Review Article
Regulation of auditory plasticity during critical periods and following
hearing loss
Dora Persic a, 1
, Maryse E. Thomas b, 1
, Vassilis Pelekanos c, 1
, David K. Ryugo d, e, f, 2
,
Anne E. Takesian b, 2
, Katrin Krumbholz c, 2
, Sonja J. Pyott a, *, 2
a
University of Groningen, University Medical Center Groningen, Groningen, Department of Otorhinolaryngology and Head/Neck Surgery, 9713, GZ,
Groningen, the Netherlands
b
Eaton-Peabody Laboratories, Massachusetts Eye & Ear and Department of Otorhinolaryngology and Head/Neck Surgery, Harvard Medical School, Boston,
MA, USA
c
Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, University Park, Nottingham, UK
d
Hearing Research, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
e
School of Medical Sciences, UNSW Sydney, Sydney, NSW, 2052, Australia
f
Department of Otolaryngology, Head, Neck & Skull Base Surgery, St Vincent’s Hospital, Sydney, NSW, 2010, Australia
a r t i c l e i n f o
Article history:
Received 10 December 2019
Received in revised form
15 March 2020
Accepted 14 April 2020
Available online 20 April 2020
Keywords:
Developmental critical periods
Sensory deprivation
Auditory cortex
Auditory brainstem
Neuronal reorganization
Hearing loss
Hidden hearing loss
Synaptopathy
Aging
Tinnitus
a b s t r a c t
Sensory input has profound effects on neuronal organization and sensory maps in the brain. The
mechanisms regulating plasticity of the auditory pathway have been revealed by examining the consequences
of altered auditory input during both developmental critical periodsdwhen plasticity facilitates
the optimization of neural circuits in concert with the external environmentdand in
adulthooddwhen hearing loss is linked to the generation of tinnitus. In this review, we summarize
research identifying the molecular, cellular, and circuit-level mechanisms regulating neuronal organization
and tonotopic map plasticity during developmental critical periods and in adulthood. These
mechanisms are shared in both the juvenile and adult brain and along the length of the auditory
pathway, where they serve to regulate disinhibitory networks, synaptic structure and function, as well as
structural barriers to plasticity. Regulation of plasticity also involves both neuromodulatory circuits,
which link plasticity with learning and attention, as well as ascending and descending auditory circuits,
which link the auditory cortex and lower structures. Further work identifying the interplay of molecular
and cellular mechanisms associating hearing loss-induced plasticity with tinnitus will continue to
advance our understanding of this disorder and lead to new approaches to its treatment.
Crown Copyright © 2020 Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Contents
1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Developmental critical periods in the auditory cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Evidence of cortical plasticity in the adult auditory cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. Mechanisms of juvenile and adult plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4.1. Disinhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4.2. Lifting the brakes on structural plasticity: perineuronal nets (PNNs) and myelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.3. Synaptic remodelling: synaptogenesis, synapse unsilencing, and synaptic scaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.4. Neuromodulatory mechanisms: linking learning and attention to map plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5. Plasticity in subcortical auditory structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5.1. Inhibitory circuits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
* Corresponding author.
E-mail address: s.pyott@umcg.nl (S.J. Pyott).
1
Equal first.
2
senior author contributors.
Contents lists available at ScienceDirect
Hearing Research
journal homepage: www.elsevier.com/locate/heares
https://doi.org/10.1016/j.heares.2020.107976
0378-5955/Crown Copyright © 2020 Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Hearing Research 397 (2020) 107976
5.2. PNNs and myelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5.3. Synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.4. Neuromodulatory mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
6. Hearing loss, (maladaptive) plasticity in the auditory pathway, and the emergence of tinnitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1. Overview
A remarkable feature of sensory pathways in the brain is their
organization of sensory representations in the form of topographic
maps. In the auditory domain, frequency receptive fields of neurons
form an orderly tonotopic map. Tonotopy is preserved along the
auditory neuraxis and reflects the topographically organized projections
from the cochlea. Organization of the tonotopic map is
genetically predetermined and laid out coarsely during prenatal
development. It is subsequently refined in an activity-dependent
manner, first by spontaneous activity and, following hearing
onset, by evoked activity (Clause et al., 2014; Kandler et al., 2009;
Tritsch et al., 2010; Sanes and Woolley, 2011; Wang and Bergles,
2015). The crucial role of auditory experience for the proper
development of the tonotopic map is evident during critical periods,
when the quality of the acoustic environment leaves a robust
imprint on the receptive fields of cortical neurons (Zhang et al.,
2001). Although organization of the tonotopic map was traditionally
considered resistant to alterations following the closure of the
critical period, converging evidence indicates retained (albeit
reduced) plasticity in the adult brain. This plasticity can be
observed at different levels of neuronal organization, ranging from
molecular, cellular and synaptic changes in excitability, to shifts in
tuning of single neurons, to large-scale, stable reorganization of the
tonotopic map. Many aspects of auditory plasticity and their
perceptual consequences have been reviewed elsewhere (Irvine,
2018; Keuroghlian and Knudsen, 2007; Pienkowski et al., 2011;
Schreiner and Polley, 2014; Syka, 2002; Weinberger, 2007). Here,
we focus on the molecular and cellular mechanisms regulating
neuronal organization and map plasticity during developmental
critical periods and in the adult brain. We emphasize changes in
regulation driven by peripheral auditory deprivation, for instance,
through hearing loss. We conclude with a discussion of how plasticity
and neuronal reorganizationdtriggered by overt and also
hidden hearing lossdmay contribute to tinnitus.
2. Developmental critical periods in the auditory cortex
Critical periods (CPs) are defined epochs of early postnatal
development, when structural and functional neural circuits are
shaped by passive experience with the external environment
(Hensch, 2004; Kuhl, 2010). These windows of plasticity drive the
maturation of subcortical and cortical sensory representations,
with consequences for emerging behavior and cognition (Hess,
1958; Lenneberg, 1967; Lorenz, 1935; Scovel, 1969). In the auditory
system, this rapid optimization facilitates feature-specific
expertise such as phoneme identification, language acquisition,
absolute pitch, and musical aptitude (Penhune, 2011; Werker and
Hensch, 2015; Zhao and Kuhl, 2016), yet also represents a period
of susceptibility to impoverished environments (Bures et al., 2017;
Knudsen, 2004; Sanes and Woolley, 2011; Uylings, 2006). For
example, prelingual deafness has permanent impact on the
development of auditory circuits. Children born deaf may regain
hearing with cochlear implants but demonstrate sustained
perceptual and language deficits that are more pronounced with
delayed implantation (Kral and Sharma, 2012; Kral et al., 2019;
Nicholas and Geers, 2006; Svirsky et al., 2004).
Plasticity of the cortical tonotopic map is the chief model of CP
plasticity in the auditory system. The tonotopic map is established
during a CP for frequency tuning, when passive acoustic experiences
influence map organization across species (Keuroghlian and
Knudsen, 2007; Kral, 2013; Sanes and Woolley, 2011; Werker and
Hensch, 2015). In rodents, exposure to pure tones results in the
expanded representation of the tone frequency within the tonotopic
map (Han et al., 2007; Kim and Bao, 2009; Zhang et al., 2001).
