Abstract and Figures

The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
Wakefulness suppresses influx of CSF tracers. (A) Diagram of experimental setup used for two-photon imaging of CSF tracer movement in real time. To avoid disturbing the state of brain activity, a cannula with dual ports was implanted in the cisterna magna for injection of CSF tracers. ECoG and EMG were recorded to monitor the state of brain activity. (B) Threedimensional (3D) vectorized reconstruction of the distribution of CSF tracers injected in a sleeping mouse and then again after the mouse was awakened. The vasculature was visualized by means of cascade blue-dextran administered via the femoral vein. FITC-dextran (green) was first injected in the cisterna magna in a sleeping mouse and visualized by collecting repeated stacks of z-steps. Thirty min later, the mouse was awakened by gently moving its tail, and Texas red-dextran (red) was administered 15 min later. The experiments were performed mostly asleep (12 to 2 p.m.). The arrow points to penetrating arteries. (C) Comparison of time-dependent CSF influx in sleep versus awake. Tracer influx was quantified 100 mm below the cortical surface; n = 6 mice; *P < 0.05, two-way ANOVA with Bonferroni test. (Right) The tracer intensity within the two arousal states at the 30-min time point was compared. **P < 0.01, t test. (D) ECoG and EMG recordings acquired during sleep and after the mouse was awakened. Power spectrum analysis of all the animals analyzed in the two arousal states (n = 6 mice; *P < 0.05, t test). (E) 3D reconstruction of CSF tracer influx into the mouse cortex. FITC-dextran was first injected in the awake stage, and cortical influx was visualized by means of two-photon excitation for 30 min. The mouse was then anesthetized with ketamine/xylazine (intraperitoneally), and Texas red-dextran was injected intracisternally 15 min later. The vasculature was visualized by means of cascade blue-dextran. Arrows point to penetrating arteries. (F) Comparison of timedependent CSF influx in awake versus ketamine/xylazine anesthesia; n = 6 mice; *P < 0.05, two-way ANOVA with Bonferroni test. (Right) The tracer intensity during the two arousal states at the 30-min time point was compared. **P < 0.01, t test. (G) ECoG and EMG recordings in the awake mouse and after administration of ketamine/xylazine. Power spectrum analysis of all the animals analyzed in the two arousal states; n = 6 mice; *P < 0.05, t test.
… 
Adrenergic inhibition increases CSF influx in awake mice. (A) CSF tracer influx before and after intracisternal administration of a cocktail of adrenergic receptor antagonists. FITC-dextran (yellow, 3 kD) was first injected in the cisterna magna in the awake mouse, and cortical tracer influx was visualized by means of two-photon excitation for 30 min. The adrenergic receptor antagonists (prazosin, atipamezole, and propranolol, each 2 mM) were then slowly infused via the cisterna magna cannula for 15 min followed by injection of Texas red-dextran (purple, 3 kD). The 3D reconstruction depicts CSF influx 15 min after the tracers were injected in cisterna magna. The vasculature was visualized by means of cascade blue-dextran. Arrows point to penetrating arteries. (B) Comparison of tracer influx as a function of time before and after administration of adrenergic receptor antagonists. Tracer influx was quantified in the optical section located 100 mm below the cortical surface; n = 6 mice; *P < 0.05, two-way ANOVA with Bonferroni test. (Right) The tracer intensity during the two arousal states at the 30-min time point was compared. **P < 0.01, t test. (C) Comparison of the interstitial concentration of NE in cortex during head-restraining versus unrestrained (before and after), as well as after ketamine/xylazine anesthesia. Microdialysis samples were collected for 1 hour each and analyzed by using high-performance liquid chromatography. **P < 0.01, one-way ANOVA with Bonferroni test. (D) TMA + iontophoretic quantification of the volume of the extracellular space before and after adrenergic inhibition; n = 4 to 8 mice; **P < 0.01, t test. (E) Power spectrum analysis, n = 7 mice; **P < 0.01, one-way ANOVA with Bonferroni test.
… 
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Sleep Drives Metabolite Clearance
from the Adult Brain
Lulu Xie,
1
*Hongyi Kang,
1
*Qiwu Xu,
1
Michael J. Chen,
1
Yonghong Liao,
1
Meenakshisundaram Thiyagarajan,
1
John ODonnell,
1
Daniel J. Christensen,
1
Charles Nicholson,
2
JeffreyJ.Iliff,
1
Takahiro Takano,
1
Rashid Deane,
1
Maiken Nedergaard
1
The conservation of sleep across all animal species suggests that sleep serves a vital function.
We here report that sleep has a critical function in ensuring metabolic homeostasis. Using
real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice,
we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial
space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial
fluid. In turn, convective fluxes of interstitial fluid increased the rate of b-amyloid clearance
during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced
removal of potentially neurotoxic waste products that accumulate in the awake central nervous
system.
Despite decades of effort, one of the greatest
mysteries in biology is why sleep is re-
storative and, conversely, why lack of
sleep impairs brain function (1,2). Sleep dep-
rivation reduces learning, impairs performance
in cognitive tests, prolongs reaction time, and is
a common cause of seizures (3,4). In the most
extreme case, continuous sleep deprivation kills
rodents and flies within a period of days to weeks
(5,6). In humans, fatal familial or sporadic in-
somnia is a progressively worsening state of
sleeplessness that leads to dementia and death
within months or years (7).
Proteins linked to neurodegenerative diseases,
including b-amyloid (Ab)(8), a-synuclein (9), and
tau (10), are present in the interstitial space
surrounding cells of the brain. In peripheral tissue,
lymph vessels return excess interstitial proteins to
the general circulation for degradation in the liver
(11). Yet despite its high metabolic rate and the
fragility of neurons to toxic waste products, the
brain lacks a conventional lymphatic system. In-
stead, cerebrospinal fluid (CSF) recirculates
through the brain, interchanging with interstitial
fluid (ISF) and removing interstitial proteins,
including Ab(12,13). The convective exchange
of CSF and ISF is organized around the cerebral
vasculature, with CSF influx around arteries,
whereas ISF exits along veins. These pathways
were named the glymphatic system on the basis
of their dependence on astrocytic aquaporin-4
(AQP4) water channels and the adoption of
functions homologous to peripheral lymphatic
removal of interstitial metabolic byproducts (14).
