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Int. J. Devl Neuroscience 28 (2010) 105–109
Contents lists available at ScienceDirect
International Journal of Developmental Neuroscience
journal homepage: www.elsevier.com/locate/ijdevneu
Perinatal exposure to music protects spatial memory against callosal lesions
Anca Amagdei, Felicia Rodica Balteş, Julia Avram, Andrei C. Miu *
Program of Cognitive Neuroscience, Department of Psychology, Babes-Bolyai University, 37 Republicii St., Cluj-Napoca, CJ 400015, Romania
ARTICLE
INFO
ABSTRACT
Article history:
Received 28 May 2009
Received in revised form 21 July 2009
Accepted 30 August 2009
Keywords:
Music
Neuroprotection
Spatial memory
Corpus callosum
Callosotomy
Several studies have indicated that the exposure of rodents to music modulates brain development and
neuroplasticity, by mechanisms that involve facilitated hippocampal neurogenesis, neurotrophin
synthesis and glutamatergic signaling. This study focused on the potential protection that the perinatal
exposure to music, between postnatal days 2 and 32, could offer against functional deficits induced by
neonatal callosotomy in rats. The spontaneous alternation and marble-burying behaviors were
longitudinally measured in callosotomized and control rats that had been exposed to music or not. The
results indicated that the neonatal callosotomy-induced spontaneous alternation deficits that became
apparent only after postnatal day 45, about the time when the rat corpus callosum reaches its maximal
levels of myelination. The perinatal exposure to music efficiently protected the spontaneous alternation
performance against the deficits induced by callosotomy. The present findings may offer important
insights into music-induced neuroplasticity, relevant to brain development and neurorehabilitation.
ß 2009 ISDN. Published by Elsevier Ltd. All rights reserved.
An increasing literature has started to document the effects of
music on brain development and neuroplasticity in animal models.
Even compared with species-specific auditory stimuli, the exposure
of chicken embryos to music induces increased volumes and neuron
densities in brainstem auditory nuclei (Wadhwa et al., 1999).
Indeed, developing rats that have been prenatally exposed to music
also show increased hippocampal neurogenesis, as well as facilitated
spatial memory (Fukui and Toyoshima, 2008; Kim et al., 2006).
The effects of music on neurogenesis might be mediated by the
neurotrophin synthesis in the brain. The perinatal exposure to music
reduces the level of nerve growth factor (NGF), and increases the
level of brain-derived neurotrophic factor (BDNF) in the hippocampus
and hypothalamus of mice (Angelucci et al., 2007a,b). Music
is also associated with the superior performance of mice in passive
avoidance tasks (Angelucci et al., 2007a). In addition, a similar
manipulation increases the levels of the BDNF-receptor, tyrosine
kinase receptor B (TrkB), and 3-phosphoinositide-dependent
protein kinase-1 (PDK1), which is one of the downstream targets
in BDNF/TrkB signaling (Chikahisa et al., 2006). The activation of this
signaling pathway correlates negatively with the number of errors
that mice make in a cross-maze.
Perinatal music exposure also stimulates glutamate signaling
by increasing the levels of AMPA receptor GluR2 subunit in the
Abbreviations: BDNF, brain-derived neurotrophic factor; CC, corpus callosum; NGF,
nerve growth factor; PDK1, 3-phosphoinositide-dependent protein kinase-1; PN,
postnatal day; TrkB, tyrosine kinase receptor B.
* Corresponding author. Tel.: +40 264 590967; fax: +40 264 590967.
E-mail address: andrei_miu@emcoglab.org (A.C. Miu).
auditory cortex and cingulate gyrus of rats (Xu et al., 2007), as well
as NMDA receptor NR2B subunit in the auditory cortex (Xu et al.,
2009). The latter effect is also associated with increased auditory
discrimination in developing rats. Finally, postnatal music
exposure increases the dopamine levels in the neostriatum, which
are associated with reduced systolic blood pressure in spontaneously
hypertensive rats (Sutoo and Akiyama, 2004). Overall,
these findings in animal models argue for the specific neurobiological
effects of music exposure, which not surprisingly seem to be
enhanced during brain development.
