such as spike-count correlations (23), can be
understood as arising from the On-Off dynamics (fig. S12 and supplementary text 3.8). Correlated variability can be affected by cognitive
factors (24–26). In particular, spike-count correlations can increase or decrease during selective attention (27–30), and changes in the On-Off
dynamics account for changes in spike-count
correlations during attention in our data (fig.
S13 and supplementary text 3.8.4). Recent models
parsimoniously attribute changes in spike-count
correlations during attention to fluctuations in
shared modulatory signals (31), with smaller spike-count correlations accounted for by reduced fluctuations in these modulatory signals (32). The
On-Off dynamics observed here could underlie
the apparent trial-to-trial fluctuations in shared
modulatory signals (32, 33) but can account for
within-trial fluctuations as well (fig. S12 and supplementary text 3.8.5).
What mechanisms underlie the spatially and
temporally precise control of cortical state during
selective attention? Our results suggest that global
mechanisms governing cortical states may themselves also operate on a local scale or, alternatively, may interact with separate attentional
control mechanisms operating locally. Indeed,
neuromodulators known to act on a brain-wide
scale (1, 34, 35) also mediate the effects of selective attention (36) and influence circuits that
control selective attention (37). On the other hand,
cortico-cortical inputs appear to influence state
changes in a spatially targeted manner (38, 39).
Because diffuse neuromodulatory signals are interspersed with topographically precise projections throughout the cortex, local modulation of
cortical state is likely to be widespread, extending to modalities beyond vision and serving many
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This work was supported by NIH grants EY014924 and NS076460,
a Stanford NeuroVentures grant, Medical Research Council
(MRC) grant MR/K013785/1, and Wellcome Trust grant 093104.
We thank E. I. Knudsen, K. Harris, S. Ganguli, R. N. S. Sachdev, and
M. Zirnsak for their comments on the manuscript. We thank
D. S. Aldrich for technical assistance. All behavioral and
electrophysiological data are presented in (14) and are archived at
the Stanford Neuroscience Institute server at Stanford University.
T.A.E., N.A.S., T.M., and K.B. designed the study. N.A.S. and T.M.
designed the experiments. N.A.S. performed experiments, spike
sorting, microsaccade detection, and RF measurements. M.A.G.
and A. T. performed experiments for the additional laminar data set.
T.A.E. analyzed and modeled the data. T.A.E., N.A.S., T.M., and
K.B. discussed the findings and wrote the paper.
Materials and Methods
Figs. S1 to S13
16 May 2016; accepted 31 October 2016
Gliogenic LTP spreads widely in
M. T. Kronschläger,* R. Drdla-Schutting,* M. Gassner, S. D. Honsek,
H. L. Teuchmann, J. Sandkühler†
Learning and memory formation involve long-term potentiation (LTP) of synaptic strength. A
fundamental feature of LTP induction in the brain is the need for coincident pre- and
postsynaptic activity. This restricts LTP expression to activated synapses only (homosynaptic
LTP) and leads to its input specificity. In the spinal cord, we discovered a fundamentally
different form of LTP that is induced by glial cell activation and mediated by diffusible,
extracellular messengers, including D-serine and tumor necrosis factor (TNF), and that travel
long distances via the cerebrospinal fluid, thereby affecting susceptible synapses at remote
sites. The properties of this gliogenic LTP resolve unexplained findings of memory traces in
nociceptive pathways and may underlie forms of widespread pain hypersensitivity.
Activity-dependent, homosynaptic long-term potentiation (LTP) (1) at synapses in noci- ceptive pathways contributes to pain am- plification (hyperalgesia) at the site of an injury or inflammation (2–5). Homosyn-
aptic LTP can, however, not account for pain
amplification at areas surrounding (secondary
hyperalgesia) or remote from (widespread hy-
peralgesia) an injury. It also fails to explain hy-
peralgesia that is induced independently of
neuronal activity in primary afferents—e.g., by
the application of or the withdrawal from opioids
(opioid-induced hyperalgesia) (6). Glial cells are
believed to contribute to these forms of hyper-
algesia and to LTP in nociceptive pathways (7–10).
Induction of homosynaptic LTP can be accom-
panied by LTP in adjacent, inactive synapses
converging onto the same neuron, especially early
in development. The respective molecular signals
for this heterosynaptic form of LTP are thought
to be confined within the cytoplasm of the ac-
tivated neuron, spreading tens of micrometers
only (11). We have now tested the hypothesis
that, in contrast to current beliefs, activation of
glial cells is causative for the induction of LTP at
spinal C-fiber synapses and that this gliogenic
LTP constitutes a common denominator of homo-
and heterosynaptic LTP in the spinal cord.
Our previous study revealed that selective activation of spinal microglia by fractalkine induces
Department of Neurophysiology, Center for Brain Research,
Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria.
*These authors contributed equally to this work. †Corresponding
author. Email: email@example.com