Music Biology: All This Useful Beauty


Current Biology Vol 24 No 6
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in re-modelling of other parts of the
nervous system, including the memory
centres of the brain in the hippocampus
[10]. Here, it interacts with stress
hormones secreted from the adrenal
gland (cortisol in man; corticosterone
in mice), mediated by the nuclear
hormone glucocorticoid receptor, GR
[11]. GR is known to be an important
regulator of BDNF, and is thought to be
the key link between early life stress
effects on brain function and dendritic
development, many of which can
persist throughout life. We are only just
starting to appreciate how nuclear
hormone signaling systems couple to
the circadian clockwork, and recent
studies now point to a direct interaction
between proteins encoded by
so-called core clock genes (PERIOD,
CRYPTOCHROME, REVERB) and
hormone signaling pathways [12].
For instance, there is now evidence
that rhythmic action of glucocorticoids
may depend on oscillations of
CRYPTOCHROME, which forms a
physical partnership with the GR to
repress its action at specific phases of
the cycle [13]. So, although the authors
did not explore this, one important
question is whether auditory
responses, and long-term effects on
nerve damage, might be mediated by
stress hormones, which themselves
are tightly clock-controlled. Adrenal
glucocorticoids will likely also be
strongly activated by strong noise
stimulation, but if they are key players,
then the rhythmic interaction of the
GR with the core clockwork of the
cochlea may be involved.
Finally, there is an obvious and
important practical implication for
human health. Noise levels at work
are controlled by a complex legal
framework, which defines tolerable
levels, and requires the wearing of
protective hearing devices. To what
extent has such legislation accounted
for possible circadian effects in man,
and would it not now be important to
assess whether shift-workers are
especially vulnerable? In addition,
many people voluntarily expose
themselves to excessive noise in
discos and night-clubs, and anecdotal
evidence suggests that this appears to
be an exclusively nocturnal activity in
our species. It is now important to test
whether we show similar phasic effects
to mice — with increased vulnerability
at night. One intriguing prediction is
that we might be better able to cope
with noise in the night-time, since in
man the daily rhythm of adrenal stress
hormones rises in the day, and falls at
night — the opposite to that seen in
nocturnal mice.
References
1. Bailes, H.J., and Lucas, R.J. (2010). Melanopsin

and inner retinal photoreception. Cell. Mol. Life
Sci. 67, 99–111.

2. Frankland, P.W., and Ralph, M.R. (1995).
Circadian modulation in the rat acoustic startle
circuit. Behav. Neurosci. 109, 43–48.

3. Meltser, I., Cederroth, C.R., Basinou, V.,
Savelyev, S., Lundkvist, G.S., and Canlon, B.
(2014). TrkB-mediated protection against
circadian sensitivity to noise trauma in the
murine cochlea. Curr. Biol. 24, 658–663.

4. Yoo, S.H., Yamazaki, S., Lowrey, P.L.,
Shimomura, K., Ko, C.H., Buhr, E.D.,
Siepka, S.M., Hong, H.K., Oh, W.J., Yoo, O.J.,
et al. (2004). PERIOD2::LUCIFERASE real-time
reporting of circadian dynamics reveals
persistent circadian oscillations in mouse
peripheral tissues. Proc. Natl. Acad. Sci. USA
101, 5339–5346.

5. Yang, T., Kersigo, J., Jahan, I., Pan, N., and
Fritzsch, B. (2011). The molecular basis of
making spiral ganglion neurons and connecting
them to hair cells of the organ of Corti. Hearing
Res. 278, 21–33.

6. Fariñas, I., Jones, K.R., Tessarollo, L.,
Vigers, A.J., Huang, E., Kirstein, M., de
Caprona, D.C., Coppola, V., Backus, C.,
Reichardt, L.F., et al. (2001). Spatial shaping of
cochlear innervation by temporally regulated
neurotrophin expression. J. Neurosci. 21,
6170–6180.

7. Patapoutian, A., and Reichardt, L.F. (2001).
Trk receptors: mediators of neurotrophin
action. Curr. Opin. Neurobiol. 11, 272–280.

