown for rats from both groups. Note that the only staining class
population that changed with exploration (relative to the caged
controls) was the Arc cytoplasmic+/H1a
INF+ double-label class (black bars). Arc
cyto, Arc cytoplasmic.
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DISCUSSION |
The current findings demonstrate that transcription of the IEGs
Arc and H1a is dynamically regulated by
physiological activity in the same hippocampal and cortical neurons.
Double-label FISH revealed distinct temporal and spatial patterns of
Arc and H1a RNA appearance after MECS (Fig. 1)
and behavioral experience (Figs. 2-4). The highest proportion of
Arc INF-positive cells was observed in the rats killed
immediately after exploration (Figs. 2, 3), indicating rapid induction
of Arc transcription. This period of transcription is very
brief, because the proportion of Arc INF-positive cells
returned to control levels within 16 min after exploration, and
Arc mRNA was prominent within the cytoplasm by 30 min (Figs. 2-4) (Guzowski et al., 1999). In contrast, the proportion of
H1a INF-positive cells detected with the 3'UTR riboprobe did
not change until 25 min after exploration. At that time, the proportion
of H1a INF-positive cells was highest and was similar to
that of Arc INF-positive neurons from the rats killed
immediately after exploration (Figs. 2, 3). Double-label FISH performed
on brain sections of rats that had explored a novel environment 30 min before being killed revealed >90% correspondence of neurons positive for cytoplasmic Arc mRNA and H1a INF (Fig. 4).
Thus, with a discrete behavioral stimulus of known onset and limited
duration, transcriptional activation of Arc and
H1a is coincident in single neurons of the hippocampus and
parietal cortex.
The coincident transcription of Arc and H1a may
be regulated by the mitogen-activated protein kinase
(MAPK)/extracellular signal-regulated protein kinase (ERK) cascade. The
finding that a MAPK/ERK inhibitor blocked forskolin-induced
Arc transcription in cultured hippocampal neurons (Waltereit
et al., 2001) is consistent with this hypothesis. In addition,
pretreatment with MAPK kinase (MEK) inhibitors blocked LTP and
prevented increases in ERK2 and cAMP response element-binding protein
phosphorylation as well as increases in Arc RNA expression
caused by the local infusion of BDNF in the dentate gyrus of intact
rats (Ying et al., 2002). Similarly, MEK inhibitors blocked
glutamate-induced increases in H1a transcription in cultured
cerebellar granule cells (Sato et al., 2001). Thus, the coincident
transcription of Arc and H1a demonstrated here
could result from the activation of the MAPK/ERK pathway rather than
from the activation of separate, parallel pathways acting on the
promoters of these genes. However, it must be noted that although
Arc and H1a may use the same mechanisms for
transcriptional activation, H1a is subject to additional
levels of activity-dependent regulation, including the use of an
alternative transcription termination signal and conversion of an
intronic sequence (in constitutive forms) to an exonic sequence (in IEG forms) (Bottai et al., 2002).
The distinct temporal patterns of Arc and H1a INF
are explained by the different architectures of the transcription units for these genes (Arc mRNA is derived from a limited primary
transcript; ~3.5 kb with two small introns; GenBank accession number
AF177701), whereas H1a mRNA is derived from a primary
transcript spanning ~50 kb (Bottai et al., 2002). Thus, the time
course of appearance of H1a INF is dependent on the position
of the riboprobe along the primary transcript: Riboprobes to either
exon 1 or intron 1 of Homer 1 detect H1a INF with
induction kinetics indistinguishable from that of Arc
INF (Bottai et al., 2002), whereas those to the 3'UTR detect
H1a INF with much delayed kinetics (Figs. 1-4) (Bottai et
al., 2002).
The coincident expression of Arc and H1a seen
after experience (Fig. 4) and the temporally offset
appearance/disappearance of Arc and H1a INF (Fig.