Recent studies in humans show that music exposure can also be
beneficial in neurorehabilitation (Sarkamo et al., 2008). Music
listening is associated with facilitated recovery of verbal memory
and focused attention, as well as less affective symptoms in
patients with middle cerebral artery stroke (Sarkamo et al., 2008).
Music also enhances visual awareness in neuropsychological
patients with visual neglect, by inducing positive affect associated
with the increased activation and functional coupling of the
frontal, spared parietal, and occipital cortical areas involved in
emotion, attention, and early vision processing (Soto et al., 2009).
Similar mechanisms may contribute to the beneficial effects that
learning to play musical instruments has on the motor recovery of
stroke patients (Schneider et al., 2007). However, it has been
acknowledged that the effects of an enriched sound environment
on recovery from neural damage have only been studied in a
handful of human studies and no animal models (Sarkamo et al.,
2008). To our knowledge, the only relevant study in this line
included music in a more general enriched environment experimental
condition applied to developing rats that had undergone
0736-5748/$36.00 ß 2009 ISDN. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijdevneu.2009.08.017

106
A. Amagdei et al. / Int. J. Devl Neuroscience 28 (2010) 105–109
Fig. 1. A schematic outline of the experimental design of this study. ‘‘’’ designates manipulation; ‘‘O’’ designates measurement.
experimental status epilepticus (Faverjon et al., 2002). This study
showed that, as part of the enriched environment, music increases
the hippocampal neurogenesis and a key transcription factor (i.e.,
phosphorylated cyclic AMP response element protein) in the
molecular cascade of learning neuroplasticity, and facilitates
spatial memory.
The present study focused on the effects of perinatal exposure
to music on behavioral performance in developing rats that
underwent callosotomy in their first postnatal (PN) day (PN1).
Based on previous suggestions that music influences behavior via
mechanisms that it shares with spatial processing (Aoun et al.,
2005; Cupchik et al., 2001; Rauscher et al., 1998), or facilitated
emotional arousal (Thompson et al., 2001), we chose to assess
spatial memory and emotional reactivity in the present study. To
this purpose, the non-invasive and ethologically relevant procedures
of spontaneous alternation in a T-maze (Deacon and Rawlins,
2006), and marble burying (Deacon, 2006) were used. In light of
previous observations that the development and functions of the
corpus callosum (CC) are influenced by music (Patston et al., 2007;
Schlaug et al., 1995), the present study tested the potential
beneficial effects of music against neonatal callosotomy. Therefore,
the design of this animal model was carefully adapted to be
relevant to the human literature on music, brain and behavior.
1. Experimental procedures
Wistar female rats (N = 12) were allowed to mate with male rats for 24 h. One
day later, females were separated from males, and housed individually under
controlled temperature (20–22 8C) and light–dark cycle (light on from 07:00 to
19:00). Food and water were available ad libitum. The resulting N = 57 pups were
randomly distributed in four experimental groups: control; callosotomy; control
+ music; and callosotomy + music. The survival rate was 96.49%, and two
callosotomized animals were excluded from the analyses because they displayed
signs of extracallosal damage. Therefore, the data reported here are based on the
following samples: N = 14 control (7 females); N = 13 callosotomy (6 females);
N = 10 control + music (6 females); and N = 16 callosotomy + music (8 females).
Until PN21, the pups were housed together with their mother. Weanlings were then
separated by sex and housed in groups of 3–6 animals per cage.
