this Fc structure was present before infection
or was triggered by DENV infection itself. To
address this, we compared the Fc of antibodies
obtained from TH+ patients during the early and
convalescent phases of disease. The convalescent
phase was marked by a significant drop in both
afucFc and IgG1/IgG2 ratio (Fig. 4, A and B),
indicating that, in patients with severe disease,
DENV infection itself triggered an elevation in
IgGs with enhanced affinity for FcgRIIIA.
The present finding that some individuals respond to DENV infection by producing IgGs
with higher affinity for FcgRIIIA indicates a host
determinant of susceptibility to severe DENV
disease. Further studies will determine how this
patient selectivity may contribute to additional
mechanisms underlying ADE of DENV disease.
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We thank S. Zhang and R. Sherwood at the Cornell Proteomics and
Mass Spectrometry Facility for helpful discussions and excellent
technical support. The authors also thank the staff of the Stanford
Clinical Virology Laboratory for their assistance with dengue
virus serologic testing. T. T. W. thanks B. Coller, S. J. Schlesinger,
and the Rockefeller University KL2 Clinical Scholars Program
for training and support. T. T. W. was supported, in part, by grant
UL1TR001866 from the National Center for Advancing
Translational Sciences, NIH, and the Clinical and Translational
Science Award program. J.S. thanks S. Wang and S. Gunisetty for
helping with preparation of sera from patient samples. K.P. was
funded by NIH IRO1AI099385. S.B. was supported by an American
Foundation for AIDS Research Mathilde Krim Fellowship in Basic
Biomedical Research (109519-60-RKVA). Research reported in this
publication was supported by the National Institute of Allergy
and Infectious Diseases of the NIH under award numbers
U19AI111825 (J.V.R.), U19AI109946 (J.V.R.), U19AI057266 (R.A.
and J. W.), and U01AI115651 (R.A.). The influenza A virus challenge
study was supported by the Intramural Research Program of the
National Institute of Allergy and Infectious Diseases (NIAID), as
well as the NIAID Extramural Clinical Research Acceleration
Program. Support and infrastructure were also provided by The
Rockefeller University and by Stanford University School of
Medicine. Analysis of clinical samples in this work was approved by
the Institutional Review Board of Rockefeller University (protocol
#TWA-0804) (T. T. W.). The content is solely the responsibility of the
authors and does not necessarily represent the official views of NIH.
The data presented in this manuscript are in the main paper and in the
Materials and Methods
Figs. S1 to S4
Tables S1 and S2
16 August 2016; accepted 4 January 2017
Overlapping memory trace
indispensable for linking, but not
recalling, individual memories
Jun Yokose,1,2 Reiko Okubo-Suzuki,1,2 Masanori Nomoto,1,2 Noriaki Ohkawa,1,2*
Hirofumi Nishizono,2,3 Akinobu Suzuki,1,2 Mina Matsuo,3 Shuhei Tsujimura,1,2
Yukari Takahashi,4 Masashi Nagase,4 Ayako M. Watabe,4
Masakiyo Sasahara,5 Fusao Kato,4 Kaoru Inokuchi1,2†
Memories are not stored in isolation from other memories but are integrated into
associative networks. However, the mechanisms underlying memory association remain
elusive. Using two amygdala-dependent behavioral paradigms—conditioned taste aversion
(CTA) and auditory-cued fear conditioning (AFC)—in mice, we found that presenting the
conditioned stimulus used for the CTA task triggered the conditioned response of the AFC
task after natural coreactivation of the memories. This was accompanied through an
increase in the overlapping neuronal ensemble in the basolateral amygdala. Silencing of
the overlapping ensemble suppressed CTA retrieval-induced freezing. However, retrieval
of the original CTA or AFC memory was not affected. A small population of coshared
neurons thus mediates the link between memories. They are not necessary for recalling
Memories are often stored in intercon- nected networks of the brain to associate with one another (1–5). The simultaneous retrieval of two independent memories ometimes links the original memories,
generating a qualitatively new memory. Memory
is encoded in a specific cell ensemble that is
activated during learning (6–9), and individual
memories are generally represented by different
cell ensembles. Acquisition of a new memory can
be modified by the simultaneous and artificial
reactivation of a specific neuronal ensemble cor-
responding to that prestored memory, generat-
ing synthetic or false memories (10, 11). When
an association is formed between conditioned
and unconditioned stimuli (CS and US, respec-
tively) in Pavlovian conditioning, cell ensembles
corresponding to each stimulus overlap, and this
is thought to link these stimuli (4, 12–14). We
investigated the nature of these overlapping
neuronal ensembles in the association of mem-
ories governed by repeated and simultaneous
Mice were trained independently on two behavioral tasks: conditioned taste aversion (CTA)
on days 5 and 6 and auditory-cued fear conditioning (AFC) on day 10 (Fig. 1A). After each memory was formed, animals received synchronous
1Department of Biochemistry, Faculty of Medicine, Graduate
School of Medicine and Pharmaceutical Sciences, University of
Toyama, 2630 Sugitani, Toyama 930-0194, Japan. 2Core
Research for Evolutional Science and Technology (CREST),
Japan Science and Technology Agency (JST), University
of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
3Division of Animal Experimental Laboratory, Life Science
Research Centre, University of Toyama, 2630 Sugitani,
Toyama 930-0194, Japan. 4Department of Neuroscience,
Jikei University School of Medicine, Tokyo 105-8461, Japan.
5Department of Pathology, Faculty of Medicine, University of
Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
*Present address: Precursory Research for Embryonic Science and
Technology (PRESTO), JST, University of Toyama, 2630 Sugitani,
Toyama 930-0194, Japan. †Corresponding author. Email: inokuchi@