Deletion of AQP4 channels reduces clearance of
exogenous Abby 65%, suggesting that convec-
tive movement of ISF is a substantial contributor
to the removal of interstitial waste products and
other products of cellular activity (12). The in-
terstitial concentration of Abis higher in awake
than in sleeping rodents and humans, possibly
indicating that wakefulness is associated with
increased Abproduction (15,16). We tested the
alternative hypothesis that Abclearance is increased
during sleep and that the sleep-wake cycle reg-
ulates glymphatic clearance.
We used in vivo two-photon imaging to com-
pare CSF influx into the cortex of awake, anes-
thetized, and sleeping mice. The fluorescent
tracers were infused into the subarachnoid CSF
via a cannula implanted in the cisterna magna
for real-time assessment of CSF tracer movement.
Electrocorticography (ECoG) and electromyogra-
phy (EMG) were recorded in order to continuous-
ly monitor the state of brain activity (Fig. 1A and
fig. S1). In initial experiments, the volume and rate
of tracer infusion were adjusted so as to avoid
changes in behavior state or ECoG (fig. S1). Be-
cause mice sleep much of the day, a small mo-
lecular weight tracer, fluorescein isothiocyanate
(FITC)dextran (3 kD) in aCSF, was infused at
midday (12 to 2 p.m.) via the cannula implanted
in the cisterna magna. In sleeping mice, a robust
influx of the fluorescent CSF tracer was noted
along periarterial spaces, in the subpial regions,
and in the brain parenchyma similar to previous
findings in anesthetized mice (Fig. 1, B and C,
and fig. S2) (12). ECoG power spectrum analysis
depicted a relatively high power of slow waves
that is consistent with sleep (Fig. 1D). CSF tracer
infusion (Texas red-dextran, 3 kD) was repeated
in the same mouse after it was awakened through
gentle handling of its tail. Unexpectedly, arousal
sharply reduced tracer influx compared with that
of the sleeping state. Periarterial and parenchy-
mal tracer influx was reduced by ~95% in awake
as compared with sleeping mice during the 30-min
imaging session (Fig. 1, B and C, and fig. S2).
ECoG showed a reduction in the relative prev-
alence of slow (delta) waves concomitant with a
significant increase in the power of fast activity,
confirming that the animals were awake (n=6
mice, P< 0.05, paired ttest) (Fig. 1D). To inves-
tigate whether the state of brain activity indeed
controlled CSF influx, we repeated the experi-
ments in a new cohort of mice in which all ex-
periments were performed when the animals were
awake (8 to 10 p.m.). Because mice normally do
not sleep at this time of day, we first evaluated
CSF tracer influx in the awake state by means of
intracisternal infusion of FITC-dextran. CSF tracer
influx into the brain was largely absent and only
slowly gained access to the superficial cortical
layers (Fig. 1, E and F, and fig. S2). After 30 min
imaging of CSF tracer in the awake state, the
animals were anesthetized with intraperitoneal
administration of ketamine/xylazine (KX). Texas
red-dextran was administered 15 min later, when
a stable increase in slow wave activity was noted
(Fig. 1, E and F). Texas red-dextran rapidly flushed
in along periarterial spaces and entered the
brain parenchyma at a rate comparable with that
of naturally sleeping mice (Fig. 1, B and E).
Ketamine/xylazine anesthesia significantly in-
creased influx of CSF tracer in all mice anal-
yzed [n= 6 mice, P< 0.05, two-way analysis of
variance (ANOVA) with Bonferroni test], which
was concomitant with a significant increase in the
powerofslowwaveactivity(n= 6 mice, P<0.05,
paired ttest) (Fig. 1, G and F). Thus, glymphatic
CSF influx is sharply suppressed in conscious
alert mice as compared with naturally sleeping or
anesthetized littermates.
Influx of CSF is in part driven by arterial
pulse waves that propel the movement of CSF
inward along periarterial spaces (12). It is un-
likely that diurnal fluctuations in arterial pulsa-
tion are responsible for the marked suppression
of convective CSF fluxes during wakefulness be-
cause arterial blood pressure is higher during phys-
ical activity. An alternative possibility is that the
awake brain state is linked to a reduction in the
volume of the interstitial space because a con-
stricted interstitial space would increase resistance
to convective fluid movement and suppress CSF
influx. To assess the volume and tortuosity of the
interstitial space in awake versus sleeping mice,
we used the real-time iontophoretic tetramethyl-
ammonium (TMA) method in head-fixed mice
(Fig. 2A and fig. S3) (17,18). TMA recordings in
cortex of sleeping mice collected at midday (12
to 2 p.m.) confirmed that the interstitial space
volume fraction (a) averaged 23.4 T1.9% (n=6
mice) (19). However, the interstitial volume frac-
tion was only 14.1 T1.8% in awake mice recorded
at 8 to 10 p.m. (n= 4 mice, P< 0.01, ttest) (Fig.
2B). Analysis of cortical ECoG recorded by the
TMA reference electrode confirmed that the power
of slow wave activity was higher in sleeping than
in awake mice, which is concurrent with a lower
power of high-frequency activity (Fig. 2C).
To further validate that the volume of the in-
terstitial space differed in awake versus sleeping
mice, we also obtained TMA recordings in awake
mice in the late evening (8 to 10 p.m.) and re-
peated the recordings in the same mice after ad-
ministration of ketamine/xylazine. This approach,
1
Division of Glial Disease and Therapeutics, Center for Trans-
lational Neuromedicine, Department of Neurosurgery, Uni-
versity of Rochester Medical Center, Rochester, NY 14642, USA.
2
Department of Neuroscience and Physiology, Langone Med-
ical Center, New York University, New York, NY 10016, USA.
*These authors contributed equally to this work.
