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Is silence golden? Effects of auditory stimuli and their absence on adult hippocampal neurogenesis

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Abstract

We have previously hypothesized that the reason why physical activity increases precursor cell proliferation in adult neurogenesis is that movement serves as non-specific signal to evoke the alertness required to meet cognitive demands. Thereby a pool of immature neurons is generated that are potentially recruitable by subsequent cognitive stimuli. Along these lines, we here tested whether auditory stimuli might exert a similar non-specific effect on adult neurogenesis in mice. We used the standard noise level in the animal facility as baseline and compared this condition to white noise, pup calls, and silence. In addition, as patterned auditory stimulus without ethological relevance to mice we used piano music by Mozart (KV 448). All stimuli were transposed to the frequency range of C57BL/6 and hearing was objectified with acoustic evoked potentials. We found that except for white noise all stimuli, including silence, increased precursor cell proliferation (assessed 24 h after labeling with bromodeoxyuridine, BrdU). This could be explained by significant increases in BrdU-labeled Sox2-positive cells (type-1/2a). But after 7 days, only silence remained associated with increased numbers of BrdU-labeled cells. Compared to controls at this stage, exposure to silence had generated significantly increased numbers of BrdU/NeuN-labeled neurons. Our results indicate that the unnatural absence of auditory input as well as spectrotemporally rich albeit ethological irrelevant stimuli activate precursor cells-in the case of silence also leading to greater numbers of newborn immature neurons-whereas ambient and unstructured background auditory stimuli do not.
SHORT COMMUNICATION
Is silence golden? Effects of auditory stimuli and their absence
on adult hippocampal neurogenesis
Imke Kirste Zeina Nicola Golo Kronenberg
Tara L. Walker Robert C. Liu Gerd Kempermann
Received: 9 July 2013 / Accepted: 16 November 2013 / Published online: 1 December 2013
ÓThe Author(s) 2013. This article is published with open access at Springerlink.com
Abstract We have previously hypothesized that the rea-
son why physical activity increases precursor cell prolif-
eration in adult neurogenesis is that movement serves as
non-specific signal to evoke the alertness required to meet
cognitive demands. Thereby a pool of immature neurons is
generated that are potentially recruitable by subsequent
cognitive stimuli. Along these lines, we here tested whether
auditory stimuli might exert a similar non-specific effect on
adult neurogenesis in mice. We used the standard noise
level in the animal facility as baseline and compared this
condition to white noise, pup calls, and silence. In addition,
as patterned auditory stimulus without ethological rele-
vance to mice we used piano music by Mozart (KV 448).
All stimuli were transposed to the frequency range of
C57BL/6 and hearing was objectified with acoustic evoked
potentials. We found that except for white noise all stimuli,
including silence, increased precursor cell proliferation
(assessed 24 h after labeling with bromodeoxyuridine,
BrdU). This could be explained by significant increases in
BrdU-labeled Sox2-positive cells (type-1/2a). But after
7 days, only silence remained associated with increased
numbers of BrdU-labeled cells. Compared to controls at
this stage, exposure to silence had generated significantly
increased numbers of BrdU/NeuN-labeled neurons. Our
results indicate that the unnatural absence of auditory input
as well as spectrotemporally rich albeit ethological irrele-
vant stimuli activate precursor cells—in the case of silence
also leading to greater numbers of newborn immature
neurons—whereas ambient and unstructured background
auditory stimuli do not.
Keywords Plasticity Stem cells Hippocampus
Mouse Learning
Introduction
Adult neurogenesis adds plasticity to the dentate gyrus of
the hippocampus and is involved in key functions such as
pattern separation (Aimone et al. 2010; Clelland et al.
