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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 history:

Received 28 May 2009

Received in revised form 21 July 2009

Accepted 30 August 2009




Spatial memory

Corpus callosum


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.



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


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


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.


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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