The rats in the auditory enriched conditions were exposed to music during
their active nocturnal period. A playlist that included 42 piano compositions of
Wolfgang Amadeus Mozart (see Supplementary Material) was continuously
played (65–75 dB) for 12 h, between 19:00 and 07:00. In contrast to other
similar studies, we chose to expose rats to a wider set of musical stimuli in
order to maximize their auditory enrichment, especially considering that due to
their higher absolute auditory threshold, they hear about half (i.e., sounds
>500 Hz, corresponding to a point between B 5 and C 5 on the keyboard) of the
available piano notes in a given sonata (Steele, 2003). They are deaf to air-borne
sounds (i.e., but not bone sound conduction) until PN11, but they display
cochlear microphonic responses from PN2, and auditory brainstem responses
from PN7–10 (Steele, 2003). The rats in the two experimental groups
(control + music, and callosotomy + music) were exposed to this music each
night, between PN2 and PN32 (see Fig. 1). Therefore, this developmental period
starts after the neural circuit that supports hearing becomes functional, and
covers the time when the myelination and functional maturation of the CC takes
place in the brain of rats.
In PN1, the pups underwent callosotomy or sham surgery, as described in
Manhaes et al. (2003). Briefly, a small incision was made on the rat’s scalp cartilage,
behind the sinusoidal lambda and over the superior colliculus. A miniscalpel was
then inserted caudorostrally underneath the dorsal sagittal sinus and moved
slightly downward while pulled back. Finally, a small amount of thrombin was
applied near the incision to control bleeding, and the incision was then closed using
acrylate glue. Neonates were placed back with their littermates in warmed cages
and after approximately 12 h they were returned to their mother. For the sham
surgery, the procedure was identical except that the miniscalpel was not actually
inserted in the brain.
The behavioral assessment was done at four time points during development
(Fig. 1), which were carefully selected considering the following developmental
landmarks in rats: the body volume doubles and the anatomical features of the
external ear develop around PN5 in rat pups; their coat starts to develop, and motor
coordination improves by PN7–12; their eyes open at PN12–14. Therefore, the first
behavioral assessments were done at PN16, and followed-up at PN45, PN75 and
PN104 (Baker et al., 1979).
Spontaneous alternation in a T-maze and marble burying were measured
according to standard protocols (Deacon, 2006; Deacon and Rawlins, 2006).
Essentially, the spontaneous alternation in a T-maze measures the natural
tendency of rats to alternate the choice of an arm if information concerning the
arm that they previously visited is available in their spatial working memory
(Clark et al., 2000; Deacon and Rawlins, 2006). In addition to being less aversive
compared to other spatial memory procedures (e.g., Morris water maze),
spontaneous alternation is also more sensitive to hippocampal dysfunction and
AMPA receptor manipulations (Deacon and Rawlins, 2005; Reisel et al., 2002),
which have also been related to the effects of music in rodents. The procedure
involved a forced choice, in which the animal is placed in the start arm and
allowed to enter the open arm (i.e., the other one is blocked by a guillotine door);
after confined in that arm for 30 s, the animal is gently replaced in the start area,
facing away from the arms; in the following free-choice phase, it is allowed to
choose between the two open arms. Therefore, each trial includes a forced and a
free-choice phase, and it was limited to 2 min, according to standard protocols
(Deacon and Rawlins, 2006). In order to avoid experimenter and side preference
biases, the experimenter was blind to the animal’s group, and the arm that was
blocked during the forced choices was counterbalanced between days and
groups. In addition, the rates of spontaneous alternation were corrected for
response biases (Clark et al., 2000; Douglas, 1966; Miu et al., 2006). Five trials
are usually sufficient for rats to develop >75% alternation rates (Dember and
Richman, 1989),butinthisstudyandaccordingto(Clark et al., 2000), each rat
was given two trials, separated by 2 h, each day for 5 days (10 trials total). In
addition to the number of alternations, the response latencies were also
recorded as general indices of sensory-motor integrity. One week before
spontaneous alternation testing, rats were placed on a food restriction schedule
that reduced their body weights to 80–85% of baseline and then maintained their
weights at that level.
