the current notion of spatially uniform inhi-
bition underlying place cell properties and
reconcile several models of place field emer-
gence ( 1 , 25 , 26 , 29 , 32 ).
Optogenetic perturbation during the theta
cycles and SPW-Rs revealed opposite excit-
ability rules, and the SPW-R data were best
fitted by a balanced network model ( 33 – 35 ).
Even though SPW-R represents the highest
excitability state of the CA1 network, the con-
tributing individual neurons decrease their
excitability. This negative gain enables larger
rate changes of slow firing, compared to fast
firing, neurons during SPW-R. By contrast,
the reciprocal mode of operation during ex-
ploration allows for larger in-field gain for
faster-firing, compared to slow-firing, neu-
rons. Brain state–dependent shifts between
the reciprocal and balanced E/I modes of ope-
rations may be brought about by the altered
temporal relationship between interneuron
and pyramidal cell spiking and the consequent
Vm( 36 ), perhaps set by subcortical neuro-
modulators. SPW-R is a naturalVmchanger
( 37 ) during which more neurons fire than can
be accounted for by place cells active during
waking experience ( 37 – 39 ). These spikes are
emitted by those neurons whose sparse spiking
activity also contributes to the same hippo-
campal map.
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ACKNOWLEDGMENTS
We thank L. Menéndez de la Prida, A. Fernandez-Ruiz, A. Navas-Olivé,
R. Huszar, E. Barrio-Alonso, and members of our laboratory for helpful
comments on the project.Funding:This work was supported by
the European Molecular Biology Organization (EMBO) postdoctoral
fellowship (EMBO ALTF 1161-2017) and Human Frontiers Science
Program (HFSP) postdoctoral fellowship (LT0000717/2018) to M.V.; a
Leon Levy Neuroscience Fellowship to I.Z.; and NIH MH107396, NS
090583, NSF PIRE grant (1545858), U19 NS107616, U19 NS104590,
and NSF NeuroNex MINT grant 1707316.Author contributions:M.V. and G.B. designed the experiments. M.V. performed and
analyzed the experiments with I.Z. G.B. and M.V. wrote the paper
with contributions from other authors.Competing interests:E.Y. is
a cofounder of NeuroLight Technologies, a for-profit manufacturer
of neurotechnology. The other authors declare no competing
interests.Data and material availability:E.Y. is inventor on
patents applications US Patent 9,247,889 (2016) and US Patent
9,642,545 (2017) held by the University of Michigan that covers
the neural probes with optical stimulation capability. All data
needed to evaluate the conclusions are present in the paper
and/or the supplementary materials and are publicly available in
the Buzsaki Lab Databank: https://buzsakilab.com/wp/public-
data/. Custom MATLAB scripts can be downloaded from https://
github.com/buzsakilab/buzcode.SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abm1891
Material and Methods
Figs. S1 to S15
References ( 40 – 54 )
MDAR Reproducibility Checklist31 August 2021; accepted 23 December 2021
10.1126/science.abm1891DEVELOPMENTEstablishment of mouse stem cells that can
recapitulate the developmental potential
of primitive endoderm
Yasuhide Ohinata1,2*, Takaho A. Endo^3 , Hiroki Sugishita^2 , Takashi Watanabe^3 , Yusuke Iizuka^2 ,
Yurie Kawamoto^2 , Atsunori Saraya^1 , Mami Kumon^2 , Yoko Koseki^2 , Takashi Kondo^2 ,
Osamu Ohara3,4, Haruhiko Koseki1,2The mammalian blastocyst consists of three distinct cell types: epiblast, trophoblast (TB), and primitive
endoderm (PrE). Although embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) retain the
functional properties of epiblast and TB, respectively, stem cells that fully recapitulate the
developmental potential of PrE have not been established. Here, we report derivation of primitive
endoderm stem cells (PrESCs) in mice. PrESCs recapitulate properties of embryonic day 4.5 founder
PrE, are efficiently incorporated into PrE upon blastocyst injection, generate functionally competent PrE-
derived tissues, and support fetal development of PrE-depleted blastocysts in chimeras. Furthermore,
PrESCs can establish interactions with ESCs and TSCs and generate descendants with yolk sacÐlike
structures in utero. Establishment of PrESCs will enable the elucidation of the mechanisms for PrE
specification and subsequent pre- and postimplantation development.E
piblast, trophoblast (TB), and primitive
endoderm (PrE) are differentiated from
the zygote by the late blastocyst stage of
mouse preimplantation development and
contribute to generate the major parts of
the embryo, placenta, and yolk sac, respec-
tively, during postimplantation development.Our understanding of the functional proper-
ties of epiblast and TB has been enhanced by
the use of embryonic stem cells (ESCs) and
trophoblast stem cells (TSCs), which retain
functional properties of epiblast and TB, re-
spectively, and have provided experimental
platforms to dissect their functions ( 1 , 2 ). By
contrast, although extraembryonic endoderm
cells (XENCs) have been derived from PrE,
they do not fully recapitulate the developmen-
tal potential of the PrE ( 3 ).
ThePrElineageisvitalfornormalembry-
onic development and is the origin of the vis-
ceral endoderm (VE) of the visceral yolk sac,
the parietal endoderm (PE) of the parietal yolk
sac, and the marginal zone endoderm (MZE)
lining the boundary between the placenta and574 4 FEBRUARY 2022•VOL 375 ISSUE 6580 science.orgSCIENCE
(^1) Department of Cellular and Molecular Medicine, Graduate
School of Medicine, Chiba University, 1-8-1 Inohana, Chuo
ward, Chiba 260-8670, Japan.^2 Laboratory for Developmental
Genetics, RIKEN Center for Medical Sciences (IMS), 1-7-22
Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
(^3) Laboratory for Integrative Genomics, RIKEN Center for
Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi,
Yokohama 230-0045, Japan.^4 Facility for Clinical Omics
Analysis, Kazusa DNA Research Institure, 2-6-7 Kazusakamatori,
Kisarazu, Chiba 292-0818, Japan.
*Corresponding author. Email: [email protected]
RESEARCH | REPORTS