8. Hegarty, J.L., Kay, A.R., and Green, S.H. (1997).
Trophic support of cultured spiral ganglion
neurons by depolarization exceeds and is
additive with that by neurotrophins or cAMP
and requires elevation of [Ca2+]i within a set
range. J. Neurosci. 17, 1959–1970.

9. Jang, S.W., Liu, X., Pradoldej, S., Tosini, G.,
Chang, Q., Iuvone, P.M., and Ye, K. (2010).
N-acetylserotonin activates TrkB receptor in a
circadian rhythm. Proc. Natl. Acad. Sci. USA
107, 3876–3881.

10. Gómez-Palacio-Schjetnan, A., and
Escobar, M.L. (2013). Neurotrophins and
synaptic plasticity. Curr. Top. Behav. Neurosci.
15, 117–136.

11. Numakawa, T., Adachi, N., Richards, M.,
Chiba, S., and Kunugi, H. (2013). Brain-derived
neurotrophic factor and glucocorticoids:
reciprocal influence on the central nervous
system. Neuroscience 239, 157–172.

12. Han, D.H., Lee, Y.J., Kim, K., Kim, C.J., and
Cho, S. (2014). Modulation of glucocorticoid
receptor induction properties by core circadian
clock proteins. Mol. Cell Endocrinol. 383,
170–180.

13. Lamia, K.A., Papp, S.J., Yu, R.T., Barish, G.D.,
Uhlenhaut, N.H., Jonker, J.W., Downes, M., and
Evans, R.M. (2001). Cryptochromes mediate
rhythmic repression of the glucocorticoid
receptor. Nature 480, 552–556.
Faculty of Life Sciences, University of
Manchester, Manchester M13 9PT, UK.
E-mail: andrew.loudon@manchester.ac.uk
http://dx.doi.org/10.1016/j.cub.2014.01.054
Music Biology: All This Useful Beauty
Some healthy people fail to derive pleasure from music despite otherwise
preserved perceptual and reward responses. Such ‘musical anhedonia’ implies
the existence of music-specific brain reward mechanisms, which could provide
a substrate for music to acquire biological value.
Camilla N. Clark, Laura E. Downey,
and Jason D. Warren

Few problems in biology are as
tantalising as the problem of music.
Music is universal in human societies,
apparently ancient and apt to generate
powerful emotional responses [1].
These are all properties that a
biologically salient stimulus ought to
have; however, these abstract sounds
serve no obvious biological purpose
and, unlike language, have no
straightforward messaging function.
This apparent paradox has long
polarised neurobiologists and
philosophers alike: in one account,
music had a specific role in human
evolution, probably linked to emotional
social signalling [2]; in the other, it is a
mere neural confection, a spandrel of
language [3].
One important line of evidence in

support of a biological role for music
is the existence of specific neural
mechanisms that process it: if evolution
fashioned music-specific brain
systems, it is reasonable to conclude
that music (or proto-music) filled some
evolutionary role for our species and
to ask what that role might have been.
Evidence for such music-specific brain
systems has mainly been adduced
in patients with focal brain damage
who show dissociated patterns of
performance when processing music
versus other kinds of complex sounds
[4]. Such cases, while informative,

mailto:andrew.loudon@manchester.ac.uk
http://dx.doi.org/10.1016/j.cub.2014.01.054
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pose substantial challenges of
interpretation.

A new study reported in this issue of
Current Biology by Mas-Herrero et al.
[5] sheds fresh light on this issue, by
demonstrating that some healthy
people derive little pleasure from music
and lack autonomic responses to it,
even though they perceive music
normally and show preserved
responses to other rewarding stimuli.
Such selective ‘musical anhedonia’
might, by demonstrating
music-specific brain reward systems,
suggest how and why music acquired
reward potential for the wider human
population.

Music Engages Ancient Brain Reward
Systems
The new findings of Mas-Herrero et al.
[5] build on a growing body of work
delineating the neurobiological basis of
musical reward. A sensory stimulus is,
in general, ‘rewarding’ if it engenders
a pleasure response that encourages
behavioural repetition [1]. Music fits
this bill very well: intensely pleasurable
responses to music (shivers down the
spine or ‘chills’) are specifically and
reliably triggered by particular
musical features — such as the
resolution of tonal ambiguity [6] — and
listeners typically seek to repeat
the experience. Musical shiver has
been shown to activate a distributed
brain network including
phylogenetically ancient limbic, striatal
and midbrain structures that are also
engaged by cocaine and sex [7]. The
mesolimbic striatal dopaminergic
system encodes musical reward by
modulating the connectivity of nucleus
accumbens with auditory cortical and
other brain regions involved in the
perceptual analysis and evaluation of
music [8].