Corresponding author. E-mail: nedergaard@urmc.rochester.
edu
www.sciencemag.org SCIENCE VOL 342 18 OCTOBER 2013 373
REPORTS
which eliminated interanimal variability in elec-
trode placement and TMA calibration, showed
that anesthesia consistently increased the intersti-
tial space volume fraction by >60%, from 13.6 T
1.6% for awake mice to 22.7 T1.3% in the same
mice after they received ketamine/xylazine (n=10
mice, P< 0.01, paired ttest) (Fig. 2D). Analysis
of ECoG activity extracted from the TMA ref-
erence electrode showed that ketamine/xylazine
increased the power of slow wave activity in all
animals analyzed (Fig. 2E). Thus, the cortical
interstitial volume fraction is 13 to 15% in the
awake state as compared to 22 to 24% in sleeping
or anesthetized mice. Tortuosity of the interstitial
space did not differ significantly according to
changes in the state of brain activity; awake, sleep-
ing, and anesthetized mice all exhibited a lvalue
in the range of 1.3 to 1.8, which is consistent with
earlier reports (n= 4 to 10 mice, P>0.1,ttest)
(Fig.2,BandD)(1921). Recordings obtained
300 mm below the cortical surface did not differ
significantly from those obtained at 150 mm, sug-
gesting that preparation of the cranial window
was not associated with tissue injury (n= 6 mice,
P>0.4,ttest) (Fig. 2D and fig. S3D). Other reports
have shown that the interstitial volume is ~19% in
anesthetized young mice but declines to ~13% in
1 m
V
1 s
1 m
V
1 s
CSF tracers
ECoG 2PLM
A
BC
D
F
G
E
Time (min)
Time (min)
*
**
**
*
***
*
0
20
40
60
80
100
Delta Theta Alpha Beta
% Prevalence
Sleep
Awake
Sleep
Awake
Sleep
Awake
0
20
40
60
80
100
Delta Theta Alpha Beta
% Prevalence
Awake
KX
Awake
KX Awake
KX
*
***
EMG
0 µm
200 µm
0 µm
200 µm
100 µm
100 µm
Sleep Awake
Sleep
Awake
Awake KX
Z
X
Y
0
20
40
60
80
100
0
20
40
60
80
100
0102030
CSF tracer (% area covered)
CSF tracer (% area covered)
CSF tracer (% area covered)
CSF tracer (% area covered)
KX
Awake
0102030
0
20
40
60
80
100
0
20
40
60
80
100
Fig. 1. Wakefulness suppresses influx of CSF tracers. (A)Diagramof
experimental setup used for two-photon imaging of CSF tracer movement in
real time. To avoid disturbing the state of brain activity, a cannula with dual
ports was implanted in the cisterna magna for injection of CSF tracers. ECoG
and EMG were recorded to monitor the state of brain activity. (B) Three-
dimensional (3D) vectorized reconstruction of the distribution of CSF tracers
injected in a sleeping mouse and then again after the mouse was awakened.
The vasculature was visualized by means of cascade blue-dextran administered
via the femoral vein. FITC-dextran (green) was first injected in the cisterna
magna in a sleeping mouse and visualized by collecting repeated stacks of
z-steps. Thirty min later, the mouse was awakened by gently moving its tail,
and Texas red-dextran (red) was administered 15 min later. The experiments
were performed mostly asleep (12 to 2 p.m.). The arrow points to pene-
trating arteries. (C) Comparison of time-dependent CSF influx in sleep versus
awake. Tracer influx was quantified 100 mm below the cortical surface; n=6
mice; *P< 0.05, two-way ANOVA with Bonferroni test. (Right) The tracer
intensity within the two arousal states at the 30-min time point was com-
pared. **P<0.01,ttest. (D) ECoG and EMG recordings acquired during
sleep and after the mouse was awakened. Power spectrum analysis of all the
animals analyzed in the two arousal states (n=6mice;*P< 0.05, ttest). (E)
3D reconstruction of CSF tracer influx into the mouse cortex. FITC-dextran was
first injected in the awake stage, and cortical influx was visualized by means
of two-photon excitation for 30 min. The mouse was then anesthetized with
ketamine/xylazine (intraperitoneally), and Texas red-dextran was injected intra-
cisternally 15 min later. The vasculature was visualized by means of cascade
blue-dextran. Arrows point to penetrating arteries. (F)Comparisonoftime-
dependent CSF influx in awake versus ketamine/xylazine anesthesia; n=6mice;
*P< 0.05, two-way ANOVA with Bonferroni test. (Right) The tracer intensity
during the two arousal states at the 30-min time point was compared. **P<
0.01, ttest. (G) ECoG and EMG recordings in the awake mouse and after
administration of ketamine/xylazine. Power spectrum analysis of all the animals
analyzed in the two arousal states; n=6mice;*P<0.05,ttest.
18 OCTOBER 2013 VOL 342 SCIENCE www.sciencemag.org
374
REPORTS
aged mice (22). Collectively, these observations
support the notion that influx of CSF tracers is
suppressed in awake mice as a result of contrac-
tion of the interstitial space: The smaller space
during wakefulness increases tissue resistance to
interstitial fluid flux and inward movement of
CSF. This effect of arousal state on interstitial
volume likely holds major implications for diffu-
sion of neurotransmitters, such as glutamate (23).
Because previous analysis indicates that as
much as 65% of exogenously delivered Abis
cleared by the glymphatic system (12), we tested
whether interstitial Abis cleared most efficiently
during sleep. Radiolabeled
125
I-Ab
1-40
was injected
intracortically in three groups of animals: freely
behaving awake mice, naturally sleeping mice,
and animals anesthetized with ketamine/xylazine
(fig. S4). Brains were harvested 10 to 240 min later
for analysis of
125
I-Abretention. Abwas cleared
twofold faster in the sleeping mice as compared
with the awake mice (n=23to29mice,P<
0.05, ANOVA with Bonferroni test) (Fig. 3, A
and B, P<0.05).Abclearance did not differ be-
tween sleeping and anesthetized mice. Because Ab
is also removed from CNS via receptor-mediated
transport across the blood-brain barrier (24), we
also analyzed the clearance of an inert tracer,
14
C-
inulin.