This robust plasticity is restricted to a short three-day period,
usually reported as postnatal days 11e14, following the maturation
of peripheral auditory structures (Barkat et al., 2011; de VillersSidani
et al., 2007). This plasticity occurs in primary auditory cortex
but not auditory thalamus, implicating plasticity at thalamocortical
or intracortical synapses (Barkat et al., 2011). CPs have also
been described for other sound features including binaural hearing,
tuning bandwidth, temporal sequences, frequency modulation, and
amplitude modulation (Caras and Sanes, 2015; Insanally et al.,
2009; Nakahara et al., 2004; Polley et al., 2013). In general, CPs
are thought to occur in a hierarchical sequence, with representations
for basic features consolidating before more complex ones (de
Villers-Sidani and Merzenich, 2011; Insanally et al., 2009; Sanes
and Woolley, 2011). Fig. 1A and B depict this developmental trajectory
in the rodent primary auditory cortex.
Interestingly, the timing of CPs is itself plastic and can be
influenced by the sensory environment (Takesian and Hensch,
2013; Voss et al., 2017). Unstructured, noisy environments postpone
CP closure (Chang and Merzenich, 2003), whereas exposure
to highly structured pulsed tones or pulsed white noise hastens CP
closure (Zhang et al., 2002; Zhou and Merzenich, 2012). Enriched
sensory environments also keep the CP open longer and have
opposite effects to deprivation, stimulating dendritic growth and
improving auditory response properties (Bose et al., 2010; Bures
et al., 2018; Cai et al., 2010). Effects of sound exposure on CP
timing can be further restricted to specific functional regions
within the auditory cortex. For example, band-limited noise delays
tonotopic refinement only for portions of the tonotopic map within
the noise band (de Villers-Sidani et al., 2008). The presence of highfidelity
sensory inputs is, therefore, necessary for the normal progression
of critical periods and the functional and structural
maturation of the primary auditory cortex (de Villers-Sidani and
Merzenich, 2011), as has been analogously demonstrated in primary
visual cortex (Crair et al., 1998).
The absence of early sensory experience is expected to have the
most profound effects on auditory cortical representations. Rodent
studies indicate that complete sensorineural hearing loss during
development disrupts synaptic inhibition and increases excitability
throughout the central auditory pathway, resulting in broadened
frequency tuning (reviewed in Sanes and Bao, 2009; Takesian et al.,
2009). Neonatal high frequency hearing loss induced through
D. Persic et al. / Hearing Research 397 (2020) 1079762
cochlear lesions or traumatic noise exposure alters cortical tonotopy,
shifting the tuning preference of neurons in high frequency
regions to lower frequencies (Eggermont and Komiya, 2000;
Harrison et al., 1991). Even transient hearing loss during development,
such as that experienced by children with otitis media, can
result in persistent changes in inhibitory synapses (Mowery et al.,
2015, 2019; Takesian et al., 2012) that could contribute to sustained
perceptual deficits later in life (Caras and Sanes, 2015;
Takesian et al., 2012; Whitton and Polley, 2011). However, heightened
plasticity during early life may also serve to functionally
enhance inputs from spared sensory structures during auditory
deprivation (Bavelier and Neville, 2002; Kral, 2007; Sharma et al.,
2015), often consistent with improved perceptual abilities in the
intact modalities (Lomber et al., 2010; Meredith et al., 2011). This
cross-modal plasticity occurs more prominently in higher-order
auditory areas as opposed to primary auditory cortex (Kral, 2007)
and has been found to preserve the functional role of cortical regions,
such as stimulus localization, despite enhancing responses to
a novel modality (Meredith et al., 2011).
3. Evidence of cortical plasticity in the adult auditory cortex
Just as early sensory experience is necessary for the normal
development of sensory brain regions, the continued presence of
patterned sensory inputs is also critical for adult brain function.
Decades of research have shown that both loss of sensory input
from the periphery (e.g., Chino et al., 1992; Diamond et al., 1993;
Maier et al., 2003; Robertson and Irvine, 1989) and significant
changes in the sensory environment (e.g., Pienkowski and
Eggermont, 2009; Zhou et al., 2011) can result in the reorganization
of adult sensory cortices across species. For example, seminal
studies examining plasticity of the somatosensory cortex in adult
nonhuman primates reported that, after finger deafferentation, the
deprived cortical territory was invaded by an expansion of the
neighboring finger representations (Merzenich et al., 1983a, 1983b;
Pons et al., 1991). These findings indicate that the mechanisms that
constrain plasticity after the CP can be at least partially released to
permit reorganization of sensory representations in the mature
cortex. In this section, we highlight evidence that shows the potential
for CP-like plasticity in the mature auditory cortex following
alteration of acoustic inputs.
Large scale topographic map changes in auditory cortex have
been demonstrated following peripheral deafferentation.
Restricted damage to the auditory periphery induces robust plasticity
in auditory cortex of both juvenile and adult animals
(Pienkowski and Eggermont, 2011), mirroring earlier findings in
somatosensory cortex. For example, spatially-restricted lesions of
the adult cochlea cause an over-representation in primary auditory
cortex of the frequencies that stimulate cochlear regions flanking
the damage, distorting the cortical tonotopic map (Eggermont and
Komiya, 2000; Rajan et al., 1993; Robertson and Irvine, 1989). Acute
exposure to intense pure tones also causes a profound reorganization
of tonotopic maps in the adult primary auditory cortex,
accompanied by the broadening of tuning curves and increases in
both spontaneous and sound-evoked activity (Calford et al., 1993;
Kimura and Eggermont, 1999; Norena et al., 2003, 2008).
Fig. 1. Auditory plasticity in development and adulthood in rodent models. A. Auditory development is characterized by multiple overlapping and successive critical periods
(CPs) during which sensory representations are formed. CP timing is malleable and depends on the maturation of plasticity regulators. Following maturation, sensory representations
are stable, and CPs can only be reopened if molecular brakes are lifted. A natural increase in dysregulated plasticity is observed with aging, which may be accelerated by
hearing loss. B. Trajectory of tonotopic map development in the primary auditory cortex. Left: The juvenile tonotopic map is characterized by incomplete maturation prior to CP
closure. Middle: Mature tonotopic representations form an orderly frequency gradient along the caudal to rostral axis. Right: Tonotopic disorganization has been observed with
aging. C. Tonotopic map reorganization due to enhanced, CP-like, plasticity. Left: Passive tone pip exposure during the CP for tonotopic map plasticity results in an overrepresentation
of the exposed tone frequency within the tonotopic map. Middle: Frequency over-representation can be induced in the adult cortex by pairing nucleus basalis
stimulation with tone presentation. Right: Peripheral hearing loss in a restricted frequency range can result in an over-representation of the spared frequencies.
D. Persic et al. / Hearing Research 397 (2020) 107976 3
Mounting evidence has shown that even non-traumatic sound
experience may result in central auditory plasticity. Extended
(week-long) exposure to moderate-intensity tones is associated
with reduced neural excitability in the cat auditory cortex
(Pienkowski and Eggermont, 2012). This reduction in activity is
restricted to the portion of the auditory cortex corresponding to the
exposure frequency range and likely reflects homeostatic plasticity
in response to chronic stimulation. Prolonged exposure to aroundthe-clock
broadband white noise at non-traumatic intensities has
also been found to result in disorganization of tonotopic gradients
and disruption of frequency processing in the adult rat primary
auditory cortex (Thomas et al., 2019; Zheng, 2012; Zhou and
Merzenich, 2012). This phenomenon has been proposed to occur
through a reopening of CP plasticity since exposure to pure tones
following noise exposure results in their exaggerated representation
within the tonotopic map (Thomas et al., 2019; Zhou and
Merzenich, 2012). In contrast to CP plasticity, however, sound
exposure must be persistent and long-lasting to induce map plasticity
in adulthood.