2009) and avoidance of catastrophic interference (Appleby
and Wiskott 2009; Wiskott et al. 2006) by adding flexi-
bility to the network in situations where novel information
has to be integrated into established representations (Gar-
the et al. 2009; Dupret et al. 2008). Adult neurogenesis is
regulated by behavioral activity. Both physical activity and
exposure to a challenging environment increase adult
neurogenesis but do so by different means (Kronenberg
et al. 2003). Non-specific stimuli like physical activity
enhance the proliferation of precursor cells and lead to an
increased potential in form of a larger pool of
I. Kirste Z. Nicola T. L. Walker G. Kempermann (&)
CRTD, DFG Research Center for Regenerative Therapies
Dresden, Fetscherstraße 105, 01307 Dresden, Germany
e-mail: gerd.kempermann@crt-dresden.de;
gerd.kempermann@dzne.de
I. Kirste
Brain Imaging and Analysis Center (BIAC), Duke University
Medical Center, Durham, NC 27710, USA
G. Kronenberg
Klinik und Poliklinik fu
¨r Psychiatrie und Psychotherapie,
Charite
´- Universita
¨tsmedizin Berlin, Charite
´Campus Mitte,
10117 Berlin, Germany
R. C. Liu
Department of Biology, Emory University, Atlanta, GA, USA
G. Kempermann
German Center for Neurodegenerative Diseases (DZNE)
Dresden, Arnoldstraße 18b, 01307 Dresden, Germany
123
Brain Struct Funct (2015) 220:1221–1228
DOI 10.1007/s00429-013-0679-3
‘neuroblasts’’ and immature neurons that can be recruited
in case of a cognitive challenge. In contrast, exposure to an
enriched environment promotes the survival of newborn
neurons. Accordingly, the two interventions turned out to
be additive in their effect (Fabel et al. 2009).
The new immature neurons own particular functionality
in that they are more likely to generate action potentials in
response to incoming stimuli due to their particular balance
between excitatory and inhibitory input (Marin-Burgin
et al. 2012). The threshold for LTP induction is reduced in
these neurons (Schmidt-Hieber et al. 2004; Snyder et al.
2001). In fact, the LTP that is measurable in the dentate
gyrus under physiological conditions is contributed by the
newborn neurons during this critical period of their
development (Garthe et al. 2009; Saxe et al. 2006). Thus,
the immature new neurons are assumed to be more easily
excitable than older cells, biasing the input towards the
more plastic subpopulation of cells (Marin-Burgin et al.
2012). The hypothesis is that this mechanism allows flex-
ible adaptation and learning of new information in previ-
ously established contexts. Non-specific stimuli would
increase precursor cell proliferation to increase a pool of
cells that can be recruited if cognitive demand arises (for
detailed discussion see: Fabel et al. 2009).
The finding that exercise would have this effect on
proliferation raised the question, whether other non-spe-
cific stimuli would also lead to an increased availability of
potentially recruitable cells. Presumably, the intrinsic
stimulus during physical activity essentially consists of
proprioception and vision. Likewise, there are numerous
reports on links between the vestibular system and hippo-
campal function [(Brandt et al. 2005); see Ref. Smith et al.
(2010) for review] even though effects on adult neuro-
genesis have not yet been specifically addressed. In order to
identify relevant sensory stimuli independent of locomo-
tion, we here focused on auditory input as a potential signal
to affect adult hippocampal neurogenesis.
Noise trauma with inner ear hair cell loss has led to a
reduction of precursor cell proliferation in the hippocam-
pus of rats (Kraus et al. 2010). A potential positive regu-
latory effect of sound on the early steps of adult
hippocampal neurogenesis, however, has not yet been
explored. We asked how different types of auditory stimuli
would affect the baseline regulation of adult hippocampal
neurogenesis (Fig. 1a).
We used ambient noise in the animal facility (animal
house noise) as baseline and exposed our mice to four
different conditions: (1) white noise as unstructured audi-
tory stimulus; (2) mouse pup calls as structured stimulus
that is for mice common and relevant; (3) Mozart piano
music as a structured stimulus, unknown and presumably
irrelevant to mice; and (4) silence.
Materials and methods
Animals
All experiments were performed according to national and
institutional guidelines and were approved by the Institu-
tional Animal Care and Use Committee (IACUC) of
Emory University.
Forty female C57BL/6J mice were obtained from The
Jackson Laboratory (Bar Harbor, Maine, USA) and were 6
to 8 weeks old at the beginning of the experiments. For all
experiments, mice were held under standard laboratory
housing conditions with a 12-h light/dark cycle and
ad libitum access to food and water. Delivered mice were
given a minimum of 5 days for habituation after arrival and
housed in groups of five animals per cage (N=10 per
group).
In comparison to other mouse strains, C57BL/6 animals
have certain advantages in adult neurogenesis research
because they typically show high neurogenic activity
within the dentate gyrus, which responds readily to
extrinsic stimuli (Kronenberg et al. 2003). We thus decided
to use C57BL/6 despite the age-related presbyacusis that is
typical for that strain (Hunter and Willott 1987).