14
C-inulin was cleared more efficiently (greater
than twofold) in sleeping and anesthetized mice
as compared with awake mice (Fig. 3, C and D).
What drives the brain statedependent changes
of the interstitial space volume? The observation
that anesthesia increases glymphatic influx and
efflux (Figs. 1 and 3), suggests that it is not cir-
cadian rhythm but rather the sleep-wake state itself
that determines the volume of the interstitial space
and therefore the efficiency of glymphatic solute
clearance. Arousal is driven by the concerted re-
lease of neuromodulators (25). In particular, locus
coeruleusderived noradrenergic signaling appears
critical for driving cortical networks into the awake
state of processing (26,27). In peripheral tissues,
such as kidney and heart, noradrenaline regulates
the activity of membrane transporters and chan-
nels that control cell volume (28). We hypothe-
sized that adrenergic signaling in the awake state
modifies cell volume and thus the size of the in-
terstitial space. We first assessed whether suppres-
sion of adrenergic signaling in the awake conscious
brain can enhance glymphatic tracer influx by pre-
treating awake mice with a cocktail of adrenergic
receptor antagonists or vehicle (aCSF) 15 min be-
fore infusion of fluorescent CSF tracers (27). The
adrenergic receptor antagonists were administered
through a cannula inserted into the cisterna magna,
with an initial bolus followed by slow continuous
drug infusion. Administration of adrenergic an-
tagonists induced an increase in CSF tracer influx,
resulting in rates of CSF tracer influx that were
more comparable with influx observed during sleep
or anesthesia than in the awake state (Fig. 4, A
and B, and fig. S5). We asked whether increases
in the level of norepinephrine (NE) resulting from
stress during restraining at the microscope stage
affected the observations. Microdialysis samples
TMA+
iontophoresis
TMA+
iontophoresis
TMA+
iontophoresis
TMA+
2PLM
150 µm
A
DE
BC
0
0.05
0.1
0.15
0.2
0.25
0.3
Awake KX Awake KX
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
0
0.05
0.1
0.15
0.2
0.25
0.3
AwakeSleep AwakeSleep
Alpha
Alpha
0
0.2
0.4
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0.8
1
1.2
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1.6
1.8
Lambda
Lambda
**
**
**
KX
Awake
0
20
40
60
80
100
Delta Theta Alpha Beta
% Prevalence
Sleep
Awake
*
* *
*
**
0
20
40
60
80
100
Delta Theta Alpha Beta
% Prevalence
0
0.05
0.1
0.15
0.2
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Awake KX
Alpha
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Awake KX
Lambda
Fig. 2. Real-time TMA
+
iontophoretic quantification of the volume of
the extracellular space in cortex. (A)TMA
+
was delivered with an ion-
tophoresis microelectrode during continuous recordings by a TMA
+
-sensitive
microelectrode located a distance of ~150 mm away. The electrodes were filled
with Alexa488 and Alexa568, respectively, so that their distance could be de-
termined with two-photon excitation (insert over objective). A smaller ex-
tracellular space results in reduced TMA
+
dilution, reflected by higher levels of
detected TMA
+
.(B) The extracellular space is consistently smaller (a)inawake
than in sleeping mice, whereas the tortuosity remained unchanged (l); n=4
to 6 mice; **P<0.01,ttest. (C) Power spectrum analysis of ECoG recordings; n=
6mice;*P<0.05,ttest. (D) The extracellular space was consistently smaller in
the awake state than after administration of ketamine/xylazine in paired
recordings within the same mouse, whereas tortuosity did not change after
anesthesia; n=10mice;**P<0.01,ttest. (Bottom) TMA measurements
obtained during the two arousal states compared for each animal. (E)Power
spectrum analysis of ECoG; n=6mice;*P<0.05,ttest.
Fig. 3. Sleep improves clearance of Ab.
(A). Time-disappearance curves of
125
I-Ab
1-40
after its injection into the frontal cortex in
awake (orange triangles), sleeping (green
diamonds), and anesthetized (red squares,
ketamine/xylazine) mice. (B) Rate constants
derived from the clearance curves. (C)Time-
disappearance curves of
14
C-inulin after its
injection into the frontal cortex of awake
(orange triangles), sleeping (green diamonds),
and anesthetized (red squares, ketamine/
xylazine) mice. (D) Rate constants derived
from the clearance curves. A total of 77 mice
were included in the analysis: 25 awake, 29
asleep, and 23 anesthetized, with 3 to 6
mice per time point. *P<0.05compared
with awake, ANOVA with Bonferroni test.
125I-Aβ40 recovery (%)
Time (min)
Time (min)
14C-inulin recovery (%)
Rate constant (min–1) Rate const ant (min–1)
C
A
D
B
Sleep
KX
Awake
Sleep
KX
Awake
060120180240
0
25
50
75
100
0 60 120 180 240
0
25
50
75
100
**
0
0.01
0.02
0.03
Awake Sleep KX
0
0.02
0.04
0.06
0.08
Awake Sleep KX
**
www.sciencemag.org SCIENCE VOL 342 18 OCTOBER 2013 375
REPORTS
of the interstitial fluid showed that the NE con-
centration did not increase in trained mice during
restraining but that NE, as expected, fell after ad-
ministration of ketamine/xylazine (Fig. 4C).
