SYNAPSE 69:1525 (2015)

Sleep Deprivation Induces Differential

Morphological Changes in the
Hippocampus and Prefrontal Cortex in
Young and Old Rats
1
~ 1 ISRAEL CAMACHO-ABREGO,2,3 MONTSERRAT MELGAREJO-GUTIERREZ,

EVA ACOSTA-PENA,
2
4
1




GONZALO FLORES, RENE DRUCKER-COLIN, AND FABIO GARCIA-GARCIA *
1
Department of Biomedicine, Health Sciences Institute, Veracruzana University, Luis Castelazo-Ayala s/n, Industrial-Animas, Xalapa, Veracruz 91190, Mexico
2
Laboratory of Neuropsychiatry, Universidad Aut
onoma de Puebla, 14 Sur 6301, CU San Manuel, Puebla,
Puebla 72570, Mexico
3
Department of Physiology, National Biological School of Sciences, Prolongaci
on de Carpio and Plan de Ayala s/n,
Santo Tomas, IPN, Mexico DF 11340, Mexico
4
Institute of Cellular Physiology, National University of Mexico, A.P. 70-250, Mexico DF 04510, Mexico

KEY WORDS

aging; synaptic plasticity; dendritic morphology; Golgi-Cox staining

ABSTRACT
Sleep is a fundamental state necessary for maintenance of physical and
neurological homeostasis throughout life. Several studies regarding the functions of sleep
have been focused on effects of sleep deprivation on synaptic plasticity at a molecular
and electrophysiological level, and only a few studies have studied sleep function from a
structural perspective. Moreover, during normal aging, sleep architecture displays some
changes that could affect normal development in the elderly. In this study, using a GolgiCox staining followed by Sholl analysis, we evaluate the effects of 24 h of total sleep
deprivation on neuronal morphology of pyramidal neurons from Layer III of the prefrontal cortex (PFC) and the dorsal hippocampal CA1 region from male Wistar rats at two
different ages (3 and 22 months). We found no differences in total dendritic length and
branching length in both analyzed regions after sleep deprivation. Spine density was
reduced in the CA1 of young-adults, and interestingly, sleep deprivation increased spine
density in PFC of aged animals. Taken together, our results show that 24 h of total sleep
deprivation have different effects on synaptic plasticity and could play a beneficial role in
cognition during aging. Synapse 69:1525, 2015. VC 2014 Wiley Periodicals, Inc.
INTRODUCTION
Sleep appears to be critical for the survival and
integrity of most living organisms. Despite emerging
evidence about molecular and cellular processes in
the brain that change in relationship with the sleep/
wake cycle, function of sleep remains unknown.
Links between sleep and brain plasticity during early
life, as well as in the adult organism, have been considered, and these links have been studied for many
years through a large number of animal and human
studies. It is known that animals and humans sleep
more during neonatal periods than at any other time
of life (Carskadon and Dement, 2005; Frank and Heller, 1997), suggesting that sleep may be important for
brain development and synaptic plasticity during
early life. Sleep has also been implicated in plastic
cerebral changes that underlie learning and memory
in the adult brain (Graves et al., 2001; Maquet, 2001;
Marshall and Born, 2007; Stickgold, 2005).
2014 WILEY PERIODICALS, INC.

Evidence indicates that hippocampus is essential

for retention of recent memory, whereas cortex participates in storing of remote memory (Frankland and
Bontempi, 2005). Anatomical and electrophysiological
studies have demonstrated the existence of monosynaptic projections from CA1 hippocampus to the prefrontal cortex (PFC; Ferino et al., 1987; Hoover and
Vertes, 2007; Jay and Witter, 1991), and as long-term
potentiation (LTP, a plasticity-related event) can be
None of the funding institution had any further role in the study design, collection, analyses and interpretation of data, writing of the report or in the
decision to submit the paper for publication.
Contract grant sponsor: CONACYT; Contract grant numbers: 133178,
138663, 215331.
*Correspondence to: Fabio Garca-Garca, Department of Biomedicine,
Health Sciences Institute, Veracruzana University, Luis Castelazo Ayala s/n,
Industrial-Animas, Xalapa, Veracruz 91190, Mexico. E-mail: fgarcia@uv.mx
Received 11 April 2014; Revised 17 June 2014; Accepted 18 August 2014
DOI: 10.1002/syn.21779
Published online 1
(wileyonlinelibrary.com).