Auditory brainstem response
To control for potential hearing loss, 10 additional animals
were used for measurement of the auditory brainstem
response (ABR) in order to determine the average hearing
ability of this strain at the given age of 8 weeks. This
information was used to define the exposure parameters for
the animals in the experiment.
Before testing, mice were anesthetized with 100 mg/kg
body weight Ketamine and 0.3 mg/kg Medetomidine by
intraperitoneal injection. During recording of the ABR, the
eyes were covered with eye ointment to prevent dryness.
Once no more motor reflexes could be induced from the
animal, silver wires were placed subdermally posterior to
the stimulated ear, at the skull midline (ground) and at the
contralateral bulla.
The recordings were done with a calibrated sound
delivery system (Tucker-Davis Technologies, Gainesville,
FL, USA) and BioSig program. Click trains and tones at 7,
32 or 65 kHz were presented to the anesthetized females at
a sampling rate of 223,214.06 per second. All tones were
presented with 3 ms duration, intensity in the range of 0 dB
SPL to 75 dB SPL, and an onset/offset ramp of 1.5 ms.
Auditory evoked activity was recorded, amplified
(910,000), and filtered (10 Hz–3 kHz). The hearing
threshold was defined as the lowest intensity at which
reliable responses were recorded.
1222 Brain Struct Funct (2015) 220:1221–1228
123
At the end of the recordings, animals were injected
subcutaneously with 0.05 ml lactated Ringer solution to
prevent dehydration. The mice were monitored until they
awoke and normal grooming and drinking behavior was
observed.
Exposure to sound stimuli
Ten animals of each group were placed into an anechoic
sound isolation box (Acoustic Systems, Austin, TX, USA)
for 2 h/day at the beginning of the dark phase of the light–
No. of BrdU+ cells
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Pup calls vs. White noise
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Differentiation
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EEffects on proliferation: significance FBrdU+/Sox2+ cells GEffects on BrdU+/Sox2+ cells
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Fig. 1 Regulation of adult hippocampal neurogenesis in dependency
of auditory stimuli. aWe used two different approaches to address
both proliferation and survival/differentiation by injection of BrdU
either 24 h before daily sounds exposure or after daily sound exposure
(see ‘Materials and methods’’ for details). During the auditory
stimulation for 2 h each day, animals were kept in anechoic sound
isolation box to prevent outside interference (c). Auditory brain stem
responses were measured in mice at the experimental age of 8 weeks
to control for hearing abilities during the experiments and to adjust
the dB levels (b). While white noise did not show any effect on the
number of proliferating cells in the adult dentate gyrus, all other
stimuli significantly increased the size of the population of BrdU?
cells (d,e,a). In case of exposure to silence as well as Mozart’s piano
music (KV 448), we found particular increase in the population of
BrdU-marked Sox2-positive precursor cells (f,g). The side length of
the box in the large panel of (f) equals 150 lm. Differentiation, in
contrast, was only significantly affected by silence (h,k) with a slight
increase in the number of BrdU/NeuN double-positive new Neurons
(i)
Brain Struct Funct (2015) 220:1221–1228 1223
123
dark cycle. Dependent on the experimental group, they
were either exposed to standard animal house noise (group
designated as ‘‘Ambient’’), isolation from all sounds
(‘‘Silence’’), white noise (‘‘White noise’’, with a bandwidth
of 4–80 kHz), previously recorded pup calls (‘‘Pup calls’’)
or Mozart’s Sonata for two pianos in D major, KV 448
(‘‘Mozart’’). The music was presented with a sample rate of
97,656.25 per second. The other sounds were presented at a
sampling rate of 223,214.06 per second. The Mozart piece
was transposed into the hearing range of C57BL/6J mice.
First, a low pass filter was set to 1,236 Hz and applied ten
times to the music. The wav file was then transposed by
five octaves. Afterwards a high-pass filter was set to
5,953 Hz and applied two times. Spectral analysis showed
a peak at 10 kHz. More than 90 % of the power lay
between 5 and 20 kHz. Spectral analysis of the pup calls
showed an average frequency of 65 kHz; the pup calls
had been collected and modified as described elsewhere
(Liu et al. 2003). The white noise was applied at an
intensity of 70 dB SPL. All other stimuli varied in intensity
(70 ±10 dB SPL).