We next evaluated whether adrenergic recep-
tor inhibition increased interstitial volume in the
same manner as sleep and anesthesia. We used
the TMA method to quantify the effect of local
adrenergic inhibition on the volume of the inter-
stitial space. To restrict adrenergic inhibition to
the cortex, receptor antagonists were applied di-
rectly to the exposed cortical surface rather than
intracisternal delivery. TMA recordings showed
that inhibition of adrenergic signaling in cortex
increased the interstitial volume fraction from
14.3 T5.2% to 22.6 T1.2% (n= 4 to 8 mice, P<
0.01, ttest). Interstitial volume was significantly
greater than in awake littermates exposed to ve-
hicle (aCSF) (P< 0.01) but comparable with the
interstitial volume in sleeping or anesthetized
mice (P=0.77andP= 0.95, respectively, ttest)
(Fig. 4D). Cortical ECoG displayed an increase
in the power of slow waves when exposed to
adrenergic receptor antagonists (n= 7 mice, P<
0.01, one-way ANOVA with Bonferroni test). In
accordance with earlier findings (27), analysis of
the power spectrum showed that inhibition of ad-
renergic signaling transformed the cortical ECoG
of awake mice into a more sleep-like, albeit less
regular, profile (Fig. 4E). These analyses suggest
that adrenergic signaling plays an important role
in modulating not only cortical neuronal activity
but also the volume of the interstitial space. NE
triggers rapid changes in neural activity (27,28),
which in turn can modulate the volume of the in-
terstitial space volume (29). Nevertheless, addi-
tional analysis is clearly required to determine
which cell types contribute to expansion of the
interstitial space volume during sleep, anesthesia,
or blockade of NE receptors (Figs. 2, B to D,
and 4D).
Because of the high sensitivity of neural cells
to their environment, it is essential that waste
products of neural metabolism are quickly and
efficiently removed from the brain interstitial space.
Several degradation products of cellular activity,
such as Aboligomers and amyloid depositions,
have adverse effects on synaptic transmission (30)
and cytosolic Ca
2+
concentrations (31)andcan
trigger irreversible neuronal injury (32). The exist-
ence of a homeostatic drive for sleepincluding
accumulation of a need to sleepsubstance during
wakefulness that dissipates during sleephas been
proposed (33). Because biological activity is inev-
itably linked to the production of metabolic degra-
dation products, it is possible that sleep subserves
the important function of clearing multiple poten-
Awake
NE receptor antagonists
Awake
NE receptor antagonists
NE
receptor
antagonists
DE
A
C
Alpha
Lambda
0
0.05
0.1
0.15
0.2
0.25
0.3
Awake NE
receptor
anta
g
onists
Awake NE
receptor
anta
g
onists
0
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1
1.2
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1.6
1.8
**
**
0
20
40
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80
100
Delta Theta Alpha Beta
% Prevalence
**
** **
**
**
Awake NE
receptor
antagonists
0 µm
100 µm
200 µm
Awake
1 m
V
4 m
V
1 s
Z
X
Y
NE (nM)
CSF tracer (% area covered)
0
10
20
30
40
50
Unrestrained
Restrained
Unrestrained
KX
0
0.5
1
1.5
B
Time (min)
*
NE receptor antagonists
Awake
0
10
20
30
40
50
0102030
CSF tracer (% area covered)
Fig. 4. Adrenergic inhibition increases CSF influx in awake mice. (A)
CSF tracer influx before and after intracisternal administration of a cocktail
of adrenergic receptor antagonists. FITC-dextran (yellow, 3 kD) was first in-
jected in the cisterna magna in the awake mouse, and cortical tracer influx
was visualized by means of two-photon excitation for 30 min. The adrenergic
receptor antagonists (prazosin, atipamezole, and propranolol, each 2 mM)
were then slowly infused via the cisterna magna cannula for 15 min followed
by injection of Texas red-dextran (purple, 3 kD). The 3D reconstruction de-
picts CSF influx 15 min after the tracers were injected in cisterna magna. The
vasculature was visualized by means of cascade blue-dextran. Arrows point to
penetrating arteries. (B)Comparisonoftracerinfluxasafunctionoftime
before and after administration of adrenergic receptor antagonists. Tracer in-
flux was quantified in the optical section located 100 mm below the cortical
surface; n=6mice;*P< 0.05, two-way ANOVA with Bonferroni test. (Right)
The tracer intensity during the two arousal states at the 30-min time point
was compared. **P<0.01,ttest. (C) Comparison of the interstitial concen-
tration of NE in cortex during head-restraining versus unrestrained (before
and after), as well as after ketamine/xylazine anesthesia. Microdialysis sam-
ples were collected for 1 hour each and analyzed by using high-performance
liquid chromatography. **P<0.01,one-wayANOVAwithBonferronitest.
(D)TMA
+
iontophoretic quantification of the volume of the extracellular
space before and after adrenergic inhibition; n=4to8mice;**P<0.01,t
test. (E) Power spectrum analysis, n=7mice;**P<0.01,one-wayANOVA
with Bonferroni test.
18 OCTOBER 2013 VOL 342 SCIENCE www.sciencemag.org
376
REPORTS
tially toxic CNS waste products. Our analysis
indicates that the cortical interstitial space increases
by more than 60% during sleep, resulting in effi-
cient convective clearance of Aband other com-
pounds (Figs. 2 and 3). The purpose of sleep has
been the subject of numerous theories since the
time of the ancient Greek philosophers (34). An
extension of the findings reported here is that
the restorative function of sleep may be due to the
switching of the brain into a functional state that
facilitates the clearance of degradation products of
neural activity that accumulate during wakefulness.
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Acknowledgments: This study was supported by NIH/National
Institute of Neurological Disorders and Stroke (NS078167
and NS078304 to M.N. and NS028642 to C.N.). We thank
S. Veasey for comments on the manuscript.
Supplementary Materials
www.sciencemag.org/content/342/6156/373/suppl/DC1
Materials and Methods
Figs. S1 to S5
References
30 May 2013; accepted 28 August 2013
10.1126/science.1241224
Reading Literary Fiction Improves
Theory of Mind
David Comer Kidd*and Emanuele Castano*
Understanding othersmental states is a crucial skill that enables the complex social relationships
that characterize human societies. Yet little research has investigated what fosters this skill,
which is known as Theory of Mind (ToM), in adults. We present five experiments showing that
reading literary fiction led to better performance on tests of affective ToM (experiments 1 to 5) and
cognitive ToM (experiments 4 and 5) compared with reading nonfiction (experiments 1), popular
fiction (experiments 2 to 5), or nothing at all (experiments 2 and 5). Specifically, these results
show that reading literary fiction temporarily enhances ToM. More broadly, they suggest that ToM
may be influenced by engagement with works of art.