September

2014

in

Wiley

Online

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elicited in the PFC after hippocampal stimulation, it

was proposed that these projections from hippocampus to PFC are involved in learning and memory
processes (Laroche et al., 1990).
On the other hand, sleep deprivation affects cognition, attention, working memory, and emotional
behaviors controlled by brain regions such as the neocortex, hippocampus, and amygdala (Nilsson et al.,
2005; Smith et al., 2002; Yoo et al., 2007). It has also
been demonstrated that sleep deprivation induces
changes in behavior as well as in synaptic and membrane excitability of hippocampal CA1 and PFC neurons (McDermott et al., 2003; Winters et al., 2011).
Additionally, neurogenesis (Guzm
an-Marn et al.,
2005, 2007), proliferation, differentiation, and survival of new cells in the hippocampus of adult rats
are severely affected by sleep deprivation (GarcaGarca et al., 2011; Guzm
an-Marn et al., 2003;
Roman et al., 2005). Some studies have provided evidence that the expression of certain genes involved in
synaptic plasticity changes in response to sleep or
sleep loss (Andersen et al., 2009; Cirelli and Tononi,
2000; Taishi et al., 2001).
Several changes in sleep/wake patterns are observed
during normal aging, which include frequent awakenings during sleep and increased daytime naps (Bliwise, 2005; Mendelson and Bergmann, 1999).
Likewise, aging has also been associated with a deterioration of cognitive function, learning and memory
(reviewed in Bishop et al., 2010). In addition, despite
initial studies suggest that cognitive decline observed
with aging could be due to neuronal loss (Brody, 1955),
more recent studies have shown that it is regionrestricted and much less prevalent than previously
thought (Madeira et al., 1995; Merrill et al., 2001;
Mohammed and Santer, 2001) and that more subtle
changes such as modifications in dendrite complexity,
dendritic spines, or even axons occur in neurons with
age (reviewed in Dickstein et al., 2007; Pannese,
2011), and as seen before, frontal regions and hippocampus are particularly prone to alterations due to
both sleep/wake changes and aging process (Bertini
et al., 2010; Tucker et al., 2011; Winters et al., 2011).
Additionally, as changes in dendritic length, dendritic
arborization, and spines (sites for synaptic contact)
are correlated to the degree of neuronal connectivity
and thus number of synapses, it is possible to make
inferences about these parameters by measuring total
dendritic length, dendritic length per branch order,
and spine density (McAllister, 2000; Uylings and van
Pelt, 2002). Golgi-Cox staining and Sholl analysis
have been broadly used to evaluate these differential
aspects of neuronal morphology (Binley et al., 2014;
Levine et al., 2013; Milosevic and Ristanovic, 2007),
and for that reason, we have used it in this study.
Therefore, it has been hypothesized that sleep
deprivation may compromise neurophysiological and
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behavioral events; however, relatively few studies

