session compared to after the first training session,
demonstrating that the amount of training correlated with the strength of hippocampal-PPC
ripple coupling (Fig. 4C).
In this study, we have identified ripple frequency oscillations that were present in association but not in primary sensory cortical areas.
These association areas, including parietal, retro-
splenial, anterior cingulate, and medial prefrontal
cortex, are reciprocally anatomically and func-
tionally connected with medial temporal lobe
structures (1, 2) and exhibit extensive cortico-
cortical connections (33). Hippocampal and neo-
cortical ripples co-occur in these areas, reflecting
either a direct hippocampal–entorhinal cortex–
neocortex excitation (10, 14) or an indirect common
drive by cortical slow oscillations (12, 20, 34, 35).
The coordination of cortical ripples with “down”
to “up” state transitions, and the correlation
of both hippocampal and cortical ripples with
sleep spindles, suggests that cortical ripples may
form part of the hippocampal-cortical dialogue
during NREM sleep. Following induction of
long-term hippocampal-dependent memory,
coupling of hippocampal and neocortical ripples increased significantly. Analogous to hippocampal ripples, cortical ripples may signify
information transfer involving association cortex.
Overall, our findings suggest that ripple oscilla-
tion mechanisms of NREM sleep in both hippo-
campal and neocortical association areas support
memory consolidation. Note added in proof: After
our manuscript went in press, a paper relevant to
the findings presented here was published (36).
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This work was supported by NIH grants UO1NS099705, U01NS090583,
and MH107396 and Defense Advanced Research Projects Agency
(DARPA) N66001-17-C-4002. The device fabrication was performed
Cornell NanoScale Science & Technology Facility (CNF) at a member of
the National Nanotechnology Coordinated Infrastructure (NNCI), which
is supported by the National Science Foundation (grant ECCS-
1542081). D. K. was supported through the Simons Foundation (junior
fellow). J.N.G. was supported by the Pediatric Scientist Development
Program. We thank O. Rauhala (University of Minnesota) and
S. Rogers (N YU Langone Medical Center), M. Skvarla (CNF), R. Ilic
(CNF), and M. Metzler (CNF) and Buzsaki Lab members for their
support. The authors declare that they have no competing interests. All
data needed to evaluate the conclusions in the paper are present in
the paper and/or the supplementary materials. Additional data related
to this paper may be requested from the authors.
Materials and Methods
Figs. S1 to S9
9 May 2017; accepted 6 September 2017
372 20 OCTOBER 2017 • VOL 358 ISSUE 6361
Fig. 4. Coupling of hippocampal and PPC ripples during NREM sleep in a spatial memory task.
(A) Schematic of behavioral protocol. Blue boxes indicate sleep sessions for assessing coupling of
hippocampal and PPC ripples. SE, sleep after exploration; S1 and S2, sleep sessions after first and
second training sessions, respectively. (B) Top: sample path of a rat (black) over maze surface relative to
water reward locations (red) during exploration (left), during last five trials of second training session
(middle), and during five trials of testing 24 hours later (right). Bottom: sample cross-correlograms
between PPC and hippocampal ripples during post-exploration (SE) sleep session (left; time 0 =
occurrence of hippocampal ripple; n = 13,206 cortical ripples and 7252 hippocampal ripples) and
posttraining sleep session (S2; right; n = 5225 cortical ripples and 3128 hippocampal ripples; red lines
represent 95% confidence intervals). (C) Group statistics demonstrating progressive increase in
hippocampal–PPC ripple coupling across sleep sessions occurring after sequential posttraining sleep
sessions (S1 and S2) compared to after free exploration (SE). Inset demonstrates changes in coupling
for each individual rat, with coupling modulation calculated as the ratio of the cross-correlogram peak
[“a” in panel (B); maximal value within ± 50 ms] to the baseline of the cross-correlogram [“b” in panel (B);
midpoint of upper and lower boundary of 95% confidence interval averaged over 10 s of cross-correlation].
Normalized coupling modulation was calculated by subtracting the average coupling strength of
hippocampal and PPC ripples during sleep before initiation of behavior protocol from the coupling strength
obtained during SE, S1, and S2 for each rat (pooled over 5 days of training). Edges of the large diamond
plot correspond to –1 standard error, median, and +1 standard error (from bottom to top), with embedded
square representing the mean; whiskers show minimum and maximum values (n = 6, Kruskal–Wallis
test; P = 0.013, Bonferroni correction; *P < 0.05 between groups as determined by post-hoc testing).
Blue diamonds show values for individual rats.