The capacity to identify and understand
otherssubjective states is one of the most
stunning products of human evolution. It
allows successful navigation of complex social
relationships and helps to support the empathic
responses that maintain them (15). Deficits in
this set of abilities, commonly referred to as Theo-
ry of Mind (ToM), are associated with psycho-
pathologies marked by interpersonal difficulties
(68). Even when the ability is intact, disengage-
ment of ToM has been linked to the breakdown
of positive interpersonal and intergroup relation-
ships (9).
Researchers have distinguished between af-
fective ToM (the ability to detect and understand
othersemotions) and cognitive ToM (the infer-
ence and representation of othersbeliefs and in-
tentions) (7,8). The affective component of ToM,
in particular, is linked to empathy (positively) and
antisocial behavior (negatively) (7,8). It is thus
not surprising that we foster ToM in our children
by having them attend to the emotional states of
others: Do you think he is happy or sad as a
consequence of your action?Such explicit en-
couragements to understand others usually di-
minish when children appear to skillfully and
empathically engage in interpersonal relation-
ships. Cultural practices, though, may function
to promote and refine interpersonal sensitivity
throughout our lives. One such practice is read-
ing fiction.
Familiarity with fiction, self-reported em-
pathy, and performance on an advanced af-
fective ToM test have been correlated (10,11),
and limited experimental evidence suggests that
reading fiction increases self-reported empathy
(12,13). Fiction seems also to expand our knowl-
edge of otherslives, helping us recognize our
similarity to them (10,11,14). Although fiction
may explicitly convey social values and reduce
the strangeness of others, the observed relation
between familiarity with fiction and ToM may
be due to more subtle characteristics of the text.
That is, fiction may change how, not just what,
people think about others (10,11,14). We sub-
mit that fiction affects ToM processes because
it forces us to engage in mind-reading and
character construction. Not any kind of fiction
achieves that, though. Our proposal is that it is
literary fiction that forces the reader to engage in
ToM processes.
The category of literary fiction has been con-
tested on the grounds that it is merely a marker
of social class, but features of the modern lit-
erary novel set it apart from most best-selling
thrillers or romances. Miall and Kuiken (1517)
emphasize that through the systematic use of
phonological, grammatical, and semantic stylistic
devices, literary fiction defamiliarizes its readers.
The capacity of literary fiction to unsettle readers
expectations and challenge their thinking is also
reflected in Roland Barthess(18) distinction be-
tween writerly and readerly texts. Although readerly
textssuch as most popular genre fictionare
intended to entertain their mostly passive readers,
writerlyor literarytexts engage their read-
ers creatively as writers. Similarly, Mikhail Bakhtin
(19) defined literary fiction as polyphonic and
proposed that readers of literary fiction must con-
tribute their own to a cacophony of voices. The
absence of a single authorial perspective prompts
readers to enter a vibrant discourse with the au-
thor and her characters.
Bruner (20), like Barthes and Bakhtin, has
proposed that literature engages readers in a dis-
course that forces them to fill in gaps and search
for meanings among a spectrum of possible
meanings(p. 25). Bruner argues that to elicit
The New School for Social Research, 80 Fifth Avenue, New
York, NY 10011, USA.
*Corresponding author. E-mail: kiddd305@newschool.edu
(D.C.K.); castanoe@newschool.edu (E.C.)
www.sciencemag.org SCIENCE VOL 342 18 OCTOBER 2013 377
REPORTS
... The glymphatic system is most active during sleep and is suppressed by noradrenaline transmission during wakefulness 25 . Moreover, hypertension stiffens arterial walls, thus reducing perivascular pumping and impeding the flow of CSF in perivascular spaces and glymphatic clearance 26 . ...
... Moreover, hypertension stiffens arterial walls, thus reducing perivascular pumping and impeding the flow of CSF in perivascular spaces and glymphatic clearance 26 . Furthermore, the reduced noradrenergic tonus prevailing during normal sleep facilitates CSF flow increases in brain interstitium and paravascular spaces 25,27,28 . These findings emphasize the importance of hypocretin, AAN brainstem nuclei, and nocturnal sleep for maintaining brain CSF homeostasis. ...
... Since the cardiac pulsation is known to drive CSF flow also in the ventricular system 71-73 , these present results may reflect the altered flow of CSF along the aqueduct and through the lateral ventricles in narcolepsy type 1 patients. A recent study showed that interstitial brain volume increases during sleep, while noradrenaline activity decreased this volume during wakefulness, indicating that declining noradrenalinedriven vasomotor tone during sleep is conducive to CSF flow through the brain 25 . In narcolepsy type 1, the presumed loss of hypocretin-producing cells of the hypothalamus deprives the AAN nuclei of an excitatory input, which may lead to postulated inconsistent neurotransmitter release from these nuclei, notably the noradrenergic LC. ...
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Background Narcolepsy is a chronic neurological disease characterized by daytime sleep attacks, cataplexy, and fragmented sleep. The disease is hypothesized to arise from destruction or dysfunction of hypothalamic hypocretin-producing cells that innervate wake-promoting systems including the ascending arousal network (AAN), which regulates arousal via release of neurotransmitters like noradrenalin. Brain pulsations are thought to drive intracranial cerebrospinal fluid flow linked to brain metabolite transfer that sustains homeostasis. This flow increases in sleep and is suppressed by noradrenalin in the awake state. Here we tested the hypothesis that narcolepsy is associated with altered brain pulsations, and if these pulsations can differentiate narcolepsy type 1 from healthy controls. Methods In this case-control study, 23 patients with narcolepsy type 1 (NT1) were imaged with ultrafast fMRI (MREG) along with 23 age- and sex-matched healthy controls (HC). The physiological brain pulsations were quantified as the frequency-wise signal variance. Clinical relevance of the pulsations was investigated with correlation and receiving operating characteristic analysis. Results We find that variance and fractional variance in the very low frequency (MREGvlf) band are greater in NT1 compared to HC, while cardiac (MREGcard) and respiratory band variances are lower. Interestingly, these pulsations differences are prominent in the AAN region. We further find that fractional variance in MREGvlf shows promise as an effective bi-classification metric (AUC = 81.4%/78.5%), and that disease severity measured with narcolepsy severity score correlates with MREGcard variance (R = −0.48, p = 0.0249). Conclusions We suggest that our novel results reflect impaired CSF dynamics that may be linked to altered glymphatic circulation in narcolepsy type 1.