have investigated links between sleep loss and structural changes in neurons. Despite the seemingly similar effects of age and sleep deprivation on cognition
and the prevalence of sleep changes with age, little is
known about the impact of sleep loss on cellular morphology in aging neurons. For that reason, the aim of
this study was to evaluate the effects of total sleep
deprivation on neuronal morphology in the hippocampus and cortex of both young and aged animals.
MATERIALS AND METHODS
Subjects
A total of 28 male Wistar rats (14 young-adult
rats, 3 months old; 14 aged rats, 22 months; seven
for control and seven for sleep deprivation for each
age) were used in this study. These animals were
obtained from our animal facility (School of Medicine)
and were kept in a temperature-controlled environment (22 C 6 1 C) and a 12:12 light/dark cycle with
lights turned on at 8:00 a.m., with free access to food
and water throughout the experimental procedure.
All procedures described were approved by the Institutional Animal Care and Use Committee in agreement with the national guide for the care and use of
laboratory animals (NOM-062-ZOO-1999). Every
effort was made to minimize the number of animals
used and to ensure them minimal pain and
discomfort.
Electrode implantation surgery and sleep
recording
After deep anaesthesia with ketamine-xylazine (87
and 13 mg/kg, respectively), three stainless steel miniature screws, used as electrodes, were implanted
over the frontal and parietal bones to record a cortical electroencephalogram (EEG). Two stainless steel
R -coated
TeflonV
wire electrodes were bilaterally
inserted into neck muscles to record the electromyographic (EMG) activity. Cortical and muscular electrodes were soldered to a recording plug, which was
attached to the skull with dental acrylic. Immediately
after surgery, animals received an intramuscular
injection of ketorolac and ampicillin (3.5 and 10 mg/
kg, respectively) to reduce pain, inflammation, and
prevent any infection. All animals were allowed a 7day postsurgery recovery period, followed by 1 day of
habituation with the cable connected and housed in
the recording chamber. After habituation, EEG and
EMG signals were recorded during 24 h, starting at
8:00 a.m., and then stored in a computer hard disk
for subsequent offline analysis. Two groups (one
young-adult and one aged, n 5 7 per group) were
used to obtain sleep recordings without any other
manipulation, thus serving as control groups.
Sleepwake cycle stages were manually scored in
12-s epochs using standard criteria as follows:

DENDRITIC MORPHOLOGY AFTER SLEEP DEPRIVATION

wakefulness (WAKE): EEG with low-amplitude and

high-frequency waves coupled to high-voltage EMG
activity; nonrapid eye movement sleep (NREM): EEG
rich in high-amplitude and low-frequency waves and
low voltage for EMG; and rapid eye movement sleep
(REM): highly regular theta EEG activity and loss of
muscle tone with occasional twitches. The presence of
at least 80% of each stage per epoch was considered
an episode of stage.
Total sleep deprivation
Two experimental groups (young-adults and aged,
n 5 7 per group) were used for 24 h of total sleep
deprivation, starting at 8:00 a.m. Briefly, rats were
kept awake by gentle touching in their tails, coat, or
whiskers, soft shaking of their cages, or handling
them to prevent falling asleep. Gentle handling is a
common procedure used to perform total sleep deprivation in rodents because it induces minimal stress
(Franken et al., 1991; Melgarejo-Gutierrez et al.,
2013; Romcy-Pereira and Pavlides, 2004).
EEG and EMG activities were recorded throughout
the sleep deprivation period, ensuring that animals
did not show bouts of microsleep (5- to 10-s episode of
slow wave activity), which are characteristic of prolonged sleep loss.
Sleep deprivation was carried out in batches of
three rats at a time (randomly chosen from both
sleep-deprived groups), allowing researchers to pay
close attention to the animals behavior. The 12:12-h
photoperiod was maintained during the 24 h of sleep
deprivation, and during the lights-off period, a dim
red light was turned on to continue the sleep
deprivation.
Golgi-Cox staining
Immediately after sleep recording and total sleep
deprivation, animals were deeply anesthetized with
sodium pentobarbital (75 mg/kg, i.p.) and then perfused intracardially with 0.9% saline solution. Brains
were removed and stained by modified Golgi-Cox
method following a previously described protocol
(Silva-Gomez et al., 2003). Brains were first
immersed in Golgi-Cox solution for 14 days in the
dark, followed by 3 days in 30% sucrose solution. Coronal sections (200 mm thick) from PFC and dorsal
hippocampus (DH) were obtained using a vibrotome.
Sections were collected on clean gelatin-coated microscope slides and treated with ammonium hydroxide,
followed by immersion in Kodak Film Fixer, rinsed
with distilled water, dehydrated, cleared, and finally
mounted, using resinous medium.
Microscopic observation and Sholl analysis
Pyramidal neurons from Layer III of PFC (Cingulate1 area and prelimbic cortex, plates 79 from Paxinos and Watson, 1986) and CA1 region of DH (plates