Immunohistochemistry
To assess effects of auditory stimuli on precursor cell
proliferation, the animals were exposed to the stimulus 2 h/
day for 3 consecutive days, followed by an intraperitoneal
injection of 50 mg/kg bodyweight Bromodeoxyuridine
(BrdU, Sigma) 24 h after the last exposure (Fig. 1a). Again
24 h later, mice were killed and the brain was removed.
To address net neurogenesis (survival and differentia-
tion), animals were injected with BrdU (50 mg/kg) and
exposed to auditory stimulus for seven consecutive days.
Perfusion was performed 24 h after the last exposure. In
this particular paradigm BrdU counts reflect early survival
rates of newly generated cells.
For the collection of the brains, all animals were deeply
anesthetized with a mixture of 10 % Ketamine (0.3 ml/
20 g body weight) and 2 % Xylaxin (0.1 ml/20 g body-
weight) and perfused transcardially with 0.9 % NaCl fol-
lowed by 4 % paraformaldehyde (PFA) in 0.1 M KPBS
buffer, pH 7.4. Brains were dissected from the skull,
postfixed in 4 % PFA at 4 °C for 24 h and then transferred
into 30 % sucrose in 0.1 M phosphate buffer, pH 7.4, for
dehydration until they had sunk. Brains were then cut on a
dry ice-cooled copper block with a table top sliding
microtome (Leica, Bensheim) into 40-lm-thick coronal
sections. Slides were stored at 4 °C in cryoprotectant
solution containing 25 % ethylene glycol, 25 % glycerol,
25 % glycerin and 0.05 M phosphate buffer.
All sections were stained free floating with all anti-
bodies diluted in Tris-buffered saline (TBS), pH 7.4,
containing 3 % donkey serum and 0.1 %Triton X-100. For
BrdU-immunohistochemistry, one-in-six sections from
each brain were transferred into TBS and washed briefly.
Sections were pretreated with 0.6 % H
2
O
2
to block
endogenous tissue peroxidase. After rinsing in TBS, the
DNA was denatured in 2 N HCl for 30 min at 37 °C.
Afterwards the sections were rinsed in 0.1 M borate buf-
fer, pH 8.5, and thoroughly washed in TBS. Brain slices
were incubated with the primary antibody overnight at
4°C. Primary and secondary antibodies were diluted in
TBS supplemented with 0.1 % Triton X-100 and 3 %
donkey serum (TBS-plus). As primary antibody we used
rat anti-BrdU in a concentration of 1:500 (Harlan Seralab,
Loughborough, UK). On the next day, the sections were
rinsed in TBS and TBS-plus and incubated with the sec-
ondary antibody for 2 h at room temperature. As sec-
ondary antibody we used donkey anti-rat-biotin-SP
(Dianova, Hamburg, Germany) at a concentration of
1:250. ABC reagent (Vectastain Elite, Vector Laborato-
ries, Burlingame, CA, USA) was applied for 1 h at a
concentration of 9 ll/ml. Diaminobenzidine (DAB)
(Sigma, Munich, Germany) was used as a chromogen at a
concentration of 0.25 mg/ml in TBS with 0.01 % H
2
O
2
and 0.04 % nickel chloride. The stained sections were
thoroughly washed, incubated in Neoclear for 10 min and
mounted with Neomount.
Immunofluorescence
For immunofluorescence, 1-in-12 series of each brain were
triple-labeled. The sections were transferred into TBS and
washed briefly. The DNA was denatured in 2 N HCl for
30 min at 37 °C. Sections were then rinsed in 0.1 M borate
buffer, pH 8.5, and thoroughly washed in TBS and TBS-
plus. The brain sections were incubated with the primary
antibodies overnight at 4 °C. Primary and secondary anti-
bodies were diluted in TBS supplemented with 0.1 %
Triton X-100 and 3 % donkey serum (TBS-plus). The next
day, sections were rinsed in TBS and TBS-plus and incu-
bated with secondary antibodies for 4 h at room tempera-
ture in the dark. Sections were then washed with TBS and
coversliped in polyvinyl alcohol with diazabicyclooctane
(DABCO) as anti-fading agent.
The primary antibodies were applied in the following
concentrations: anti-BrdU (rat, 1:500; Harlan Seralab),
anti-doublecortin (goat, 1:200; Santa Cruz Biotechnolo-
gies), anti-SOX2 (rabbit, 1:400, Chemicon, Temecula,
USA), anti-NeuN (mouse, 1:100; Chemicon, Temecula,
USA), anti-S100beta (rabbit, 1:2,500, Swant).