Later in life may also be a period during which sensory representations
are unusually plastic. Noisy or absent sensory inputs
caused by natural age-related degeneration of the auditory periphery
may contribute to dysregulated plasticity in the aged
auditory cortex (Kamal et al., 2013). Aging is accompanied by
reduced representational stability, poorer temporal processing, and
disrupted tonotopy in auditory cortex (Kamal et al., 2013;
Mendelson and Ricketts, 2001; Turner et al., 2005). A recent report
found that the tonotopic map of aged rats exhibits plastic reorganization
in response to passive tone exposure, similar to CP plasticity
(Cisneros-Franco et al., 2018). However, unlike the CP, this
plasticity does not result in the formation of stable representations,
as map reorganization could be easily ‘overwritten’ by a second
pure tone exposure. While aging has long been associated with a
loss of neural plasticity, this study instead suggests that there is
enhanced, but dysregulated, plasticity in the aged brain, which may
have deleterious effects on auditory processing and learning by
allowing nonspecific sensory experiences to distort existing cortical
representations.
4. Mechanisms of juvenile and adult plasticity
The findings above (Section 3) demonstrate the ability for
altered sensory inputs to drive cortical reorganization in the adult
auditory cortex. Understanding the molecular, cellular and circuit
mechanisms for this heightened plasticity may provide insight into
therapeutic strategies to either prevent or induce the re-wiring of
aberrant cortical circuits beyond early life. Among these mechanisms,
the maturation of several molecular and structural brakes
serves to close CPs, notably through the developmental increase of
inhibitory transmission and structural barriers to plasticity. In this
section, we focus on the mechanisms that underlie experiencedependent
and deprivation-induced plasticity in the developing
and mature auditory cortex. We draw on parallel findings from the
visual and somatosensory domains, which have also demonstrated
the brain’s capacity to reopen a state of heightened plasticity
following alteration of sensory inputs. Importantly, similar molecular
mechanisms appear to be shared during CP and adult plasticity
and are illustrated in Fig. 2.
4.1. Disinhibition
The onset of sensory experience triggers the maturation of
inhibition (Kandler, 2004), which may act to suppress spontaneous
activity generated by the cochlea prior to hearing in favor
of sensory-evoked activity (Toyoizumi et al., 2013). A concurrent
increase in brain-derived neurotrophic factor (BDNF) contributes
to the development of adult-like auditory cortical representations
(Anomal et al., 2013). BDNF may promote the maturation of
GABAergic interneuron populations, including parvalbumin (PV)expressing
interneurons, heavily implicated in visual CP plasticity
(Hensch, 2005; Huang et al., 1999; Itami et al., 2007). Indeed,
boosting inhibition using benzodiazepines (Hensch et al., 1998;
Fagiolini and Hensch, 2000; Fagiolini et al., 2004), stimulating the
maturation of inhibitory circuits with BDNF (Hanover et al.,1999), or
activating transcription factors enriched in interneurons (Beurdeley
et al., 2012; Durand et al., 2012; Krishnan et al., 2015; Spatazza et al.,
2013) can trigger CP onset in the visual cortex.
Reducing inhibitory transmission appears sufficient to revert
the mature cortex to a state of juvenile plasticity permissive of
changing cortical connections (Morishita and Hensch, 2008). In
auditory cortex, inactivating PV cells using a chemogenetic
approach permits CP-like tonotopic reorganization (CisnerosFranco
and de Villers-Sidani, 2019). Likewise, ocular dominance
plasticity in visual cortex can be reactivated by decreasing GABAmediated
inhibition through fluoxetine treatment (Maya
Vetencourt et al., 2008) and pharmacological inhibition of the
GABA-synthesizing enzyme GAD or GABAA receptors (Harauzov
et al., 2010; Kuhlman et al., 2013). Enriched environments may
also restore plasticity through reduced GABAergic inhibition (Sale
et al., 2007).
Both juvenile and adult hearing loss are associated with acute
and long-term decreases in cortical inhibition. A loss of acoustic
input during development (Kotak et al., 2005; Mowery et al., 2015;
Sarro et al., 2008; Takesian et al., 2010, 2012) or adulthood (Balaram
et al., 2019; Browne et al., 2012; Llano et al., 2012) leads to
decreased inhibition in primary auditory cortex, indicated by
reduced expression of GABAergic markers, such as GAD67, GABAa1
and GABAb2/3 receptors, reduced synaptic inhibitory currents, and
reduced sensitivity of cortical networks to GABAA receptor
blockade. Aging has also been associated with downregulated
inhibitory markers in the rodent primary auditory cortex, including
reduced GAD expression, GABAA receptor subunit protein levels
and binding, and PV-positive and somatostatin (SST)-positive cell
densities (Burianova et al., 2009; Caspary et al., 2013; Kamal et al.,
2013; Ouda et al., 2008; Ouellet and de Villers-Sidani, 2014). This
age-related decrease in inhibition is likely to be compounded by a
natural degeneration of the auditory periphery and hearing loss
associated with aging (Caspary et al., 2008; Ouda et al., 2015;
Recanzone, 2018)
Reductions in PV interneuron-mediated inhibition have been
implicated in cortical disinhibition following adult acoustic deprivation.
Within hours after mild or severe loss of auditory nerve
fibers, a drop in PV interneuron-mediated inhibition is observed in
the adult mouse primary auditory cortex (Resnik and Polley, 2017).
This reduced inhibition is sustained for weeks, even as hearing
thresholds and cortical receptive field tuning returns to preexposure
levels. Moreover, this early dip in PV interneuronmediated
inhibition predicts the eventual recovery of soundevoked
cortical responses weeks later. A similar rapid decrease in
PV interneuron activity has been reported in the primary visual
(Kuhlman et al., 2013) and somatosensory (Gainey et al., 2018)
cortices following sensory deprivation. Interestingly, SST interneurons
in primary auditory cortex show increased spontaneous
and tone-evoked firing rates after acoustic trauma and may,
therefore, serve to counteract cortical hyperexcitability (Novak
et al., 2016). A better understanding of how the distinct populations
of cortical inhibitory interneurons dynamically respond in
the days and weeks following the onset of hearing loss will provide
important insight into the mechanisms underlying cortical hyperexcitability
and its behavioral consequences.
D. Persic et al. / Hearing Research 397 (2020) 1079764
Recent work has begun to uncover the role of specific disinhibitory
microcircuits gated by neuromodulatory mechanisms
for cortical plasticity (Froemke et al., 2007). The most superficial
cortical layer (layer 1) is sparsely populated by a diverse group of
GABAergic interneurons that express the serotonin 5HT3A receptor
(5HT3AR) and are distinct from the two other commonly
studied interneuron classes expressing PV or SST (Lee et al., 2010).
This interneuron group is uniquely positioned to influence cortical
plasticity as layer 1 receives both sound-driven inputs from the
auditory thalamus and signals from several neuromodulatory
systems, including the serotonergic and cholinergic systems (Lee
et al., 2010; Letzkus et al., 2011; Takesian et al., 2018). Although
they produce the inhibitory neurotransmitter GABA, subsets of
these interneurons have a ‘disinhibitory’ function: because they
target other inhibitory interneurons, their activity leads to a net
withdrawal of inhibition from glutamatergic neurons (Fu et al.,
2014; Letzkus et al., 2011; Pfeffer et al., 2013; Takesian et al.,
2018). This disinhibitory circuit mediates tonotopic map reorganization
during the CP, likely by inhibiting PV neurons (Takesian
et al., 2018). Superficial 5HT3AR-positive interneurons expressing
neuron-derived neurotrophic factor (NDNF) also play a role in
plasticity that underlies adult associative learning (Abs et al.,
2018). Furthermore, manipulating the activity of another group
of superficial 5HT3AR -positive interneurons expressing vasoactive
intestinal peptide (VIP) modulates plasticity in adult primary visual
cortex by inhibiting SST interneurons (Fu et al., 2014).