17

2733 from Paxinos and Watson, 1986) were selected

for this study. Five neurons from each region of each
brain hemisphere per animal (10 neurons per animal,
a total of 70 neurons per group) were drawn using
camera lucida at 2503 magnification by a trained
person who was blind to treatment conditions.
Pyramidal neurons were identified by their characteristic triangular soma-shape, apical dendrites extending toward the pial surface, and numerous dendritic
spines. Basal dendrites, including all branches, were
reconstructed for each selected neuron, and their
dendritic tracings were quantified by Sholl analysis
(Sholl, 1953). Briefly, a transparent grid with concentric rings, equivalent to 10-mm spacing, was placed
over the drawing, and the number of dendrites intersecting each ring was used to estimate the total dendritic length. The length of the dendritic arborization
was estimated by counting the number of intersections per each branch order for all neurons. Dendritic
spine density was estimated by drawing at least 10mm long segments from the terminal tips of dendrites
at high power (10003) and by counting the number
of spines.
Statistical analysis
Data are expressed as mean 6 SEM. One-way
analysis of variance (ANOVA) was used for comparison of data from sleepwake cycle analysis, in which
the independent variable was age and the dependent
variable was the stage in question; for all analyses,
P < 0.05 was considered significant. For morphological analysis, mean values of each animal for each
brain region were treated as a single measurement
for data analysis (n 5 7). Data of dendritic length
and spine number were analyzed by two-way
ANOVA, followed by the Newman-Keuls test for post
hoc comparisons, with age and sleep deprivation as
independent factors. Data of length per branch order
were also analyzed by two-way ANOVA, followed by
the Newman-Keuls test for post hoc comparisons,
with sleep deprivation and branch order as independent factors.
RESULTS
Sleepwake cycle analysis
When compared with young-adult animals, aged
animals showed a significant decrease in baseline
amount of wakefulness (young-adult 47.68% 6
3.417%; aged 40.15% 6 2.215%; P < 0.05), whereas
percentage of NREM sleep was increased (young-adult
37.36% 6 2.354%; aged 44.77% 6 1.599%; P < 0.05).
These changes were markedly present during the
dark period. The amount of REM sleep during 24 h
was not modified by age (young-adult 13.53% 6
1.177%; aged 15.07% 6 0.889%). Frequency (expressed
as episodes per hour) of NREM and REM sleep was
also altered by age showing an increase in both stages
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Fig. 1. Variations in sleepwake cycle parameters during 24 h of recording. (a) Percentage of time spent
in each stage; (b) frequency of phases, expressed as episodes per hour; and (c) average duration (minutes) of
each period. NREM, nonrapid eye movements sleep; REM, rapid eye movements sleep. *P < 0.05; **P <
0.001; ***P < 0.0001.

(NREM: young-adult 7.956 6 0.3158 episodes per

hour; aged 9.856 6 0.366 episodes per hour, P < 0.01;
REM: young-adult 5.833 6 0.4891 episodes/h; aged
7.639 6 0.4474 episodes/h, P < 0.05) predominantly
during the dark period, with no differences in the
mean duration of their bouts (NREM: young-adult
2.186 6 0.09881 min; aged 2.289 6 0.1016 min; REM:
young-adult 0.994 6 0.1045 min; aged 0.975 6 0.0548
min). Frequency of WAKE periods was unaltered;
however, its duration was reduced in the dark period
in aged animals (young-adult 9.061 6 0.931 min; aged
6.778 6 0.870 min; P < 0.001; Fig. 1).
As expected, in sleep-deprived animals, total
amount of NREM sleep was dramatically reduced in
both young-adult (1.760 6 0.5672%) and aged (4.150
6 1.325%) animals; REM sleep was completely suppressed, and WAKE was extremely increased in both
experimental groups (young-adult SD 98.41% 6
0.432%; aged SD 97.02% 6 1.011%) when compared
with their respective baseline control (Table 1).
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Sholl analysis
Estimates of total dendritic length, dendritic length
per branch order, and spine density were obtained
from a total of 280 neurons from PFC and 280 from
DH (four groups, n 5 7, 10 neurons each animal).
Sholl analysis revealed that total dendritic length of
pyramidal neurons in both regions was not affected
by sleep deprivation, independent of age (PFC:
young-adult control 2233.000 6 69.857 mm, youngadult SD 2238.429 6 68.812 mm, aged control
2100.286 6 67.088 mm, aged SD 2249.286 6 68.942
mm; DH: young-adult control 1724.571 6 52.421 mm,
young-adult SD 1759.286 6 46.663 mm, aged control
1673.000 6 48.602 mm, aged SD 1626.000 6 63.961
mm; Fig. 2).
The branch-order analysis of pyramidal neurons
revealed that SD induced a significant reduction in
dendritic length only at the seventh order in PFC
neurons in young rats when compared with young
controls (young-adult control 13.14 6 4.803 mm;