For secondary antibodies anti-rat rhodamine-X, anti-
rabbit fluorescein isothiocyanate (FITC), anti-rabbit Cy5,
anti-mouse FITC, anti-mouse Cy5, anti-goat Cy5 (all
1:250; Jackson Immunoresearch, West Grove, USA; dis-
tributor: Dianova, Hamburg, Germany) were used.
1224 Brain Struct Funct (2015) 220:1221–1228
123
Quantification and imaging
Quantification of cells labeled with DAB were determined
using light microscopy on sections 240 lm apart for BrdU
covering the entire hippocampus in its rostrocaudal
extension as described previously (Kronenberg et al. 2003).
Briefly, cells located in the granule cell layer and adjacent
subgranular zone, defined as a two-cell bodies-wide zone
of the hilus along the base of the granule cell layer were
counted. Cells in the uppermost focal plane were excluded
to avoid oversampling. For light microscopical analyses, a
Leica CTR 6000 Microscope was used.
Phenotypic analyses of BrdU-positive cells in the stated
differentiation stages were performed using multiple-
stained series on sections 480 lm apart, also covering the
entire hippocampus, using a spectral confocal microscope
(TCS SP2 and TCS SP5; Leica, Nussloch, Germany).
Appropriate gain and black level settings were determined
on control slices stained with secondary antibodies alone.
All images were taken in sequential scanning mode and
further processed in Adobe Photoshop 7.0 and CS3. Only
general contrast adaptations were made and images were
not otherwise manipulated.
Statistical analysis
Statistical analysis was performed either with Origin8 for
Windows. Factorial analysis of variance (ANOVA) was
performed for all comparisons of morphological data. Two-
way ANOVA was followed by Fisher’s post hoc test,
where appropriate. Differences were considered statisti-
cally significant at p\0.05. All graphs are displayed as
mean ±standard error of the mean (SEM).
Results
With increasing age C57BL/6 mice undergo severe pro-
gressive sensorineural hearing loss (presbyacusis) starting
around 4–5 months of age (Hunter and Willott 1987). To
ensure the audibility of the auditory stimuli to our 2-month-
old mice, we measured the auditory brainstem response
(acoustic evoked potentials) to click sounds in C57BL/6
mice (Fig. 1b). This verified that the auditory stimuli that
we intended to use in exposure would be above threshold
for C57BL/6 at this age. Clicks equivalent to all of our
stimuli are able to drive neural responses at the distinct
frequency with the applied 70 dB SPL. Ambient baseline
noise in the animal facility (Ambient) served as physio-
logical baseline for our study.
Animals were exposed to the specific stimuli for 2 h per
day for 3 days (Fig. 1a, c) in an anechoic chamber. One
day after labeling cells with BrdU, White noise did not
result in changing numbers of BrdU-positive cells, but all
other stimuli increased proliferation (ANOVA: F(4.39) =
12.17, p=1.62 910
-6
, Fig. 1d, e). The greatest numbers
of labeled cells were seen for Silence and Mozart. When
we broke down these numbers according to the expression
of Sox2 as marker for early progenitor cell stages (type-1/
2a, Fig. 1f), we saw that this increase was largely explained
at this developmental stage (Fig. 1g). The stimuli indeed
increased precursor cell proliferation.
At 7 days after division, the subset of cells that are
destined for neuronal differentiation have exited from the
cell cycle and only the minor fraction of label-retaining
precursor cells remained proliferative (Encinas et al. 2011;
Kempermann et al. 2003). The following period coincides
with the electrophysiologically critical time window. We
found that at this stage only the Silence group showed
increased numbers of BrdU-positive cells, whereas all
other groups were indistinguishable from the Ambient
controls (ANOVA: F(4.42) =10.73, p=1.41251 910
-6
Fig. 1h, i). The Silence and Ambient groups were further
analyzed for the phenotype of the newborn cells. As
known from other experiments, approximately two-thirds
of these cells were neurons (based on NeuN expression)
and around 15 % were S100b-positive astrocytes. The
proportion of neurons was increased to 62 % in the
silence condition from 57 % in the Ambient noise group
and the difference barely missed conventional statistical
significance (p=0.056). In absolute terms, Silence
resulted in statistically increased levels of neurogenesis
(BrdU/NeuN-double-positive cells) at this stage (p=0.008,
Fig. 1k).