Together, these studies highlight a diverse group of disinhibitory
neurons in superficial cortex as a promising target to regulate
adult plasticity across sensory cortices.
4.2. Lifting the brakes on structural plasticity: perineuronal nets
(PNNs) and myelin
Additional brakes on CP plasticity are applied by perineuronal
nets (PNNs) and myelin, each of which may act as structural barriers
to plasticity by prohibiting the formation of new synapses
(Bavelier et al., 2010; McGee et al., 2005; Sorg et al., 2016). PNNs are
extracellular matrix structures that preferentially form around PV
cells, coinciding with the maturation of auditory response properties
(Friauf, 2000) and potentially limiting future PV cell plasticity
(Takesian and Hensch, 2013). In vitro degradation of PNNs reduces
excitability and gain in cortex (Balmer, 2016). In vivo degradation of
PNNs in the mature brain results in decreased inhibition (Lensjo
et al., 2017) and a reopening of ocular dominance plasticity in the
adult visual cortex (Lensjo et al., 2017; Pizzorusso et al., 2002). PV
interneurons and PNNs may also regulate each other as part of a
dynamic feedback loop: work in the adult mouse visual cortex has
shown that silencing the activity of PV interneurons induces the
selective regression of their own PNNs (Devienne et al., 2019).
Less clear is the role of sensory deprivation in adulthood on the
dynamic regulation of PNNs. In the adult auditory cortex, a marked
cell type- and layer-dependent decrease in PNNs in the mouse
primary auditory cortex occurs following noise-induced hearing
loss (Nguyen et al., 2017). However, similar findings have not been
observed in other sensory cortices. Notably, whisker trimming
during the CP disrupts formation of PNNs in the somatosensory
(barrel) cortex. In contrast, whisker trimming in adulthood does
not cause a loss of PNNs, suggesting that the maintenance of
established PNNs does not require normal sensory input (McRae
et al., 2007). Similar observations have been reported in the
Fig. 2. Cellular, molecular, and circuit-level mechanisms of cortical plasticity. Regulators of plasticity are shared by the juvenile and adult auditory cortex. Cortical development
is marked by changes in inhibitory circuitry and the maturation of regulators that restrict plasticity. States of heightened plasticity similar to the immature brain can be reinstated by
the removal of these plasticity regulators and experiences such as learning, acoustic over-exposure, or sensory deprivation. Abbreviations: A1R: adenosine A1 receptor, BDNF: brain
derived neurotrophic factor, GABAAR: GABAA receptor, lynx1: ly6/neurotoxin 1 protein, mAChR: muscarinic acetylcholine receptor, MGB: medial geniculate nucleus, nAChR:
nicotinic acetylcholine receptor, NDNF: neuron-derived neurotrophic factor, PNN: perineuronal net, PV: parvalbumin, Pyr: pyramidal neuron, SST: somatostatin. VIP: vasoactive
intestinal peptide.
D. Persic et al. / Hearing Research 397 (2020) 107976 5
lateral geniculate nucleus, the thalamic relay in the visual pathway
(Sur et al., 1988).
The maturation of myelin is one of the last steps of development,
with central auditory myelination in both humans and rodents
beginning with the onset of hearing and continuing until the age of
sexual maturity (Long et al., 2018). Myelin and myelin-associated
proteins, such as neurite growth inhibitors, are known to slow axon
growth and limit experience-dependent plasticity in adult sensorimotor
and visual cortices (Kartje et al., 1999; McGee et al., 2005;
Z’Graggen et al., 1998). A growing area of research is beginning to
demonstrate the role of early sensory experience and neural activity
in the developmental time course of myelination (Chorghay
et al., 2018). For example, musical training has been found to increase
white matter connectivity in musicians who receive training
before the age of 7 (Steele et al., 2013). Decreased density of myelin
basic protein has been observed in young adult rats chronically
exposed to white noise (Kamal et al., 2013), aged rats (de VillersSidani
et al., 2010; Kamal et al., 2013), and aging humans
(Itoyama et al., 1980). A reduction in patterned sensory inputs have,
therefore, been proposed to exacerbate age-related alterations in
myelin expression (Tremblay et al., 2012).
4.3. Synaptic remodelling: synaptogenesis, synapse unsilencing,
and synaptic scaling
In the adult brain, analysis of the visual cortex points to de novo
formation of synapses as a mechanism underlying restoration of
activity in areas of deprived peripheral input. In seminal studies,
focal binocular retinal lesions resulted in the deprived area of the
primary visual cortex, termed the lesion projection zone, to initially
become quiescent. Subsequently, however, the area regained activity
and responded to loci neighboring the lesion (Gilbert et al.,
1990; Kaas et al., 1990). The recovery of functional processing has
been attributed to an increase in axonal boutons and axonal processes
with subsequent synaptogenesis (Darian-Smith and Gilbert,
1994; Keck et al., 2008; Yamahachi et al., 2009). However, the
extent of axonal sprouting appears spatially limited, such that the
center of the lesion projection zone remains silent even after peripheral
parts regained visually driven activity (Hubener and
Bonhoeffer, 2014).
In the primary auditory cortex, the contribution of axonal
rearrangement to the restoration of sound-evoked activity has not
been resolved and, in fact, is contradicted by a study examining
expression of various proteins in the primary auditory cortex of rats
following unilateral noise exposure (Browne et al., 2012). Although
various markers of inhibitory transmission were reduced in
expression, a marker of axonal sprouting, GAP43, showed reduced
expression in the ipsilateral auditory cortex and no change in the
contralateral auditory cortex, suggesting that reorganization of the
frequency map may not rely on axonal rearrangement. Alternative
mechanisms, such as the unmasking of silent synapses and Hebbian
strengthening of weak synapses (Syka, 2002) as well as neuronal
adaptation and both short- and long-term potentiation (Froemke
and Schreiner, 2015) may be involved in reorganization of cortical
frequency maps following auditory deprivation. The rapid onset of
reorganization suggests that unmasking is facilitated by disinhibition
in the short term (Eggermont, 2017b; Scholl and Wehr, 2008),
whereas Hebbian plasticity could serve to consolidate
representations.
Prolonged perturbations of neuronal activity may eventually
result in sensory map reorganization through homeostatic plasticity
mechanisms (reviewed in Eggermont, 2017; Gourevitch et al.,
2014; Zhao et al., 2016). In cases of sensory deprivation, homeostatic
plasticity serves to maintain central activity in response to
decreased activity from the periphery. First described in neocortical
cell cultures (Turrigiano et al., 1998), homeostatic synaptic scaling
counteracts an initial loss of activity following visual deprivation in
rodent (Keck et al., 2013) and human visual cortex (Castaldi et al.,
2020). The same has been demonstrated in auditory cortex
following conductive hearing loss (Teichert et al., 2017) and traumatic
noise exposure (Asokan et al., 2018). This compensatory
plasticity may result from elevated gene expression of excitatory
AMPA receptors and reduced expression of inhibitory
GABAA receptors (Balaram et al., 2019). During chronic, nontraumatic
sound exposure, homeostatic plasticity acts in the
opposite manner, serving to reduce cortical activity in a frequencyspecific
manner in order to compensate for a persistent increase in
neural activity due to narrow-band or broadband stimulation (Lau
et al., 2015; Pienkowski and Eggermont, 2011).