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DENDRITIC MORPHOLOGY AFTER SLEEP DEPRIVATION

TABLE 1. Total amount of sleepwake stages in control and sleep deprivation during 24 h
Stage

Young control

Aged control

Young SD

Aged SD

WAKE
NREM sleep
REM sleep

47.68 6 3.417
37.36 6 2.354
13.53 6 1.177

40.15 6 2.215*
44.77 6 1.599*
15.07 6 0.889

98.41 6 0.432**
1.760 6 0.567**

97.02 6 1.011**
4.150 6 1.325**

Data are percentages of time of sleep in different sleepwake stages; SD groups are compared with their respective age control. SD, sleep deprivation; , REM sleep
was not observed. Data are expressed as means 6 SEM. *P < 0.05; **P < 0.001.

Fig. 2. Effect of sleep deprivation on total dendritic length. Total dendritic length of prefrontal cortex and
dorsal hippocampus was not affected either by age or by 24 h of sleep deprivation when compared with their
corresponding control groups.

young-adult SD 0.286 6 0.1844 mm; P < 0.05). There

was no difference in branch-order length of DH neurons between control groups by age and after 24 h of
sleep deprivation (Fig. 3).
Age-dependent changes were observed in dendritic
spine density in both analyzed regions (PFC: youngadult control 9.823 6 0.2348 spines/10 mm, aged control 8.557 6 0.1821 spines/10 mm, P < 0.001; DH:
young-adult control 13.18 6 0.2369 spines/10 mm,
aged control 11.53 6 0.2384 spines/10 mm; P <
0.001). Sleep deprivation produced an increase in
spine density in PFC of aged animals (control 8.557
6 0.1821 spines/10 mm; SD 9.442 6 0.1464 spines/10
mm; P < 0.01) but not in young-adult animals. This
effect was not observed in DH, where sleep deprivation decreased the number of spines in neurons from
young-adult animals (control 13.18 6 0.2369 spines/
10 mm; SD 11.39 6 0.1326 spines/10 mm; P < 0.0001),
without affecting the aged group (Fig. 4).
DISCUSSION
Previous animal and human studies have documented that sleepwake cycle is strongly related to
cognitive processes and both events are modified by
normal aging. However, most studies about sleep and
its relation to synaptic plasticity have been mainly
focused on changes in both molecular and electrophysiological changes at synapse during sleep or after
sleep deprivation. Very few have reported details

concerning structural changes in individual neurons

after sleep or sleep deprivation. Therefore, the aim of
this study was to investigate the effect of 24 h of total
sleep deprivation on dendritic morphology of pyramidal neurons from PFC and dorsal CA1 regions making a comparison between young-adult and aged rats.
An important aspect of aging involves frequent
changes in sleep structure and circadian rhythmicity
(Van Someren, 2000). Our baseline sleepwake analysis was conducted to know how sleepwake cycle is
modified by age; interestingly, we found an increase
in total NREM percentage and frequency of NREM
and REM episodes and reductions in total wake percentage and mean duration of wake episodes particularly during dark period when rats are normally
more active. It is known that during aging, sleep pattern experiences some modifications including
increase in frequency or length of stages; however,
baseline total sleep differences between young and
old rats are not always observed (Clement et al.,
2003; Li and Satinoff, 1995; Mendelson and Bergmann, 1999; Shiromani et al., 2000). Our results
show a fragmented architecture of sleepwake cycle
related to aging. There was an unexpected increase
in total and nocturnal NREM sleep times, which is
different than other studies; however, even in previous studies, there is a discrepancy of this event and
it could due to sleep parameters recording or analyzed (such as epoch length or time of recording),
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Fig. 3. Length of dendritic branches according to their order. Sleep deprivation (SD) induced a decrease in
dendritic length only at the seventh order in pyramidal neurons from the prefrontal cortex (PFC) of youngadult sleep-deprived animals when compared with its corresponding control group. No significant changes
were observed in the hippocampal neurons; *P < 0.05.