... Res. Public Health 2022, 19, 12323 2 of 13 thus improving the cerebral structure and helping maintain a relatively stable emotion regulation level [11]. Increasing PA could influence the metabolism via increasing central dopaminergic and noradrenergic activity, enhancing serotonergic activity, and improving mood and mental health [12]. ...
... In addition to PA, sleep also plays an important role in mental health. For instance, sleeping is an important metabolic pathway that clears metabolic waste products (e.g., β-amyloid) in the brain's interstitial fluid [17] and then directly affects individuals' mental health [18,19]. Chronic sleep deprivation might lead to pathological anxiety, and the association between sleep and mental health was considered bidirectional because mental disorders could also lead to impairments in sleep [20,21]. ...
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Physical activity (PA) and sleep are both important to mental health. However, their joint effects on mental distress have not been well explored. The aim of this study was to investigate the joint effects of PA and sleep on mental health, as well as the dose-response relationships between PA and mental health under different sleep health statuses. A longitudinal panel study was adopted to evaluate the relationship between PA, sleep, and mental health among 66 healthy Chinese college students with four online questionnaire surveys. A mixed-effect model with individual-level random effect was used to analyze the interactive regulation effect of PA and sleep on mental health, and a generalized additive model with splines was further fitted to analyze dose-response relationships between variables. When sleep was at a healthy level, no significant difference in mental health was observed between different levels of PA (p > 0.05). However, poor sleepers with moderate and high PA levels indicated significantly fewer negative emotions than those with low PA levels (p = 0.001, p = 0.004). Likewise, poor sleepers who engaged in more moderate intensity PA could significantly reduce negative emotions (β = −0.470, p = 0.011) in a near-linear trend. In summary, both sleep and PA benefit mental health, and they probably regulate mental health through an interactive compensation mode. For good and poor sleepers, PA plays a different role in maintaining and improving mental health. Increasing moderate intensity PA up to moderate-and-high levels is recommended for those who simultaneously suffer from sleep and psychological health problems.
... Recent research in rodents has revealed a system of lymphatics of the brain which likely has an analogous function to the systemic lymphatics of the body. It is posited that this socalled glymphatic system functions to remove toxins from the central nervous system which accumulate during wakefulness (Xie et al., 2013). Neuronal activity results in the production of such putative neurotoxins such as beta amyloid, alpha synuclein and tau. ...
... the CNS. This sleep-related volume enhancement results in a 95% increase in clearance (Xie et al., 2013). It is likely that the glymphatic system is involved in removal of adenosine which accumulates during consciousness. ...
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This paper will review what is conventionally known of sleep homeostasis and focus on insomnia as a primary manifestation of brain dysregulation, whether as a solitary symptom or as part of a larger syndrome such as post-traumatic stress disorder, PTSD. It will discuss in brief behavioral/mindfulness treatments that have been used to treat neurologic diseases, as this is germane to the phenomenology of neurofeedback (NF). It will explore how neurofeedback may work at the subconscious level and cover the current clinical experience of the effectiveness of this technique in the treatment of insomnia. It will conclude with a case presentation.
... Extracellular Aβ is present in CSF in a soluble form, which reduces during sleep and increases during wakefulness [35]. According to Xie L et al., natural sleep increases 60% of interstitial space in the brain, which increases the clearance of metabolites in interstitial fluid, such as Aβ [36]. It was also found that disrupting sleep for one night in healthy people can cause Aβ -plaque accumulation in the brain [37]. ...
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Alzheimer's disease (AD) is the most common incurable neurodegenerative disease caused by amyloid-β plaques and tau hyperphosphorylation as neurofibrillary tangles (NFTs) in the brain, which leads to neuronal death, cognitive impairment, and memory loss. There are few therapeutic choices for this disease as a result it has become a major public health problem and the financial impact on sufferers and the social health care system is enormous. This review focuses on lifestyle interventions involved in delaying or preventing Alzheimer's disease. Lifestyle factors include unhealthy diet, smoking, alcohol consumption, sleep disturbance, stress, cardiovascular diseases, obesity, diabetes, education, and social engagement, which are considered important risk factors for the development of Alzheimer's disease. We conclude that healthy diets, exercise, and a better lifestyle can lower the risk of AD and reduce the progression of dementia in individuals.
... DP1 activation also regulates sleep by stimulating adenosine formation and subsequently activating the adenosine receptor A2A (Ahmad et al, 2019). Studies with mice showed that sleep drives Aβ clearance from the adult brain (Xie et al, 2013). Both ischemic stroke (Vijayan et al, 2017) and sleep dysregulation (Kang et al, 2017) facilitate the progression of AD pathology. ...
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We investigated the relevance of the prostaglandin D2 pathway in Alzheimer’s disease, because prostaglandin D2 is a major prostaglandin in the brain. Thus, its contribution to Alzheimer’s disease merits attention, given the known impact of the prostaglandin E2 pathway in Alzheimer’s disease. We used the TgF344-AD transgenic rat model because it exhibits age-dependent and progressive Alzheimer’s disease pathology. Prostaglandin D2 levels in hippocampi of TgF344-AD and wild-type littermates were significantly higher than prostaglandin E2. Prostaglandin D2 signals through DP1 and DP2 receptors. Microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in TgF344-AD than in wild-type rats. Expression of the major brain prostaglandin D2 synthase (lipocalin-type PGDS) was the highest among 33 genes involved in the prostaglandin D2 and prostaglandin E2 pathways. We treated a subset of rats (wild-type and TgF344-AD males) with timapiprant, a potent highly selective DP2 antagonist in development for allergic inflammation treatment. Timapiprant significantly mitigated Alzheimer’s disease pathology and cognitive deficits in TgF344-AD males. Thus, selective DP2 antagonists have potential as therapeutics to treat Alzheimer’s disease.