The unsilencing of NMDA-receptor-only synapses is also a critical
mechanism for CP plasticity in sensory cortices (Huang, 2019).
The CP for tonotopic plasticity is associated with the unsilencing of
these synapses in mouse auditory cortex. This unsilencing can
occur prematurely in response to early seizures, which subsequently
prevent CP reorganization (Sun et al., 2018). Severe hearing
loss during early development is also associated with the elimination
of AMPA-mediated long-term potentiation (LTP) (Kotak
et al., 2007). LTP at auditory thalamocortical synapses can be
unmasked in adulthood through attentional mechanisms or stimulation
of cholinergic inputs to the cortex (Chun et al., 2013;
Froemke et al., 2013), as described in more detail in the following
section (section 4.4).
Microglia also contribute to synaptic remodelling during juvenile
and adult cortical plasticity, especially following peripheral
injury or acoustic trauma. These immune cells of the central nervous
system can change from a ‘resting’ to ‘activated’ phenotype
during periods of neuroinflammation (Soulet and Rivest, 2008). In
both developmental and adult plasticity, microglia contribute to
circuit refinement by engulfing synaptic elements such as axonal
terminals and dendritic spines (Paolicelli et al., 2011; Schafer et al.,
2012; Tremblay and Majewska, 2011). Increased neural activity can
trigger greater microglial surveillance and modification of surrounding
environments under inflammatory conditions (Wu et al.,
2015), such as peripheral denervation (Ladeby et al., 2005) or
traumatic noise exposure (Saljo et al., 2001). A recent study reported
an increase in activated microglia in the adult auditory
cortex of mice following noise-induced hearing loss (Wang et al.,
2019).
4.4. Neuromodulatory mechanisms: linking learning and attention
to map plasticity
Learning-induced changes in adult tonotopic maps are thought
to require the precisely-timed release of neuromodulators
recruited by arousal or attention (for reviews see Pienkowski et al.,
2011; Schreiner and Polley, 2014). For example, pairing tones with
mild aversive shocks causes rapid shifts in the tuning of neurons
within auditory cortex toward the tone frequency (Abs et al., 2018;
Bakin and Weinberger, 1990; Edeline et al., 1993). Intensive training
on a sensory task can also induce dramatic changes in cortical
tuning and reorganization of tonotopic maps (Bieszczad and
Weinberger, 2010; David et al., 2012; Polley et al., 2006;
Recanzone et al., 1993; Reed et al., 2011).
Neuromodulatory contributions to auditory cortex may also
underlie the reopening of CPs in adulthood. Cholinergic modulation
of plasticity has been documented in seminal experiments pairing
stimulation of the nucleus basalis, the largest source of cholinergic
projections to the auditory cortex, with passive tone exposure,
resulting in over-representation of the exposure frequency
(Froemke et al., 2007, 2013; Kilgard and Merzenich, 1998;
D. Persic et al. / Hearing Research 397 (2020) 1079766
Weinberger, 2003). Cholinergic inputs to cortical layer-1 interneurons
may promote cortical plasticity by disinhibition of PV
interneurons during developmental CPs (Takesian et al., 2018) and
adulthood (Letzkus et al., 2011). Acetylcholine may also gate
cortical plasticity by acting directly on thalamocortical synapses.
Bidirectional long-term synaptic plasticity at thalamocortical synapses
is gated in the mature brain by adenosine, which blocks
glutamate release (Blundon and Zakharenko, 2013; Blundon et al.,
2011; Chun et al., 2013). Releasing this molecular brake by deleting
adenosine receptors or the adenosine synthesizing-enzyme
enables map plasticity (Blundon et al., 2017). Nucleus basalis
stimulation releases acetylcholine at these synapses, which,
through binding to muscarinic (metabotropic) acetylcholine receptors,
blocks adenosine signalling and restores CP-like plasticity
(Blundon et al., 2011; Chun et al., 2013).
The noradrenergic system has also been shown to be critical for
CP plasticity in the auditory cortex: pure-tone exposure does not
lead to tonotopic reorganization in mice that lack norepinephrine
from birth (Shepard et al., 2015), similar to seminal findings in visual
cortex (Bear and Singer, 1986; Kasamatsu and Pettigrew, 1976).
Indeed, pairing tones with electrical stimulation of the locus
coeruleus, a brain region that releases noradrenaline, leads to shifts
in frequency tuning in A1 towards the tone frequency . These
findings indicate that neuromodulatory systems generally play a
permissive role in CP plasticity and that the tightened control of
neuromodulatory action with maturation is a main factor in
restricting further experience-dependent plasticity (Morishita
et al., 2010; Takesian et al., 2018). Interestingly, basal cholinergic
cell numbers and cholinergic neurotransmission have long been
known to decline in the aged brain (McGeer et al., 1984; Perry,
1980) and likely contribute to dysregulated auditory plasticity in
later life (Caspary et al., 2008).
Together, these studies suggest that numerous interlinked
mechanisms for plasticity exist at various synaptic and cellular sites
within auditory cortex. Both in the developing and mature cortex,
many of these mechanisms converge to influence the function of
specific inhibitory circuits. Identifying circuit-level approaches to
modulate plasticity will be important to prevent or reverse the
maladaptive plasticity associated with adult hearing loss.
5. Plasticity in subcortical auditory structures
The auditory cortex receives input from the cochlea via a series
of relays in the auditory brainstem. The first is the cochlear nucleus
(CN), which has two main structural and functional divisions: the
ventral and the dorsal CN. The dorsal CN relays directly to the
inferior colliculus (IC), whereas the ventral CN first relays to the
superior olivary complex (SOC), thought to be specifically involved
in the binaural integration of acoustic input and sound localization.
Projections from the SOC again lead primarily to the IC. From the IC,
auditory signals are relayed to the medial geniculate body (MGB) in
the thalamus, and, from there, to the primary auditory cortex.
Subcortical auditory relays are thought to play an important role in
the binaural processing of sound, as well as the integration with
non-auditory information (for a more complete overview, see, for
example, Malmierca et al., 2010).
During auditory CPs, neurons in these relays undergo important
morphological and physiological changes that are dependent on
auditory input and enable fast, reliable neurotransmission. Complete
and moderate hearing loss causes changes along the length of
the auditory pathway (reviewed in Butler and Lomber, 2013) that
can even result in reorganization of tonotopic maps also present in
the auditory brainstem (reviewed in Kandler et al., 2009). Perhaps
because of their crucial role in the binaural integration of auditory
input, unilateral compared to bilateral hearing loss can exert more
profound effects on organization of the auditory brainstem (for
example Popescu and Polley, 2010). Although the auditory brainstem
was originally believed to be resistant to plasticity in adulthood
to enable the stable conveyance of information to the auditory
cortex, a variety of recent work in both animals and humans shows
that altered acoustic input can trigger behaviorally meaningful
plasticity in the adult auditory brainstem. Recent reviews have
outlined various aspects of auditory brainstem plasticity (including
Friauf et al., 2015; Oertel et al., 2019; Skoe and Chandrasekaran,
2014; Tzounopoulos and Kraus, 2009). Here, we highlight molecular,
cellular, and circuit-level mechanisms of plasticity that are
shared between the auditory cortex and auditory brainstem.