darklight conditions, or even the strain used (Clement et al., 2003; Mendelson and Bergmann, 1999;
Shiromani et al., 2000). However, a recent study demonstrated a NREM increase and decreased wakefulness in normal aged mice over 24-h recordings and
particularly during dark period (Wimmer et al.,
2013), suggesting the inability of brain to sustain
normal sleepwake cycle stages during aging. Moreover, the presence of those nocturnal naps revealed
a kind of reversed sleep pattern, similar to that
observed in older humans, which have common
reduction in nocturnal sleep and fragmented cycle;
however, total sleep time along 24 h is increased and
correlates with common diurnal naps (Dijk et al.,
2001; Monk et al., 2001; for review, see Wolkove
et al., 2007).
With regard to morphological analysis, our experiments revealed no age-dependent changes in total
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dendritic length and branching order at basal conditions in both PFC and dorsal CA1 pyramidal neurons; however, aged animals showed a significant
reduction in spine density in both regions in comparison with young-adult animals. Similar to our results,
it has been reported in aged nonhuman primates
that cortical neurons show no differences in their
total dendritic length, but there is a loss of dendritic
spines when compared with young-adult animals
(Page et al., 2002). Spine loss on basal dendrites from
pyramidal neurons occurred mainly on distal
branches, and dendrites were modified according to
the region and species analyzed (Duan et al., 2003;
Dumitriu et al., 2010; Gong et al., 2009). Additionally,
the fact that neurons from PFC and CA1 here analyzed primarily use glutamate as neurotransmitter
suggests its involvement in plastic changes observed.
The glutamate itself may control spine formation and

DENDRITIC MORPHOLOGY AFTER SLEEP DEPRIVATION

21

Fig. 4. Dendritic spine density in prefrontal cortex (PFC) and

hippocampal CA1 neurons. Age-dependent effects were observed in
both the PFC and the hippocampus, where pyramidal neurons of
aged animals showed a reduction in the number of spines when
compared with their respective young controls. After 24 h of sleep

deprivation (SD), aged animals showed increased spine density in

the PFC but not in the hippocampus. In young-adult animals, SD
produced a spine density reduction in the hippocampus but not in
the PFC; *P < 0.01; **P < 0.001; ***P < 0.0001.

retraction at glutamatergic synapses (Kalb, 1994;

McAllister, 2000; Rajan et al., 1999; Vogel and Prittie,
1995). In addition, some reports suggest that during
aging, extracellular glutamate levels gradually rise
(Nickell et al., 2005; Zoia et al., 2004, 2005) with an
increase in the sensitivity of certain neurons to the
cytotoxic effects of glutamate (Brewer, 2000). On the
other hand, a significant reduction in dendritic levels
of microtubule-associated protein 2, a marker of dendritic structure, has been observed in the aged brain
(Chauhan and Siegel, 1997).
Autoradiographic experiments suggest that aging
induces reductions in the alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) and Nmethyl-D-aspartate (NMDA) receptors density at the
hippocampal formation (Clark et al., 1992; Wardas
et al., 1997), whereas in the frontal cortex, NMDA
receptor density was decreased without changes in
AMPA receptor density (Wardas et al., 1997). In addition, neurotrophins are other possible candidates that
may regulate dendritic growth and synaptogenesis
during aging (McAllister, 2000). For example, brainderived growth factor (BDNF) and nerve growth factor (NGF) are two of the major neurotrophic factors
involved in maintenance and survival of neurons,
synaptic integrity, and synaptic plasticity (for review,
see Dwivedi, 2013) that are affected by age because
NGF levels in old rats are reduced in cortex without
change at the hippocampus and BDNF levels are
reduced in the hippocampus without changes in cortex from old rats (Perovic et al., 2013). Another
important neurotrophin is the insulin-like factor 1,
which may contribute to synaptic function decline
observed during aging (Alem
an and Torres-Alem
an,
2009; reviewed in Deak and Sonntag, 2012).