Marble burying is a behavior that is also sensitive to hippocampal lesions and
glutamate receptor manipulations (Bespalov et al., 2008; Deacon and Rawlins,
2005; Njung’e and Handley, 1991). It is still debated whether it reflects emotional
reactivity or simply species-typical digging behavior (Deacon, 2006), but recent
observations that this behavior increases in response to stress (Mikics et al., 2008),
and is inhibited by anxiolytics (Broekkamp et al., 1986) argue for its relationship
with emotional reactivity. Essentially, the procedure involved placing a single rat in
a cage filled with 5-cm deep wood chip bedding that was tamped down to make a
flat surface; 12 marbles were placed in a regular pattern, with a 4-cm distance
between them; the number of marbles buried with bedding during 30-min
observations were recorded (Deacon, 2006).
At the end of the behavioral experiments (PN110), the rats were anesthetized
using Nembutal. They were killed by a transcardial perfusion–fixation procedure,
their brains were removed and placed in 10% paraformaldehyde for 24 h,
stereotaxically dissected, and embedded in paraffin. Twenty-micrometers thick
frontal, sagittal and horizontal sections were cut using a microtome and stained for
myelin, with Nissl counterstain according to the Klüver-Barrera method. All
sections were analyzed using an Olympus CX41 microscope and representative
sections covering the rostrum, body and splenium of the corpus callosum were
selected and reconstructed.
The statistical analyses of the data were carried out using analysis of variance
(ANOVA) followed by post hoc tests, and corrected for multiple comparisons. The
experiment conformed to European Communities Council Directive 86/609/EEC
(1986), and the international guidelines for the care and use of laboratory animals
(Clark and NRC Committee, 1997).

A. Amagdei et al. / Int. J. Devl Neuroscience 28 (2010) 105–109 107
Fig. 2. Histological sections showing callosotomy (arrowheads in A–D), in comparison to the integer corpus callosum (insets in A–D) and complete midline transection (F;
arrowheads indicate the transected corpus callosum and anterior commissure). The sagittal section in E illustrates the integrity of the hippocampal commissure in
callosotomized rats, and the inset in F shows ectopic fibers located near the longitudinal fissure in a horizontal section from a callosotomized rat. Numbers in the top left
corner indicate the approximate stereotaxical frontal or sagittal plane of the section. The white squares in A–D identify the areas corresponding to those represented in insets.
2. Results
2.1. Histological verification of the lesions
The analyses of the sections indicated that all except two animals
in the callosotomy groups displayed complete section of the CC.
There were no discriminable differences between the lesions of the
two experimental groups (i.e., callosotomy and callosotomy + music).
The animals with extracallosal lesions were therefore excluded
from all subsequent analyses. We carefully verified on frontal and
sagittal sections that there was no damage to the hippocampal or
anterior commissures (see Fig. 2A–E), the hippocampus itself, and
the frontal cortex (i.e., areas that are involved in spontaneous
alternation). In frontal and horizontal sections from several animals,
we identified ectopic longitudinal bundles parallel to the interhemispheric
line (see inset in Fig. 2F). We found no evidence of ectopic
groups of neurons in the isocortex of callosotomized rats.
2.2. Behavioral results
A 4 (group: control vs. callosotomy vs. control + music vs.
callosotomy + music) 4 (test: PN16 vs. PN45 vs. PN75 vs. PN104)
repeated measure ANOVA indicated the significant main effects of
group (F [3,49] = 11.64, P < 0.0001, h 2 = 0.9) and test (F [3,49] = 5.1,
P < 0.01, h 2 = 0.83) on spontaneous alternation (Fig. 3). There
was also a marginally significant effect of test on spontaneous
alternation latencies (P = 0.051).