Discussion
The present study shows that auditory stimuli can induce a
response at the level of adult neurogenesis compared to
normal baseline ambient noise or unstructured white noise.
More interestingly, however, we found that silence and
ethologically irrelevant sounds (Mozart) showed a stron-
ger on proliferation effect than presumably natural and
relevant sounds like pup calls. Both Mozart and Silence
also represent highly novel stimuli, in line with the idea
that adult hippocampal neurogenesis plays a role in the
integration of novel information into pre-existing contexts.
To our initial surprise, silence, i.e., the complete absence
of auditory input, was the only stimulus that elicited a
strong response at the level of immature (7 day old) new
neurons. But of the tested paradigms, silence might be the
most arousing, because it is highly atypical under wild
conditions and must thus be perceived as alerting. Func-
tional imaging studies indicate that trying to hear in silence
activates the auditory cortex, putting ‘‘the sound of
Brain Struct Funct (2015) 220:1221–1228 1225
123
silence’’, the absence of expected sound, at the same level
with actual sounds (Kraemer et al. 2005; Voisin et al.
2006). The alert elicited by such unnatural silence might
stimulate neurogenesis as preparation for future cognitive
challenges.
As in our previous set of experiments, one could now
call for a combination of the non-specific and the specific
stimulus in order to see whether a learning stimulus can
recruit new neurons from the pool of new neurons gener-
ated in response to exposure to silence, as was the case for
physical activity (Fabel et al. 2009). Given the small effect
size here and challenges to the experimental design
because of the different temporal properties of the two
stimuli, this experiment is not trivial and, if done, should
possibly be included into larger-scale studies on the general
mechanisms underlying such two-step regulation. Based on
the available data, we would predict that silence-activated
progenitor cells should be usable for the response to cog-
nitive challenges, because these new neurons have survived
the initial wave of cell death after cell birth in the adult
hippocampus (Kempermann et al. 2003) and are in a time
window or critical period, during which the survival-pro-
moting forces are effective (Tashiro et al. 2007; Kee et al.
2007; Gould et al. 1999).
Loud white noise can be a strong stressor (Lai 1987;
Cheng et al. 2011). In our study, we purposefully used
white noise that did not reach this damaging level. Our data
did not reveal any substantial difference between ambient
animal house noise and white noise. The white noise
condition thus also serves as control for the anechoic
chamber in which the animals were exposed to the sounds.
In any case, the role of stress in the regulation of adult
hippocampal neurogenesis is complex. While strong acute
social stress downregulates adult neurogenesis, the picture
is less clear in other situations (Lucassen et al. 2010). The
experience of sudden silence will represent a stressor, but
so does the exposure to a running wheel (Van Praag et al.
1999). So the presence of stress per se is not incompatible
with an increase in adult neurogenesis and the activation
that is required for the neurogenic response might even be
considered as ‘‘good stress’’ or eustress.
While few humans will agree that Mozart is ‘‘etholog-
ically irrelevant noise,’’ for mice it should be. We have
chosen Mozart’s Sonata for two pianos (KV 448) some-
what tongue-in-cheek, because it has received a notorious
reputation in the context of the so-called ‘‘Mozart effect’’,
the controversial claim that listening to this sonata was
sufficient to elicit improved learning in humans (Fudin and
Lembessis 2004; Jenkins 2001). One study claimed that the
effect on humans could be replicated in rats (Rauscher
et al. 1998) and one report showed improved T-maze
learning in mice after exposure to Mozart but not
Beethoven (Aoun et al. 2005). The ‘‘Mozart effect’’ is largely
discredited, also due to a rather unprecedented financial
exploitation, even though there are actually interesting
observations related to this paradigm, including reproduc-
ible studies on reduced epileptiform changes in the EEG
(Lin et al. 2011) or on energy expenditure in preterm
infants (Lubetzky et al. 2010). Such results are usually
explained through an arousal elicited by the music (Lub-
etzky et al. 2010; Steele 2000). In this view, the Mozart
piece KV 448 (first movement) would be nothing more but
a particularly effective way to elicit a quite generic
response. What is characteristic about the particular piece,
however, is that it is highly patterned and has a rather fast
beat. It represents an auditory stimulus that is not natural to
mice and does not convey ethologically relevant informa-
tion about the world. Nevertheless, its patterned nature
might still resonate with sensory and cognitive mechanisms
available to the mouse (compare, for example: (Schneider
et al. 2010)). It would represent a stimulus of novelty and
might thus also affect neurogenesis. We found that expo-
sure to Mozart indeed induced an arousal-like effect at the
precursor cell level. Unlike the complete absence of audi-
tory signals, however, this increase in proliferating Sox2-
positive cells was not followed by an increased availability
of immature neurons. Why that might be, we can only
speculate, but the important conclusion here is that regu-
lation of neurogenesis obviously responds differentially to
different auditory stimuli.