Related to sleep deprivation, our results suggest

that 24 h of total sleep deprivation had distinct agedependent effects on structural synaptic plasticity in
each analyzed region. In young-adult animals, total
dendritic length and branching order length in both
PFC and DH were not affected by total sleep deprivation when compared with their respective control.
There was a difference at the seventh order in the
PFC; however, it was not considered to be critical in
modifying neuronal connectivity. In addition, an
important reduction in spine density was observed in
dorsal CA1 but not in PFC neurons. The basis for
these changes observed after sleep deprivation are
not clear; however, in view of dendritic spines, they
are thought to provide a reliable indicator of excitatory synaptic activity (for revisions, see Chen and
Nedivi, 2010; Gazzaley et al., 2002; Harms and
Dunaevsky, 2007), and studies have documented substantial and dramatic changes in dendritic spine
development due to induction or maintenance of LTP
(Engert and Bonhoeffer, 1999; reviewed in Yuste and
Bonhoeffer, 2001). LTP changes could be one but not
unique way involved in the hippocampal reduction of
dendritic spines here observed. This statement comes
from numerous studies that confirms sleep deprivation impairs hippocampal-dependent learning and
reduces hippocampal LTP, both in vivo (Ishikawa
et al., 2006; Kim et al., 2005; Marks and Wayner,
2005; Romcy-Pereira and Pavlides, 2004; Zagaar
et al., 2013) and in vitro (Campbell et al., 2002; Davis
et al., 2003; McDermott et al., 2003; Ravassard et al.,
2009; Tartar et al., 2006). Together, impairments in
LTP, reductions in membrane excitability especially
at the CA1 hippocampal region (Tartar et al., 2010;
Yang et al., 2010), changes in the expression of the
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NMDA receptor and subunit composition (Chen