Follow-up Student’s t-tests showed that the spontaneous
alternation performance of all groups was at the chance level in
the PN16 test (t [50] = 1.51, P = 0.1). The spontaneous alternation
performance was significantly higher than the chance level in all
subsequent tests for the two control groups (overall t [22] = 6.82,
P < 0.0001, Cohen’s d = 0.8); it approached significance (P =0.053)
in PN45 and reached statistical significance (t [14] = 2.3, P < 0.02,
Cohen’s d = 0.76) in PNs 75 and 104 for the callosotomy + music
group; and it was significantly lower than the chance level in PNs 45,
75 and 104 tests for the callosotomy group. Bonferroni-corrected
post hoc contrasts indicated the following overall pattern of
performance in the PN45–75–104 tests (mean differences between
brackets): control control + music > callosotomy + music (28%
less than control, and 20.55% less than control + music) > callosotcallosotomy
(30% less than callosotomy + music).
Follow-up Student’s t-tests also indicated a significant difference
between the spontaneous alternation latencies in PN16 test

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A. Amagdei et al. / Int. J. Devl Neuroscience 28 (2010) 105–109
Fig. 3. Spontaneous alternation performance tested at four postnatal days (PN).
Solid symbols represent the groups that were exposed to music, and open symbols
represent those that were not exposed to music. Dashed lines represent
callosotomized rats, and continuous lines represent control rats. The horizontal
line in the middle of the graph shows the chance level.
and the subsequent tests (t [50] = 4.3, P < 0.001, Cohen’s d = 1.18),
with a mean difference of 19.28 s between the PN16 (higher
latency) and the subsequent latencies. There were no statistically
significant differences between the latencies in PN45, 75 and 104
tests.
A 4 (group: control vs. callosotomy vs. control + music vs.
callosotomy + music) 4 (test: PN16 vs. PN45 vs. PN75 vs. PN104)
repeated measure ANOVA found no statistically significant effects
on the number of buried marbles in the marble-burying test.
3. Discussion
The results of this study supported our predictions that
callosotomy induces spatial memory deficits, and perinatal
exposure to music protects against these functional deficits in
developing rats. Both effects were supported by the present
longitudinal observations on rats between PN45 and PN104. In
addition, these deficits were not accompanied by alterations of
marble-burying behavior, or increases of response latencies in the
spontaneous alternation task.
Increasing evidence has shown that the neonatal callosotomy in
rodents is associated with massive reorganization of long-distance
cortical projections, as well as deficits in behaviors relying on
interhemispheric transfer of visuo-spatial information. For
instance, it was reported that this lesion induces the formation
of ectopic commisural fibers crossing to the contralateral hemisphere
through callosal remnants above the septum, or the
anterior commisure in hamsters (Lent, 1983). The same lesion in
newborn mice is associated with reduced thickness of callosally
innervated cortical areas (Ribeiro-Carvalho et al., 2006), increased
lateralization of rotations to the dominant side in free swimming
tests (Manhaes et al., 2007), and a left side bias in paw preference
tests (Manhaes et al., 2003). We previously found that callosotomy
induces spontaneous alternation deficits in adult rats, which were
not confounded by spatial preference biases (Miu et al., 2006).
Using callosotomy and crossed lesions, subsequent studies
suggested that a crossed fronto-striatal circuit underlies the
performance in a more complex operant delayed alternation task
(White and Dunnett, 2006).
The present study contributes to this literature by showing for
the first time that neonatal callosotomy is also associated with
spontaneous alternation deficits. Rats that underwent callosotomy
in PN1 had approximately 38% fewer spontaneous alternations
than controls. This deficit was apparent after PN45, which is in line
with other studies indicating that spontaneous alternation
develops at above-chance levels only after PN30 in rats (Egger
et al., 1973). Histological and neuroimaging studies also show that
CC is visible at PN1 in rats, but its myelination starts at about PN12
and reaches its maximum at PN45 (Bockhorst et al., 2008; Wiggins,
1986). Therefore, it is possible that the fronto-striatal circuit
underlying spontaneous alternation becomes functional after
myelination of the CC reaches a critical stage. At any rate, the
spontaneous alternation deficit that we induced by callosotomy at
PN1 may be clinically relevant, especially considering the relative
correspondence of brain development at PN7 in rats, and that of
premature or full-term infants (Vannucci et al., 1999). Also, in light
of the interest of perinatal callosal lesions and working memory in
humans (Santhouse et al., 2002), this rat model of callosotomyinduced
deficits in spontaneous alternation offers a framework for
experimental investigations of the effects of controlled lesions of
the CC on behaviors that depend on working memory.