Mas-Herrero et al. [5] show that
individuals with typical hedonic
behavioural and autonomic (skin
conductance) responses to music have
comparably intense responses to other
primary (biological) and secondary
reinforcers of reward, notably money.
This is not to argue, of course, that all
these reinforcers are somehow
biologically equivalent: the
neurochemical response to music is
complex and includes elements such
as oxytocin release that are more
closely aligned with social functions
such as pair bonding than arousal per
se [9]. Nevertheless, the high stake
music holds in the hedonic and
biological value system of many
members of our species is, at the least,
surprising.

Core Components of Music
Processing Show Individual Variation
Mas-Herrero et al. [5] contribute two
crucial new pieces to the puzzle of
musical reward. Firstly, they show that
the reward potential of music varies
widely between healthy people, and
that this range includes individuals
who are apparently cognitively and
physiologically largely indifferent to
music. Secondly, they show that such
anhedonia can be selective for music.

Didn’t we already suspect that some
people just don’t ‘get’ music? Now we
have a rigorous neurobiological
grounding for this suspicion. Musical
anhedonia is shown by this new study
[5] to be specific for musical reward
assignment, rather than attributable
to any deficiency in perceiving or
recognising music or musical
emotions. It is rooted in reduced
autonomic reactivity rather than simply
cognitive mislabelling. Moreover, it is
not attributable to more general
hedonic blunting, because musically
anhedonic individuals show typical
responses to other sources of
biological and non-biological
(monetary) reward.

There may be an informative analogy
here with congenital amusia (‘tone
deafness’), which affects specific
components of music perception while
apparently leaving other perceptual
and cognitive domains largely
unscathed [10,11]. A further interesting
analogy might be drawn with clinical
cases of selective musical anhedonia
resulting from strategic focal brain
damage [12]. Musical anhedonia and
tone deafness might herald a new
taxonomy of specific developmental
disorders of music processing to
complement the large evidence base
for acquired amusias [4].

Specific Brain Circuits May Signal
the Biological Value of Music
The most parsimonious interpretation
of the new findings is that there are
music-specific brain reward systems
to which individuals show different
levels of access. Mas-Herrero et al. [5]
propose that this specificity may be
instantiated in integrated profiles of
connectivity across brain networks
that link perceptual, evaluative and
reward processing mechanisms: this
suggestion sits well with previous
neuroimaging work both in the
healthy brain [8,13] and in selective
brain network degenerations
involving the coding of music versus
other categories of salient
stimuli [14,15].
Natural selection is itself

parsimonious and the existence of
specific brain substrates for music
coding in turn implies that these
evolved in response to some
biological imperative. But what might
that have been? Clues may lie in the
cognitive and neuroanatomical
architecture of music processing.
It has been suggested that music
may appeal to the inherent fondness
of our species for puzzle solving,
including the resolution of perceptual
ambiguity intrinsic to musical
scenes [16] and pattern prediction
and completion [1]. Certainly the
extensive linkages between the neural
machinery of emotion, reward
and auditory cortical mechanisms
engaged during music processing
would provide an ample
neuroanatomical substrate for musical
pattern analysis to acquire biological
resonance.
How would such an abstract activity

confer a reproductive or survival
advantage, of the sort required for
natural selection to operate? The
answer may lie in the kinds of puzzles
that music helped our hominid
ancestors to solve (Figure 1). Arguably
the most complex, ambiguous and
puzzling patterns we are routinely
required to analyse are the mental
states and motivations of other people,
with clear implications for individual
success in the social milieu. Music can
model emotional mental states and
failure to deduce such musical mental
states correlates with catastrophic
inter-personal disintegration in the
paradigmatic acquired disorder of the
human social brain, frontotemporal
dementia [17].
Furthermore, this music cognition

deficit implicates cortical areas
engaged in processing both musical
reward and ‘theory of mind’ (our ability
to infer the mental states of other
people) [14,15,17]. Our hominid
ancestors may have coded surrogate
mental states in the socially relevant
form of vocal sound patterns [2].
By allowing social routines to be
abstracted, rehearsed and potentially
modified without the substantial cost of
enacting the corresponding scenarios,
such coding may have provided an



