|
| |
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online May 19, 2008
Journal of Experimental Biology 211, 1781-1791 (2008)
Published by The Company of Biologists 2008
doi: 10.1242/jeb.013581
Sensory encoding in hearing and balance |
Inhibitory neurotransmission, plasticity and aging in the mammalian central auditory system
1 Southern Illinois University School of Medicine, Springfield, IL 62794,
USA
2 Illinois College, Jacksonville, IL 62650, USA
* Author for correspondence (e-mail: dcaspary{at}siumed.edu)
Accepted 4 February 2008
Summary
Aging and acoustic trauma may result in partial peripheral deafferentation in the central auditory pathway of the mammalian brain. In accord with homeostatic plasticity, loss of sensory input results in a change in pre- and postsynaptic GABAergic and glycinergic inhibitory neurotransmission. As seen in development, age-related changes may be activity dependent. Age-related presynaptic changes in the cochlear nucleus include reduced glycine levels, while in the auditory midbrain and cortex, GABA synthesis and release are altered. Presumably, in response to age-related decreases in presynaptic release of inhibitory neurotransmitters, there are age-related postsynaptic subunit changes in the composition of the glycine (GlyR) and GABAA (GABAAR) receptors. Age-related changes in the subunit makeup of inhibitory pentameric receptor constructs result in altered pharmacological and physiological responses consistent with a net down-regulation of functional inhibition. Age-related functional changes associated with glycine neurotransmission in dorsal cochlear nucleus (DCN) include altered intensity and temporal coding by DCN projection neurons. Loss of synaptic inhibition in the superior olivary complex (SOC) and the inferior colliculus (IC) likely affect the ability of aged animals to localize sounds in their natural environment. Age-related postsynaptic GABAAR changes in IC and primary auditory cortex (A1) involve changes in the subunit makeup of GABAARs. In turn, these changes cause age-related changes in the pharmacology and response properties of neurons in IC and A1 circuits, which collectively may affect temporal processing and response reliability. Findings of age-related inhibitory changes within mammalian auditory circuits are similar to age and deafferentation plasticity changes observed in other sensory systems. Although few studies have examined sensory aging in the wild, these age-related changes would likely compromise an animal's ability to avoid predation or to be a successful predator in their natural environment.
Key words: aging, central auditory system, GABAA receptor, glycine receptor, inhibitory neurotransmission, plasticity
Introduction
Aging and partial damage to the peripheral sensory systems of mammals
appear to result in plastic pre- and postsynaptic changes in the inhibitory
neurotransmitter systems of the primary sensory pathways. The exact nature of
these changes is dependent upon the anatomic location and function of the
inhibitory circuits within the particular primary/lemniscal sensory system.
Fig. 1 shows the primary
ascending auditory pathway. Coding of environmental acoustic signals occurs at
all levels of the central auditory pathway. The cochlear nucleus (CN) consists
of a dorsal and ventral division (DCN, VCN) having three functionally and
anatomically segregated outputs (for a review, see
Young and Oertel, 2004
). The
functions of the CN neurons are diverse, even at this early stage of auditory
brainstem pathway (Kiang et al.,
1965). There are at least five major CN neuronal response types
(Kiang et al., 1965;
Caspary, 1972;
Evans and Nelson, 1973). Those
in the ventral division primarily relay information about the timing and
intensity of sounds from the acoustic environment
(Young and Oertel, 2004).
These VCN cells extract salient temporal features of communication calls,
communicating time and intensity cues from both sides of the head to the
superior olivary complex (SOC)
(Harnischfeger et al., 1985;
Frisina et al., 1990a;
Frisina et al., 1990b;
Frisina, 2001;
Irvine et al., 2001). The SOC
is composed of three main subnuclei related to the localization of sound in
space (Masterton and Imig,
1984). The medial nucleus of the trapezoid body (MNTB) converts
the well-timed excitatory input from the VCN on one side of the head to an
inhibitory projection to the lateral superior olive (LSO)
(Harnischfeger et al., 1985).
In the LSO, the inhibitory projection from one side is compared to an
excitatory projection from the other side. This profile provides a powerful
way of comparing intensity from both sides of the head
(Irvine et al., 2001;
Moore and Caspary, 1983). In
addition, inhibitory inputs damp low-frequency, time-locked excitatory signals
from both sides of the head as they project onto the dendrites of linearly
arrayed cells in the medial superior olivary complex (MSO)
(Masterton and Imig, 1984).