The other main finding of the present study is that perinatal
exposure to music protects the development of spontaneous
alternation against callosotomy. Previous studies have found that
the effects of music on neuroplasticity in developing rats involve
hippocampal (Angelucci et al., 2007a; Kim et al., 2006) and
glutamate receptor-dependent mechanisms (Xu et al., 2007, 2009).
Perinatal exposure to music also modulates the levels of certain
neurotrophins (e.g., BDNF) in the brain (Angelucci et al., 2007b;
Chikahisa et al., 2006), in a manner that is quantitatively related to
spatial learning performance (Chikahisa et al., 2006). The
behavioral tasks that we used in the present study are sensitive
to hippocampal dysfunctions (Deacon and Rawlins, 2005; Njung’e
and Handley, 1991), as well as glutamate receptor manipulations
(Bespalov et al., 2008; Reisel et al., 2002). Therefore, perinatal
exposure to music may have protected these behaviors against
callosotomy, based on mechanisms that involve hippocampal and
glutamatergic signaling. In light of the studies showing the cortical
facilitation of experience-dependent neuronal growth following
callosotomy in rats (Adkins et al., 2002), it is also possible that the
protective effect of music that we identified in the present study is
supported by a neurotrophin-dependent mechanism. However,
the histological analyses included in the present study were
limited and did not allow us to investigate in-depth the degree to
which the protective effects of music extended to the neural level
(e.g., reorganization of neural circuits). Future immunohistochemical
and electron microscopic studies of the neural mechanisms by
which music protects spatial memory against callosotomy would
be worthwhile, especially in light of the important effect that early
music exposure has on the volume of the area of the CC in humans
(Schlaug et al., 1995). Moreover, this animal model may be relevant
to neurorehabilitation in other pathologies, such as stroke or
epilepsy (Faverjon et al., 2002; Sarkamo et al., 2008).
Animal studies of music-induced neuroplasticity have borrowed
from the human literature the claim that music may
facilitate spatial performance either by facilitated emotional
arousal, increased vigilance, or computations that music and
spatial processing share (Cupchik et al., 2001; Rauscher et al.,
1993; Thompson et al., 2001). The present study showed that
perinatal music exposure does not influence marble-burying
behavior. This behavior is increased in rats that have been exposed
to stressors (Mikics et al., 2008), an effect that may indicate the
sensitivity of marble burying to emotional arousal. Therefore, the
results reported here suggest that music stimulates spatial
information processing by mechanisms other than emotional
arousal. However, this issue needs further scrutiny using more
specific emotional reactivity tasks (e.g., open-field, fear conditioning),
and it may turn out as a point of divergence related to the
mechanisms that mediate the cognitive effects of music in animals
and humans. Music may influence brain and cognition by
emotional mechanisms in humans, and more general mechanisms
(e.g., vigilance) in animals.
In conclusion, this study offers the first evidence that neonatal
callosotomy induces spatial memory deficits that become apparent

A. Amagdei et al. / Int. J. Devl Neuroscience 28 (2010) 105–109 109
in developing rats after PN45. We have also shown that perinatal
exposure to music offers an efficient protection against these
functional deficits. These results are contributing to the developing
research on the potential neuroprotective effects of music in animals
and humans, with important implications for music-induced
neuroplasticity and neurorehabilitation.
Acknowledgements
We are grateful to several colleagues from our laboratory who
contributed to the behavioral measurements, and Dr. Constantin
Puica (Institute of Biological Research, Cluj-Napoca) who coordinated
the histological analyses. We also thank Mr. Horia Borza for
help with the space required in this study. This study was
supported by the Romanian Ministry of Education and Research
through grants CEEX 131/2006 and 124/2006.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ijdevneu.2009.08.017.
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