 

BG  

Am  

STG  

Hi  

OFC  
aTL  

vmPF  

AC  
Ins  

 NA  

Current Biology

Dopaminergic modulation
of circuit connectivity:

prediction testing

Pattern completion, resolution:
modelling affective mental states

Autonomic, affective, 
evaluative responses:
emotion and reward

Music perceptual coding:
patterns and expectations

Figure 1. A neural architecture for encoding the biological value of music.

The schematic dissected brain (upper panel) shows anatomical networks implicated in music
perceptual coding (red), emotion and reward processing (green) and higher-order cognitive
processing (blue). Key: AC, anterior cingulate cortex; Am, amygdala; aTL, anterior temporal
lobe; BG, basal ganglia; Hi, hippocampus; Ins, insula; NA, nucleus accumbens (mesolimbic stria-
tum); OFC, orbitofrontal cortex; STG, superior temporal gyrus (and connected areas surrounding
Sylvian fissure); vmPF, ventro-medial prefrontal cortex. A proposed functional architecture for
information exchange between these networks — based on empirical data [1,4,7–9,12–18] — is
outlined (lower panel; arrows code putative primary direction of information flow).

Current Biology Vol 24 No 6
R236
evolutionary mechanism by which
specific brain linkages [5] assigned
biological reward value to precursors
of music.

Future Directions
These new insights into musical
anhedonia raise many intriguing
further questions. What is its
neuroanatomical basis? The strong
prediction would lie with mesolimbic
dopaminergic circuitry, but functional
neuroimaging support is sorely
needed. What are the limits of the
phenomenon? Might typically
musically hedonic individuals show
‘musical satiety’ with frequent
exposure to their favourite music?
The extent to which music shares
a dynamic hedonic signature with,
say, chocolate could illuminate the
neurobiology of reward
reinforcers more generally. What of
the other end of the spectrum,
individuals with ‘musicophilia’ who
are hyper-hedonic for music? How
does this relate to abnormal selective
craving for music in some patients
with temporal lobe seizures and
specific neurodegenerative
pathologies [18]? Such cases seem
to mirror the phenomenon of
musical anhedonia. More
fundamentally, what are the
wider implications for our
understanding of other anhedonias?
We have all met people who seem
unmoved by food, sex or indeed,
money. Is this a matter of volition,
cognition or reward biology?

The current status of music as a
dispensable cultural artefact (like
culturally sanctioned examples of
prolonged voluntary fasting or
celibacy) is not necessarily a reliable
guide to its neurobiological history.
The work of Mas-Herrero et al. [5]
argues that the human brain is
biologically fitted to find music
rewarding. The beauty we find in music,
however useless it may appear, has
proved useful for probing the
organisation of brain reward systems.
Now we must ask if music sculpted
our hedonic brain architectures to
more fundamentally useful
neurobiological ends.

References
1. Zatorre, R.J., and Salimpoor, V.N. (2013).

From perception to pleasure: music and its
neural substrates. Proc. Natl. Acad. Sci. USA
110 (Suppl 2 ), 10430–10437.

2. Mithen, S. (2009). The music instinct: the
evolutionary basis of musicality. Ann. NY Acad.
Sci. 1169, 3–12.

3. Pinker, S. (1997). How the Mind Works
(New York: Norton).

4. Stewart, L., von Kriegstein, K., Warren, J.D.,
and Griffiths, T.D. (2006). Music and the brain:
disorders of musical listening. Brain 129,
2533–2553.

5. Mas-Herrero, E., Zatorre, R.J., Rodriguez-
Fornells, A., and Marco-Pallares, J. (2014).
Dissociation between musical and
monetary reward responses in specific
musical anhedonia. Curr. Biol. 24,
699–704.