3) enable an important modification of the cellular analysis of
temporal activity by FISH (catFISH) brain imaging method (Guzowski et
al., 1999, 2001). The power of catFISH is its ability to identify, at a
single-cell level, neuronal ensembles activated by two distinct
behavioral experiences within an animal, a property that distinguishes
catFISH from other imaging methods. In the original method,
Arc INF indicate cells active in the 5-10 min preceding
death, whereas the cytoplasmic Arc signal indicates cells
active ~30 min before death. Although catFISH has been used successfully to determine neural activity for two experiences (Guzowski
et al., 1999), quantifying the cytoplasmic IEG RNA signal can be
difficult when many cells are activated in a region with a high cell
density, such as the pyramidal cell layers of the hippocampus. However,
the combined use of Arc and 3'UTR H1a riboprobes in double-label FISH circumvents this problem by exploiting the transcription rate of RNA polymerase II (~1.4 kb/min) (Femino et al.,
1998) and the natural "genomic timers" of cellular activation afforded by the dissimilar gene structures of Arc and
H1a (Bottai et al., 2002). With this approach
(Arc/H1a catFISH), the activity history of many neurons can
be distinguished based solely on strong intranuclear signals:
Arc INF indicate cells activated by an experience shortly
before (<15 min) death, whereas H1a INF indicate cells activated at least 25 min earlier. The exclusive use of intranuclear signals greatly facilitates manual analysis and makes catFISH amenable
to computer automation for large-scale investigations of neural
population interactions during learning and memory.
Several lines of evidence suggest that both Arc and
H1a are involved in synaptic plasticity. First, the
expression of both genes is increased dramatically in the dentate gyrus
after the induction of perforant-path LTP (Link et al., 1995; Lyford et al., 1995; Brakeman et al., 1997) and in the insular cortex after the
LTP-inducing stimulation of the amygdala (Jones et al., 1999). Moreover, inhibiting hippocampal Arc protein expression
disrupts the maintenance of perforant-path LTP and impairs memory
consolidation (Guzowski et al., 2000). Biochemical evidence indicates
that Arc may be a component of NMDA receptor complexes
(Plath et al., 2001). The Homer 1 gene is alternatively
spliced from a large primary transcript to form two constitutively
expressed forms (Homer 1b and Homer 1c) and two
synaptic activity-regulated IEG forms (H1a and
ania3) (Xiao et al., 1998, 2000; Bottai et al., 2002). Homer 1b/c proteins are implicated in coupling group 1 metabotropic glutamate
receptors (mGluR) with IP3 and ryanodine
receptors and in coupling either of these intracellular receptors with
the NMDA receptor-associated PSD-95 complex (Xiao et al., 2000). It has been hypothesized that Homer 1 IEG forms, which lack the
C-terminal coiled-coil domain of the constitutive forms, act as natural
antagonists to Homer 1b/c forms to modify glutamatergic signaling
pathways (Xiao et al., 2000). Consistent with this hypothesis,
H1a transgene expression in Purkinje neurons alters
mGluR-induced Ca2+ release from
intracellular stores (Tu et al., 1998).
Arc transcription has been shown previously to be activated
in CA1 neurons in an environmental context-specific manner (Guzowski et
al., 1999), as observed for place-cell firing activity in hippocampal neurons. The striking concordance of Arc and H1a
coincident expression shown here indicates that, like Arc,
H1a is induced in the neural networks engaged in information
processing. The fact that both Arc and H1a are
dynamically expressed in the same neurons by experience and are
localized to the postsynaptic density suggests that these genes may
function in concert to modify synaptic efficacy in the hippocampal and
neocortical networks responsible for encoding the memory of discrete experiences.
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FOOTNOTES |
Received July 10, 2002; revised Sept. 10, 2002; accepted Sept. 12, 2002.
This work was supported by National Institutes of Health Grants MH60123
(J.F.G.), AG09219 (C.A.B. and P.F.W.), MH01565 (B.L.M.), and AG18230
(C.A.B., J.F.G., B.L.M., and P.F.W.). We thank Beth Takacs for
assistance with the behavioral training of the rats.
Correspondence should be addressed to Dr. J. F. Guzowski, Department of Neurosciences, Basic Medical Sciences
Building, Room 145, University of New Mexico, Health Sciences
Center, Albuquerque, NM 87131-5223. E-mail: jguzowski{at}salud.unm.edu.
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ABSTRACT
INTRODUCTION