5.1. Inhibitory circuits
Subcortical inhibitory circuits serve to sharpen auditory responses
to rapidly varying signals (reviewed in Bender and Trussell,
2011; Pollak et al., 2002). Profound changes in the balance of
excitation and inhibition occur during development (reviewed in
Sanes et al., 2010), and auditory deprivation during CPs disrupts
maturation of inhibition along the length of the auditory pathway
(reviewed in Takesian et al., 2009). These changes may reflect homeostatic
mechanisms to compensate for the loss of peripheral
input. A variety of likely co-occurring molecular mechanisms give
rise to increased excitatory gain and decreased inhibitory gain. For
example, congenitally deaf mice show enhanced intrinsic neuronal
excitability in principle neurons of the medial nucleus of the
trapezoid body (MNTB) due to alterations in ion channel expression
(Leao et al., 2004a, 2006), enhanced excitatory (glutamatergic)
synaptic transmission at endbulbs of Held, the specialized synapses
between auditory neurons and bushy cells in the CN (Oleskevich
et al., 2004), and diminished inhibitory (glycinergic) synaptic
transmission at calyx of Held synapses between bushy cells and
MNTB principle cells (Leao et al., 2004b, 2005). A similar loss of
inhibitory gain following deafness in adulthood is indicated by
increased expression of excitatory glutamate receptors and reduced
expression of inhibitory GABA and glycine receptors in various
auditory brainstem structures, including the CN (Asako et al., 2005;
Dong et al., 2010a; Suneja et al., 1998, 2000), the SOC (Buras et al.,
2006; Suneja et al., 1998, 2000), and the IC (Balaram et al., 2019;
Dong et al., 2010a, 2010b; Holt et al., 2005). Age-related hearing loss
is also associated with reduced inhibition in various structures of
the auditory brainstem (reviewed in Caspary et al., 2008). These
findings suggest that preventing the loss of inhibition or enhancing
inhibitory circuits in the auditory pathway may mitigate auditory
deficits associated with hearing loss. Indeed, recent work has
shown that augmenting inhibitory neurotransmission in the thalamocortical
pathway prevented perceptual defects induced by
transient hearing loss during the auditory CP in gerbils (Mowery
et al., 2019).
5.2. PNNs and myelin
PNNs and myelin have been studied in the auditory brainstem,
with both appearing at the onset of hearing and progressively
maturing up the neuraxis to cortex (reviewed in Long et al., 2018;
Sonntag et al., 2015). PNNs, in general, surround fast and precisely
spiking neurons and thus are, not surprisingly, found in subsets of
neurons in almost all brainstem auditory relays. They are especially
prominent around octopus cells, principal cells that fire with high
temporal precision in the ventral CN, and around principle cells in
the MNTB (Sonntag et al., 2015). Genetic attenuation of PNNs in
MNTB principle neurons reduces their excitability and alters their
firing properties (Balmer, 2016; Blosa et al., 2015). Neonatally
deafened rats show reduced expression of PNN markers in neurons
D. Persic et al. / Hearing Research 397 (2020) 107976 7
of the medial superior olive (Myers et al., 2012). These findings
motivate further work to examine the functional consequences of
altered PNNs in response to auditory deprivation and modulation
during developmental CPs and in adulthood.
Myelination is essential for rapid conduction and precise timing
of action potentials. A recent study found that, in the mouse, both
axonal diameter and myelin thickness of neurons in the MNTB
double two weeks after the onset of hearing, with a concurrent
(and expected) increase in transmitted firing rates and conduction
speed (Sinclair et al., 2017). In the same study, peripheral auditory
deprivation via ear plugging at hearing onset led to comparatively
thinner and less myelinated fibers, and ear plugging in adulthood
also reduced myelin thickness, most notably in the most myelinrich
fibers. In rats, acoustic overexposure in adulthood causes,
among other pathologies, disorganization of myelin sheaths around
axon fibers of auditory neurons (Coyat et al., 2019). The molecular
mechanisms regulating myelination either normally or in response
to altered acoustic input are unknown. Recent work examining
knockout mice indicates that b-secretase 1 (BACE1), a protease
shown to regulate myelination and myelin sheath thickness in
central and peripheral nerves, may regulate auditory-nerve myelination,
at least during development (Dierich et al., 2019).
5.3. Synaptic plasticity
During auditory CPs, neurons of the auditory brainstem undergo
dramatic morphological rearrangements that are dependent on
auditory input (reviewed in O’Neil et al., 2011; Yu and Goodrich,
2014). This structural maturation is necessary for fast and reliable
synaptic transmission, and is especially evident in the endbulbs of
Held found in the CN. Ascending processes of the auditory nerve
form progressively more arborized synaptic endings, called endbulbs
of Held, which eventually envelop the cell bodies of the bushy
cell neurons in the anterior ventral CN (Ryugo and Fekete, 1982).
Auditory deprivation during development causes profound
morphological changes in the maturation of these contacts (Baker
et al., 2010), with similar, albeit less dramatic, changes also occurring
with progressive, age-related hearing loss (Connelly et al.,
2017) and hidden hearing loss caused by cochlear synaptopathy
(Muniak et al., 2018). Specifically, endbulbs show overall reduced
branching with hypertrophy of the remaining postsynaptic densities
in both cats (Baker et al., 2010) and mice (Lee et al., 2003). This
hypertrophy appears related to the degree of hearing loss: cats with
congenital hearing loss (thresholds above 50 dB SPL) exhibit synapses
with sizes between those of totally deaf cats and normalhearing
cats (Ryugo et al., 1997). In addition, in congenitally deaf
cats, hypertrophy of the endbulb synapses is more evident in
spherical compared to globular bushy cells, whereas synapses of
bouton endings onto multipolar cells remain unaltered (Redd et al.,
2002). The hypertrophy of synapses on spherical bushy cells, where
ionotropic glutamate receptors are located, may serve to compensate
reduced input from the auditory nerve. Consistent with this
hypothesis, hypertrophy of the postsynaptic densities is significant
in spherical bushy cells, which show high levels of spontaneous
activity, modest in globular bushy cells, which show more medium
levels of spontaneous activity, and absent in multipolar cells, which
show medium-to-low levels of spontaneous activity (Redd et al.,
2000, 2002; Ryugo et al., 1997, 1998). Importantly, early restoration
of hearing via cochlear implants in congenitally deaf cats
rescues normal synaptic structure in both the CN (O’Neil et al.,
2011; Ryugo et al., 2005) and in the medial SOC (Tirko and Ryugo,
2012). Thus, restoration of input early in the ascending auditory
pathway is crucial to preventing the cascade of pathological plasticity
observed along the length of the auditory pathway in
response to both early and late deafening.
The molecular factors regulating morphological changes of
auditory synapses in response to auditory deprivation during
developmental CPs and in adulthood are still unclear. In response to
auditory deprivation, the CN shows increased expression of proapoptotic
genes during auditory CPs in contrast to increased
expression of pro-survival genes following CPs (Harris et al., 2005).
Researchers examining gene expression changes in the ventral CN
of adult rats shortly after noise exposure highlighted decreased
expression of Bdnf, Homer, and Grin1. These genes encode proteins
involved in neurogenesis and plasticity and may, therefore, play a
role in synaptic remodelling (Manohar et al., 2019). Previous work
has also implicated growth-associated protein 43 (GAP43), a brainwide
regulator of synapse structural and functional plasticity
(Holahan, 2017) and BDNF (Singer et al., 2014) in synaptic remodelling
of neurons in the CN. Re-expression of GAP43 can be induced
by unilateral cochlear ablation of neurons in the ipsilateral CN
(Fredrich and Illing, 2010; Illing et al., 1997; Kraus et al., 2011) and
ipsilateral lateral superior olive (Illing et al., 1997). GAP43 expression
is maintained into adulthood in the IC and lateral and medial
superior olivary nuclei (Illing et al., 1999), suggesting retained potential
for plasticity into adulthood. Finally, increased and prolonged
expression of activated microglia is associated with acoustic
overexposure (Baizer et al., 2015), consistent with the role of
microglia in repair after neuronal injury.