6. Huron, D. (2006). Sweet Anticipation: Music
and the Psychology of Expectation
(Cambridge: MIT Press).

7. Blood, A.J., and Zatorre, R.J. (2001). Intensely
pleasurable responses to music correlate with
activity in brain regions implicated in reward
and emotion. Proc. Natl. Acad. Sci. USA 98,
11818–11823.

8. Salimpoor, V.N., van den Bosch, I.,
Kovacevic, N., McIntosh, A.R., Dagher, A., and
Zatorre, R.J. (2013). Interactions between the
nucleus accumbens and auditory cortices
predict music reward value. Science 340,
216–219.

9. Chanda, M.L., and Levitin, D.J. (2013). The
neurochemistry of music. Trends Cogn. Sci. 17,
179–193.

10. Phillips-Silver, J., Toiviainen, P., Gosselin, N.,
and Peretz, I. (2013). Amusic does not
mean unmusical: Beat perception and
synchronization ability despite pitch deafness.
Cogn. Neuropsychol. 30, 311–331.

11. Tillmann, B., Gosselin, N., Bigand, E., and
Peretz, I. (2012). Priming paradigm reveals
harmonic structure processing in congenital
amusia. Cortex 48, 1073–1078.

12. Griffiths, T.D., Warren, J.D., Dean, J.L., and
Howard, D. (2004). ‘‘When the feeling’s
gone’’: a selective loss of musical emotion.
J. Neurol. Neurosurg. Psychiatry 75, 344–345.

13. Sescousse, G., Caldu, X., Segura, B., and
Dreher, J.C. (2013). Processing of primary
and secondary rewards: a quantitative
meta-analysis and review of human functional
neuroimaging studies. Neurosci. Biobehav.
Rev. 37, 681–696.

14. Omar, R., Henley, S.M., Bartlett, J.W.,
Hailstone, J.C., Gordon, E., Sauter, D.A.,
Frost, C., Scott, S.K., and Warren, J.D. (2011).
The structural neuroanatomy of music
emotion recognition: evidence from
frontotemporal lobar degeneration. NeuroImage
56, 1814–1821.

15. Hsieh, S., Hornberger, M., Piguet, O., and
Hodges, J.R. (2012). Brain correlates of musical
and facial emotion recognition:evidence from the
dementias. Neuropsychologia 50, 1814–1822.



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16. Pressnitzer, D., Suied, C., and Shamma, S.A.
(2011). Auditory scene analysis: the sweet
music of ambiguity. Front. Hum. Neurosci.
5, 158.

17. Downey, L.E., Blezat, A., Nicholas, J., Omar, R.,
Golden, H.L., Mahoney, C.J., Crutch, S.J., and
Warren, J.D. (2013). Mentalising music in
frontotemporal dementia. Cortex 49,
1844–1855.
18. Fletcher, P.D., Downey, L.E., Witoonpanich, P.,
and Warren, J.D. (2013). The brain basis
of musicophilia: evidence from
frontotemporal lobar degeneration. Front.
Psychol. 4, 347.

Dementia Research Centre, UCL Institute of
Neurology, University College London, 8–11
Queen Square, London, WC1N 3BG, UK.
E-mail: camilla.clark@ucl.ac.uk (C.N.C.),
l.downey@ucl.ac.uk (L.E.D.), jason.warren@
ucl.ac.uk (J.D.W.)
http://dx.doi.org/10.1016/j.cub.2014.02.013
Plant Development: From
Biochemistry to Biophysics and Back
Since plant cells cannot move relative to each other, plant organogenesis
mainly depends on the strict coordination of cell growth and proliferation.
Recent work suggests that this implies a subtle combination of biochemical
and physical interactions between neighboring cells.
Jan Traas* and Massimiliano Sassi

Plants continuously produce new
organs and tissues, which is an
essential adaptation to their sessile
nature. This constant growth originates
from two specific types of stem
cells — the shoot and root apical
meristems — that are active throughout
plants’ life cycle. Plant cells are
encased in a rigid extracellular,
polysaccharidic matrix, the cell wall,
which links them together and prevents
any form of cell migration or sliding. For
this reason, the generation of new
organs in plants is a complex process
that requires the coordinated
regulation of cell growth and
proliferation, as otherwise the
differences in growth rate would tear
the tissue apart. Vermeer and
coworkers [1], in a study recently
published in Science, have studied this
coordination during lateral root
formation, demonstrating how the
coordinated behavior of two adjacent
cell layers, located deep within the root,
underlies the initiation of lateral root
primordia (LRP).