Adult neurogenesis has been hypothesized as crucial for
flexible adaptations to environmental changes and thus
displays an evolutionary advantage (Kempermann 2012).
Modulation of the dentate gyrus cytoarchitecture caused by
auditory stimuli is a particular case of experiencing the
outside world, to which the animal has to respond. Our
findings of different neurogenic responses to sounds be
they structured or unstructured, relevant or irrelevant, and
even present or absent, might reflect the preparation for
novel information and behavioral contingencies, and thus
increase the ability to adapt to environmental changes.
Indeed, as acoustic stimuli (or possibly their absence) gain
meaning to an animal through experience, auditory cortical
plasticity occurs that may functionally improve the pro-
cessing of those sounds, as has been demonstrated for pup
calls (Liu and Schreiner 2007; Galindo-Leon et al. 2009).
Studies on auditory-dependent learning have also revealed
changes in hippocampal activation (McIntosh and Gonzalez-
Lima 1998; Grasby et al. 1993), and the conscious perception
of sounds appears to activate the hippocampus (Laureys et al.
2000). These therefore support the idea that the hippocampus
is also a site of higher order integration of sensory inputs
(Braak et al. 1996; Jones and Powell 1970).
Acknowledgements This study was financed from basic institu-
tional funds, with support from NIH DC008343. During her work on
1226 Brain Struct Funct (2015) 220:1221–1228
123
this project IK was a fellow of Max Planck International Research
School LIFE, Berlin. We are grateful to Dr. Anje Sporbert at Max
Delbru
¨ck Center for Molecular Medicine (MDC) Berlin-Buch to
support this project by providing technical assistance and access to
the Confocal Microscope, and Dr. Annette Hammes for access to the
Leica CTR 6000.
Conflict of interest The authors declare no competing financial
interests.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
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Production of new neurons in the adult hippocampus decreases with age; this decline may underlie age-related cognitive impairment. Here we show that continuous depletion of the neural stem cell pool, as a consequence of their division, may contribute to the age-related decrease in hippocampal neurogenesis. Our results indicate that adult hippocampal stem cells, upon exiting their quiescent state, rapidly undergo a series of asymmetric divisions to produce dividing progeny destined to become neurons and subsequently convert into mature astrocytes. Thus, the decrease in the number of neural stem cells is a division-coupled process and is directly related to their production of new neurons. We present a scheme of the neurogenesis cascade in the adult hippocampus that includes a proposed "disposable stem cell" model and accounts for the disappearance of hippocampal neural stem cells, the appearance of new astrocytes, and the age-related decline in the production of new neurons.
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Mozart's Sonata for two pianos in D major, K.448 (Mozart K.448), has been shown to improve mental function, leading to what is known as the Mozart effect. Our previous work revealed that epileptiform discharges in children with epilepsy decreased during and immediately after listening to Mozart K.448. In this study, we evaluated the long-term effects of Mozart K.448 on children with refractory epilepsy. Eleven children with refractory epilepsy were enrolled. All of the patients were diagnosed as having had refractory epilepsy for more than 1 year (range =1 year to 6 years 4 months, mean =3 years 11 months) and had been receiving at least two antiepileptic drugs (AED). During the study period, they listened to Mozart K.448 once a day before bedtime for 6 months. Seizure frequencies were recorded 6 months before they started listening to this music and monthly during the study period. All of the patients remained on the same AEDs during the 6-month study period. Frequencies of seizures were compared before and after listening to Mozart K.448. Eight of eleven patients were seizure free (N=2) or had very good responses (N=6) after 6 months of listening to Mozart K.448. The remaining three (27.3%) showed minimal or no effect (effectiveness <50%; unmodified or worsened seizure frequency). The average seizure reduction was 53.6 ± 62.0%. There were no significant differences in seizure reduction with IQ, etiology, or gender. We conclude that Mozart K.448 should be further studied as a potential add-on therapy in the treatment of children with refractory epilepsy.