... According to the glymphatic hypothesis, 5 subarachnoid CSF enters the brain interstitial space from the periarterial space via the AQP4 channel expressed in the astrocyte end-feet and then mixes with the interstitial fluid (ISF) and waste solutes in the brain. The resulting CSF/ISF exchange and waste products, such as Aβ, are then drained out of the brain via the perivenous efflux pathway. ...
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Background and Objectives The glymphatic system is a whole-brain perivascular network, which promotes CSF/interstitial fluid exchange. Alterations to this system may play a pivotal role in amyloid β (Aβ) accumulation. However, its involvement in Alzheimer’s disease (AD) pathogenesis is not fully understood. Here, we investigated the changes in noninvasive MRI measurements related to the perivascular network in patients with mild cognitive impairment (MCI) and AD. Additionally, we explored the associations of MRI measures with neuropsychological score, PET standardized uptake value ratio (SUVR), and Aβ deposition. Methods MRI measures, including perivascular space (PVS) volume fraction (PVSVF), fractional volume of free water in white matter (FW-WM), and index of diffusivity along the perivascular space (ALPS index) of patients with MCI, those with AD, and healthy controls from the Alzheimer’s Disease Neuroimaging Initiative database were compared. MRI measures were also correlated with the levels of CSF biomarkers, PET SUVR, and cognitive score in the combined subcohort of patients with MCI and AD. Statistical analyses were performed with age, sex, years of education, and APOE status as confounding factors. Results In total, 36 patients with AD, 44 patients with MCI, and 31 healthy controls were analyzed. Patients with AD had significantly higher total, WM, and basal ganglia PVSVF (Cohen’s d = 1.15-1.48; p < 0.001), and FW-WM (Cohen’s d = 0.73; p < 0.05) and a lower ALPS index (Cohen’s d = 0.63; p < 0.05) than healthy controls. Meanwhile, the MCI group only showed significantly higher total (Cohen’s d = 0.99; p < 0.05) and WM (Cohen’s d = 0.91; p < 0.05) PVSVF. Low ALPS index was associated with lower CSF Aβ42 ( r s = 0.41, p fdr = 0.026), FDG-PET uptake ( r s = 0.54, p fdr < 0.001), and worse multiple cognitive domain deficits. High FW-WM was also associated with lower CSF Aβ42 ( r s = −0.47, p fdr = 0.021) and worse cognitive performances. Conclusion Our study indicates that changes in PVS-related MRI parameters occur in MCI and AD, possibly due to impairment of the glymphatic system. We also report the associations between MRI parameters and Aβ deposition, neuronal change, and cognitive impairment in AD.
Chapter
Proper sleep is necessary for the body to maintain homeostasis. Sleep disorders are associated with physiological and psychological medical conditions, classified by the International Classification of Sleep Disorders (ICSD). In the third edition of the ICSD, Obstructive Sleep Apnea (OSA) is classified under Sleep-Related Disorder Breathing (SRDB) and is subcategorized as adult and pediatric OSA.OSA is a sleep-related breathing disorder characterized by episodes of breathing cessation (apnea) or reduction in airflow (hypopnea) that lasts more than 10 seconds, occurring more than five times per hour of sleep. Approximately 1 billion of the world’s population, between 30 and 69 years, are estimated to have OSA. ROSA risk factors of OSA include obesity, gender, age, genetics, and craniofacial as well as orofacial abnormalities. Common symptoms include fatigue, tiredness, lack of energy, chronic snoring, witnessed apneas during sleep, and nocturnal gasping/choking isbeing the most reliable indicator of OSA.Other symptoms may include chronic morning headaches, nocturnal gastroesophageal reflux, nocturnal sweating, and decreased libido.OSA is associated with an increased risk of medical conditions and comorbidities, such as hypertension, arrhythmias, stroke, chronic renal failure, metabolic syndrome, irritable bowel syndrome, diabetes, obesity, enlarged upper airway soft tissue, headache, mood disorders, and cognitive impairment such as deficit in attention, executive functions, and memory. This chapter offers an overview of OSA and its medical comorbidities.KeywordsObstructive sleep apneaCentral sleep apneaDental sleep applianceApnea-hypopnea indexSleep bruxismSleep apnea headacheTension-type headacheGastroesophageal refluxTemporomandibular joint disorderDepression
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Although tau is a cytoplasmic protein, it is also found in brain extracellular fluids, e.g., CSF. Recent findings suggest that aggregated tau can be transferred between cells and extracellular tau aggregates might mediate spread of tau pathology. Despite these data, details of whether tau is normally released into the brain interstitial fluid (ISF), its concentration in ISF in relation to CSF, and whether ISF tau is influenced by its aggregation are unknown. To address these issues, we developed a microdialysis technique to analyze monomeric ISF tau levels within the hippocampus of awake, freely moving mice. We detected tau in ISF of wild-type mice, suggesting that tau is released in the absence of neurodegeneration. ISF tau was significantly higher than CSF tau and their concentrations were not significantly correlated. Using P301S human tau transgenic mice (P301S tg mice), we found that ISF tau is fivefold higher than endogenous murine tau, consistent with its elevated levels of expression. However, following the onset of tau aggregation, monomeric ISF tau decreased markedly. Biochemical analysis demonstrated that soluble tau in brain homogenates decreased along with the deposition of insoluble tau. Tau fibrils injected into the hippocampus decreased ISF tau, suggesting that extracellular tau is in equilibrium with extracellular or intracellular tau aggregates. This technique should facilitate further studies of tau secretion, spread of tau pathology, the effects of different disease states on ISF tau, and the efficacy of experimental treatments.
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