Lateral roots are initiated in the
pericycle, an inner cell layer adjacent to
the vascular bundle at the center of the
root, after an initial specification of the
founder cells by the hormone auxin.
Following this priming step, these
founder cells undergo a series of
asymmetric cell divisions giving rise to
the meristem of the LRP [2]. The
pericycle is overlaid by three other cell
layers (endodermis, cortex and
epidermis, from the innermost to the
outermost, respectively) putting a
strong mechanical constraint on the
proliferation of pericycle founder cells,
and thus the emergence of the LRP [3].
It was previously shown that LRP
outgrowth requires the production of
cell wall remodeling enzymes in the
cortex and epidermis to disrupt the
adhesion between adjacent cells [4].
The endodermis is far more rigid than
the outer layers due to the presence of
the Casparian strip, a hydrophobic,
lignified structure that functions as a
solute barrier isolating the vasculature
from the outer environment and
keeps the endodermal cells tightly
connected. Vermeer and coworkers [1]
show how this hurdle is taken by the
LRP. As soon as the proliferation of
the LRP founder cells in the pericycle
begins, the overlying endodermal
cells start to shrink due to the
fragmentation of their vacuoles,
while the fusion of the inner and
outer plasma membranes creates a
gap in the tissue that allows the
protrusion of the primordium. The
Casparian strip is only partially
degraded around the gap, leaving the
connections between endodermal cells
largely unaltered. These events are
regulated by auxin through the
cell-autonomous action of the SHY2
transcriptional regulator in the
endodermis [1].

Importantly, if the endodermis
accommodation mechanism is
impaired, as when a dominant
negative version of the SHY2 protein
is expressed in the endodermis,
root founder cells fail to proliferate,
despite the pre-existing auxin-
mediated priming. The authors
suggest that, in this case, the
mechanical stress caused by an
unaccommodating endodermis
prevails, halting the genetic
programme imposed by auxin. The
work thus reveals what seems to be
part of an interplay between
biophysical and biochemical
regulation, central in the formation
of the LRP. This goes back to even
earlier stages of lateral root
specification. Previous work showed
that a transient bending of the primary
root, either manually imposed or
caused by gravitropism, induces
the formation of a LRP at the
convex side of the bending [5–7].
Root bending has been proposed
to somehow alter auxin concentrations
in the pericycle and the adjacent
vasculature by locally modifying
auxin transport [5,6]. This might be due
to mechanically induced changes in
cell polarity, cell shape or Ca2+

fluxes [5–7].
This mechanical regulation would,

however, not be the starting point.
Indeed, further upstream massive
orchestrated fluctuations in gene
transcription at the root tip seem to
confer competence of the cells to
react to the physical constraints
imposed by bending [8]. From primary
gene oscillations to the final
breakthrough of the lateral root via
mechanical priming, hormonal
specification and the biochemical
loosening of physical constraints, there
seems to be a constant ‘back-and-
forth’ between biochemical and
biophysical regulation in the process of
lateral root initiation.
This interplay between biochemical

and biophysical regulation is not
limited to the root. In the aerial part of
the plant, the shoot apical meristem
constantly generates new leaves,
flowers and floral organs. Similarly to
LRP development, the spatio-temporal
priming of the organ primordia at the
shoot apex is controlled by auxin [9].
Differently from roots, however, it is

mailto:camilla.clark@ucl.ac.uk
mailto:jason.warren@ucl.ac.uk
mailto:jason.warren@ucl.ac.uk
http://dx.doi.org/10.1016/j.cub.2014.02.013
http://crossmark.crossref.org/dialog/?doi=10.1016/j.cub.2014.02.020&domain=pdf

	Music Biology: All This Useful Beauty
	Music Engages Ancient Brain Reward Systems
	Core Components of Music Processing Show Individual Variation
	Specific Brain Circuits May Signal the Biological Value of Music
	Future Directions
	References