5.4. Neuromodulatory mechanisms
Although the role of acetylcholine as a neuromodulator regulating
plasticity has been better studied in the auditory cortex (see
Section 4.4), the cochlea and many of the intervening auditory relays
to the cortex also receive cholinergic innervation that regulates
plasticity. Both nicotinic and muscarinic cholinergic receptors are
extensively expressed throughout the auditory brainstem (Morley
and Happe, 2000), reflecting the potential for widespread influence
of cholinergic signalling along the auditory pathway. In the
auditory brainstem, cholinergic innervation arises from neurons in
the SOC and pontomesencepahlic tegmentum, which form not only
ascending but also collateral and descending projections within the
auditory brainstem (reviewed in Schofield et al., 2011). These two
structures also receive innervation from the auditory cortex
(Schofield et al., 2011). Particularly well-studied are the primarily
cholinergic olivocochlear projections from the SOC (specifically the
medial and lateral superior olives) to the cochlea (reviewed in
Fuchs and Lauer, 2019). Medial olivocochlear neurons receive input
from the CN and provide inhibitory output to cochlear outer hair
cells, creating a feedback loop that is thought to be important for
dynamic improvement of hearing in background noise. The pontomesencepahlic
tegmentum targets the MGB in the thalamus, the
IC, and the CN (Schofield et al., 2011). Although diverse effects of
acetylcholine on responses of neurons in the IC have been reported
(Schofield et al., 2011), cholinergic modulation appears to exert
more profound effects on sound-evoked (rather than spontaneous)
activity and appears to increase excitability by causing a release of
inhibition (Ayala et al., 2016). In the thalamus, a recent study
showed that activation of nicotinic acetylcholine receptors on MGB
neurons enhances both ascending inhibitory (tectothalamic) projections
and descending excitatory (corticothalamic) inputs,
potentially integrating bottom-up and top-down mechanisms to
improve signal detection (Sottile et al., 2017). Finally, thalamocortical
plasticity is malleable not only during auditory CPs (Chun
et al., 2013), but can also be unmasked by activation of muscarinic
cholinergic inputs to the thalamus (Blundon et al., 2011). In
addition to acetylcholine, glutamate, GABA, glycine, and dopamine
also regulate plasticity in the auditory brainstem as part of
descending pathways (reviewed in Schofield and Beebe, 2019).
D. Persic et al. / Hearing Research 397 (2020) 1079768
Improved understanding of the role of these various neuromodulatory
mechanisms will allow manipulation of anatomically
and functionally specific circuits to regulate plasticity in the auditory
brainstem to counteract perceptual defects induced by hearing
loss.
6. Hearing loss, (maladaptive) plasticity in the auditory
pathway, and the emergence of tinnitus
Noise- and age-related hearing loss are the biggest risk factors
for tinnitus (Elgoyhen and Langguth, 2010; Shore et al., 2016), the
perception of phantom sounds, which affects between 12 and 30%
of adults (McCormack et al., 2016; Møller, 2011). In animals, hearing
loss has been associated with changes in cortical response properties
(see Section 3), suggesting that cortical plasticity induced by
hearing loss may maladaptively trigger tinnitus. A causal relationship
between hearing loss and tinnitus through maladaptive plasticity
is supported, not only by the high comorbidity of hearing loss
and tinnitus, but also by the observation that the perceived frequency
profile of the phantom percept often coincides with the
frequency profile of the hearing loss (Norena et al., 2002;
Schecklmann et al., 2012). However, hearing loss is not always
associated with tinnitus (Møller, 2011), and individuals with
normal audiograms (but perhaps hidden hearing loss) can also
report tinnitus (e.g., Schaette and McAlpine, 2011). Much research
is currently focused on disentangling the neural changes associated
with tinnitus from those associated strictly with hearing loss.
Additional, albeit more limited, work is focused on disentangling
the confound of aging on both tinnitus and hearing loss (reviewed
in Ibrahim and Llano, 2019).
Early research implicated reorganization of the tonotopic map in
the auditory cortex as a potential neural correlate of tinnitus in
humans (e.g., Mühlnickel et al., 1998) and animals (e.g., Eggermont
and Roberts, 2004; Irvine, 2000; Kaltenbach, 2011). For example,
pure tone exposure causing mild to moderate high-frequency
hearing lossdoften associated with tinnitus in humans (Tan et al.,
2013)dled to profound reorganization of the cortical tonotopic
map in cats (Eggermont and Komiya, 2000). One study suggested a
direct causal relationship between tonotopic map reorganization
and tinnitus, showing that tone exposure paired with vagal-nerve
stimulation both reversed tonotopic map reorganization and
eliminated behavioral indicators of tinnitus in previously noiseexposed
rats (Engineer et al., 2011). However, very recent
research indicates that cortical reorganization is not necessary for
tinnitus. By examining mouse strains with different susceptibilities
to developing tinnitus, Miyakawa and colleagues showed that
cortical map distortions were associated with hearing loss but not
tinnitus (Miyakawa et al., 2019). Importantly, research with animal
models is complicated by the varied methods used to induce
tinnitus and the lack of consensus on reliable measures to detect its
presence (reviewed in von der Behrens, 2014).
In humans, brain imaging (functional magnetic resonance imaging,
fMRI) studies have found no evidence of cortical tonotopic
reorganization when examining subjects with tinnitus but normal
or near-normal hearing thresholds (Berlot et al., 2020; Langers
et al., 2012). A recent study that used subjects with or without
tinnitus but otherwise carefully matched for moderate to profound
high-frequency hearing loss found that changes in cortical responses
were associated with hearing loss and were, in fact, more
pronounced in hearing loss without than with tinnitus (Koops et al.,
2020). The direction of the changes, however, was opposite to that
predicted from the animal literature, with increased responses to
frequencies withindrather than outside ofdthe hearing loss range
(i.e., increased responses to higher frequencies). Koops et al. (2020)
presented their stimuli at equal loudness levels across subjects,
such that stimulus intensities were greater in individuals with
greater hearing loss. Thus, it is possible that the observed differences
between hearing-impaired subjects with and without
tinnitus reflect differences in the peripheral pattern of the hearing
loss (Tan et al., 2013) rather than changes arising centrally as a
consequence of hearing loss. Consistent with this idea, earlier
studies, which used constant stimulus levels, found either no
changes in cortical responses associated with hearing loss (Lanting
et al., 2008; Wolak et al., 2017) or increased responses to lower
frequencies (Ghazaleh et al., 2017), opposite to the findings of
Koops et al. (2020). Importantly, research in humans is complicated
by the heterogeneity of tinnitus causes and presentation (reviewed
in Cederroth et al., 2019).
Lack of cortical reorganization in humans with tinnitus is
consistent with brain imaging studies in the visual and somatosensory
domains. In the visual domain, macular degeneration is a
condition which, like high-frequency hearing loss, deprives a
limited part of the cortical sheet of its input. fMRI studies have
shown that, even after years of visual input deprivation due to
macular degeneration, the relevant cortical regions remain nonresponsive
(e.g., Baseler et al., 2011; Smirnakis et al., 2005;
Sunness et al., 2004), suggesting that cortical organization is stable
despite input deprivation. In fact, somatosensory studies have
suggested that cortical stability and phantom perception are
causally related. These studies exploited the fact that patients with
limb amputations often experience vivid impressions that they can
move the missing limb. They showed that such phantom perceptions
of missing limb movements can elicit orderly activations
within the deprived cortical regions (Kikkert et al., 2016) and that
the strength of the activation is associated with the severity of
phantom limb pain (Kikkert et al., 2018; Makin et al., 2013). Thus,
findings across sensory domains suggest that phantom percepts
may arise, not from cortical map reorganization, but, conversely,
from map stability.