et al., 2006; Kopp et al., 2006; McDermott et al.,
2006), impaired intracellular Ca21 concentrations
(Chang et al., 2012), and also hippocampal but not
cortical reductions in genes such as cAMP responseelement binding, calcium calmodulin-dependent pron-Marin
tein kinase II, synapsin I, BDNF (Guzma
et al., 2006), the cytoskeletal protein cortactin (Davis
et al., 2006), and phosphorylated extracellular signalregulated kinases (Ravassard et al., 2009) induced by
sleep deprivation may also play an important role in
modulation of changes observed here as all the above
mechanisms are related to dendritic spine reorganization (Ethell and Pasquale, 2005). It is worth mentioning is that not all brain regions respond in the same
way: we found that CA1 region from young-adult animals is more susceptible than the PFC to sleep deprivation; this is in agreement with the finding that
there is a dissociation between the effects of sleep
ndeprivation in the hippocampus and PFC (Guzma
Marin et al., 2006; Romcy-Pereira and Pavlides,
2004), and if we reversely correlated our findings, we
could suggest that spine formation serves as a mechanism for improvements in hippocampal-dependent
memory observed after sleep and maybe synaptic
homeostasis in PFC as we found no changes in dendritic spine density in this region, and moreover,
deactivation of the dorsolateral frontal cortex during
sleep was observed in another study (Chee and Choo,
2004). However, further information about the relation between sleep deprivation and synaptic functioning, particularly at the PFC, is required.
Similar to young-adult, aged animals did not show
differences at branching and total dendritic lengths
after sleep deprivation when compared with their
respective controls neither at CA1 nor PFC; however,
by contrast, there were no changes in spine density
from CA1, and in fact, sleep deprivation caused an
increase in spine density of PFC neurons. It is difficult to understand and more animal research is necessary; however, taking human studies as reference,
it is known that aging is accompanied by structural
and neurophysiological changes in the brain
(reviewed in Bishop et al., 2010). Interestingly, studies have shown that young-adult subjects exhibit
hemispheric lateralization in performance of memory
tests, particularly in the PFC, whereas aged subjects
show bilateral activation and recruitment of other
regions during task performance to compensate the
age-dependent decline in primary areas (Cabeza
et al., 2002; Park and Reuter-Lorenz, 2009; Rajah
and McIntosh, 2008). Something similar could happen in our study as sleep deprivation demands cortical activation for being awake, and consequently
increased spine density at aged PFC, as we showed,
could act as an alternative protective mechanism to
provide the brain the ability to better respond to
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physiological demands associated with sleep deprivation. Functional significance of these sleep-dependent
events is not clear; however, it could suggest that
sleep may play an active role in synaptic network
remodeling (Gilestro et al., 2009; Liu et al., 2010;
Vyazovskiy et al., 2008) through erasing unnecessary
connections and providing the brain additional storage capability and well functioning as proposed by
Tononi and Cirelli (2003). However, additional studies
about it are crucial to better understanding.
On the other hand, stress seems to negatively
affect dendritic morphology (Liston and Gan, 2011;
Radley et al., 2006); however, in a previous study, we
found no changes in serum corticosterone levels, and
no signs of stress-induced damage in cells were
observed as a result of our sleep deprivation method
(Melgarejo-Gutierrez et al., 2013). Recently, findings
show that higher levels of corticosterone than
observed here are necessary to induce a significant
increase in density of dendritic spines (Yoshiya et al.,
2013). Therefore, changes in dendritic spine density
and whole results observed in sleep-deprived animals
in our study are result of sleep loss per se and not
due to manipulation.
In general, our results suggest that 24 h of total
sleep deprivation is not sufficient time to dramatically damage neuronal morphology, and more than
being a harmful event, sleep deprivation may have a
plasticity-inductor role that could serve as a protective factor to prevent cognitive decline observed in
old age. In agreement to this finding, some recent
studies have studied this protective theory; MartnezVargas et al. (2012) reported that 24 h of total sleep
deprivation after a traumatic brain injury reduces
morphological damage and enhances the recovery
process; another study revealed an increase in hippocampal neurogenesis after short-term (612 h) total
sleep deprivation (Grassi Zucconi et al., 2006) and an
acceleration of cell proliferation (Junek et al., 2010).
In addition, although neurological disorders are not
considered to be sleep disorders per se, recent data
have revealed that sleep abnormalities are among the
most prevalent and common symptoms, and interestingly, sleep deprivation may contribute to a better
evolution of these disorders; for example, patients
with Parkinsons disease improve motor deficits and
symptomatology after a single night of total sleep
deprivation, where a possible change in dopaminergic
receptors may explain the improvement (Bertolucci
et al., 1987; Duran-Vazquez and Drucker-Colin, 1997;
Reist et al., 1995). Recent studies focused on patients
suffering with insomnia associated with depression
have shown that sleep deprivation therapy improves
mood and cognition (Luca et al., 2013; Martiny et al.,
2013), suggesting an important role for sleep deprivation in treatment of neurological diseases involving
sleep disturbances; however, mechanisms through it

DENDRITIC MORPHOLOGY AFTER SLEEP DEPRIVATION

happen to remain unknown. Our study suggests that

these improvements could be due to changes in dendritic spine plasticity; however, more information in
this regard is necessary.
Taken together, our current results provide a
framework for future studies that should be aimed at
the understanding of molecular, genetic, and physiological remodeling occurring as a consequence of
sleep or sleep deprivation. Further studies, particularly within the PFC, should investigate the relationship between total sleep deprivation and neuronal
morphology at different ages, and for that reason, our
current data open more lines of research.
ACKNOWLEDGMENTS
R. Drucker-Coln, F. Garca-Garca, and G. Flores
acknowledge the National Researchers System from
Mexico for membership. The authors thank Stephanie Newton for reviewing and editing the
manuscript.
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