As another strategy to disentangle the effects of hearing loss and
tinnitus, new lines of research have begun to examine the contribution
of presumably non-traumatic sound experiencedpotentially
causing hidden forms of hearing lossdto changes in cortical
responses (reviewed in Eggermont, 2017a) as well as tinnitus. Cats
exposed to either synthetic tone pips or white noise (Pienkowski
and Eggermont, 2009), or to “real-world” noise (Pienkowski et al.,
2013) at non-traumatic levels demonstrated altered neural activity
in the auditory cortex, suggesting that passive sound exposure
may lead to a tinnitus percept in the absence of overt hearing loss
(reviewed in Pienkowski and Eggermont, 2012). Independent lines
of research indicate that presumably non-traumatic noise exposure
can lead to substantial and permanent loss of synapses between the
inner hair cells and auditory neuronsdcalled cochlear synaptopathydthat
is not detectable by audiograms (reviewed in Liberman
and Kujawa, 2017), raising the possibility that tinnitus may be
triggered by audiometrically hidden forms of hearing loss such as
cochlear synaptopathy. Findings testing this prediction have so far
been inconsistent, with some work suggesting that synaptopathy is
associated with tinnitus (Forster et al., 2018; Rüttiger et al., 2013)
and other work finding no link (Hickox and Liberman, 2014;
Pienkowski, 2018). Both biological and experimental differences
(e.g., strain and species differences and methods of tinnitus
detection) may account for the variability in findings.
Research in animals has implicated a few molecular candidates
and pathways that appear specifically involved in the generation of
tinnitus following hearing loss. Downregulation of GAD65, an
enzyme required in the synthesis of the inhibitory neurotransmitter
GABA, is necessary for the generation of tinnitus following
noise-induced hearing loss (Miyakawa et al., 2019). Decreased
mobilization of Arc/Arg3.1, an activity-dependent cytoskeletal
D. Persic et al. / Hearing Research 397 (2020) 107976 9
protein required for homeostatic synaptic plasticity in mouse primary
visual cortex (Gao et al., 2010; Sedley et al., 2015), in the
auditory cortex is associated with the development of tinnitus, but
not hearing loss alone, following noise exposure (Rüttiger et al.,
2013). Genetic knockout and pharmacological blockade of TNFa, a
proinflammatory cytokine also involved in regulating homeostatic
plasticity (Steinmetz and Turrigiano, 2010; Stellwagen and
Malenka, 2006), prevented noise-induced generation of tinnitus;
conversely, TNFa administration caused tinnitus behavior in
normal-hearing animals (Wang et al., 2019). Together these findings
indicate that there are molecular factors that regulate whether
(or not) plasticity triggered by hearing loss results in tinnitus.
Although cortical map organization may be stable despite input
deprivation, there is consensus that tinnitus is associated with
altered neural activity and cortical plasticity in some form. Metabolic
measures, such as fMRI, may be insufficient to detect these
types of plasticity, as they cannot distinguish between excitatory
versus inhibitory activity (Heeger and Ress, 2002; Logothetis, 2008)
and may, therefore, fail to detect changes in inhibition following
auditory deprivation that have been observed in animals (e.g.,
Norena and Eggermont, 2003; Rajan, 1998). Consistent with this
idea, results from human studies using magnetic resonance spectroscopy
(MRS) have suggested that both hearing loss (Gao et al.,
2015) and tinnitus (Sedley et al., 2015) can be associated with reductions
in the concentration of the main inhibitory neurotransmitter,
GABA, within the auditory cortex. Similar changes have also
been observed in the visual cortex as a result of visual deprivation
(Lunghi et al., 2015).
In animals, the observation of altered neural activity in association
with noise-induced tinnitus is not restricted to the auditory
cortex, and, in fact, has been more extensively studied in subcortical
structures of the auditory pathway. Here too, research efforts
are focused on identifying the cellular and molecular changes that
distinguish hearing loss with tinnitus from hearing loss alone
(reviewed in Shore and Wu, 2019). Cortical structures also provide
descending corticofugal input, which is thought to play a role in
cortical plasticity and learning (reviewed in Malmierca and Ryugo,
2010; Suga, 2008; Suga, 2012) and may, therefore, also regulate the
generation of tinnitus. In humans, tinnitus has been found to be
associated with both increased (Boyen et al., 2014; Lanting et al.,
2008) and decreased (Hofmeier et al., 2018) activity in subcortical
structures, as well as altered connectivity between cortical and
subcortical structures (Hofmeier et al., 2018; Husain and Schmidt,
2014).
Finally, in both animals and humans, tinnitus has been linked to
hyperactivity in non-auditory brain areas (reviewed in Middleton
and Tzounopoulos, 2012), as well as altered connectivity between
non-auditory and auditory brain areas (reviewed in Husain and
Schmidt, 2014). Therefore, the maintenance of the tinnitus
percept may involve a distributed network of brain areas, including
those involved in limbic, memory and attentional function, which
have previously been thought to control the emotional/cognitive
response to tinnitus (reviewed in Elgoyhen et al., 2015;
Shahsavarani et al., 2019). Additional work is necessary to clarify
the contributions of these subcortical and non-auditory structures
to plasticity of the auditory cortex associated with tinnitus and to
distinguish the structures that generate tinnitus from those that
maintain it.
7. Conclusion
In the adult brain, a complex interplay of cellular, molecular, and
circuit-level mechanisms governs cortical plasticity in response to
altered acoustic experience and hearing loss, with likely distinct
mechanisms giving rise to hearing loss with tinnitus. Importantly,
work in animals has shown that adult plasticity requires extrinsic
alterations and possible recruitment of neuromodulatory circuits
with constraints imposed by intrinsic (genetic) programs. In
humans, there appear to be not only individual differences in the
susceptibility to tinnitus, which may result from intrinsic genetic
differences (Cederroth et al., 2017), but also individual differences
in the response to tinnitus treatment (McFerran et al., 2019). These
treatments, which currently rely on various approaches and combinations
of approaches, including hearing aids, sound therapy,
brain stimulation, cognitive and behavioral therapy, medication,
and acupuncture (Bauer et al., 2017; Brennan-Jones et al., 2019; Lin
et al., 2019), may activate pathways regulating plasticity. Therefore,
a more precise understanding of the mechanistic interplay of factors
regulating plasticity will enable the development of more
effective, reliable, and personalized treatments for tinnitus.
Acknowledgements
This work received funding from the European Research Council
(ERC) under the European Union’s Horizon 2020 research and
innovation programme (grant ID 764604) to D. P. and S. J. P.; the
Fonds de recherche du Quebec - Nature et technologies (Canada) to
M. E. T.; the National Health and Medical Research Council
(Australia, NHMRC grant ID 1080652) and the generous donations
from Alan and Lynne Rydge, Graham and Charlene Bradley, and
Haydn and Sue Daw to D. K. R.; the Medical Research Council (UK,
MRC grant ID MR/S003320/1) to K. K.; and National Institute on
Deafness and Other Communication Disorders (USA, NIDCD
R01DC018353), the Bertarelli Foundation (Switzerland), and the
Nancy Lurie Marks Family Foundation (USA) to A. E. T.
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