This structure is primarily concerned with comparing arrival time of the sound
from both sides of the head (Grothe and
Sanes, 1994). While the functions of different neuronal types in
the CN and the SOC are quite well understood, the nature of the code at the
inferior colliculus (IC), medial geniculate (MGB) and primary auditory cortex
(A1) levels are less well understood. At the IC level, neurons are involved
with refining information regarding the location of signals in the acoustic
environment and providing a rate code from complex temporally modulated
communication calls (Pollak et al.,
2003). Neurons in the IC of specialized mammals such as bats have
been shown to code echoes through specific inhibitory delay lines, a coding
modality, important in determining the location of sound, echolocation and
extracting information from voiced and unvoiced communication signals
(Carr et al., 1986;
Portfors and Wenstrup,
2001).
|
The complex processing that occurs at the level of the MGB and the A1 is
beyond the scope of the present review. Coding in the auditory cortex has been
recently reviewed (Wang,
2007; Rauschecker,
2005). As seen in the visual cortex, in the auditory cortex,
acoustically complex hierarchical analysis has been described for
awake-behaving primates (Rauschecker,
2005; Steinschneider et al.,
2008). A1 has been shown to undergo age-related plastic changes,
including down-regulation of inhibitory coding, similar to that observed at
lower levels of the auditory pathway and in visual cortex. Similar to
age-related changes, activity-dependant changes have been shown to occur in
all the primary sensory systems upon selective partial deafferentation (see
below).
Deafferentation plasticity
Aging can be thought of, in part, as a slow peripheral deafferentation,
which in turn can result in compensatory changes throughout the specific
sensory CNS. Recent aging studies of primate and feline visual cortex show an
age-related loss of orientation and directional selectivity in the responses
of visual cortical neurons, including changes consistent with a selective
down-regulation of GABA inhibition
(Schmolesky et al., 2000;
Leventhal et al., 2003;
Hua et al., 2006). Similar
changes have been observed in humans
(Betts et al., 2007).
Age-related changes of inhibitory neurotransmission occurring in ascending
circuits of the mammalian central auditory system are reviewed below. Where
relevant, the effects of adult peripheral deafferentation in the same circuits
are described.
Homeostatic plasticity describes how, in response to activity-dependent
input changes in development and deafferentation, neural systems undergo pre-
and postsynaptic compensatory changes to stay within a relatively narrow
operating range of excitation and inhibition
(Turrigiano, 2007;
Rich and Wenner, 2007).
Changes in chronic neuronal activity (over a period of days) trigger
compensatory changes in synaptic activity, which in turn, contribute to a
return toward original levels of neuronal activity
(Rich and Wenner, 2007). In
this light, the sensory literature suggests that partial peripheral
deafferentation of somatosensory, visual or auditory central pathways leads to
a selective down-regulation of inhibition, perhaps in an effort to restore the
system toward original levels of activity (D.M.C., unpublished observations).
A few selected examples illustrate how damage to, or a blockade of,
peripheral/central sensory projections results in a selective down-regulation
of normal adult GABAergic function in the central target structures. Retinal
lesions lead to a reduction of GABA levels in visual cortical regions
receiving projections from the damaged area
(Rosier et al., 1995).
Blockade of peripheral visual input reversibly reduces the number of
immunolabeled glutamic acid decarboxylase (GAD) (the synthetic enzyme for
GABA) neurons by 50% in primary visual cortex
(Hendry and Jones, 1986;
Hendry and Jones, 1988;
Jones, 1990). Whisker trimming
in adult rats results in reversible reductions of GAD immunostaining and
muscimol binding in somatosensory cortex
(Akhtar and Land, 1991;
Fuchs and Salazar, 1998).
While in spinal cord, partial peripheral nerve injury promotes a selective
functional loss of GABAergic inhibition in the superficial dorsal horn of the
spinal cord (Moore et al.,
2002).
Behavioral evidence of age-related auditory dysfunction
In humans, age-related hearing loss is associated with both peripheral and
central processing deficits that combine to make it difficult for the elderly
to process speech and other acoustic signals in noisy or complex environments
(Bergman et al., 1976;
Willott, 1991;
Divenyi and Haupt, 1997a;
Divenyi and Haupt, 1997b). A
common complaint of older adults is difficulty understanding communication
signals and speech in complex acoustic environments
(Gordon-Salant and Fitzgibbons,
1993; Dubno et al.,
1997; Snell,
1997; Strouse et al.,
1998). A decreased ability to temporally process acoustic signals
may underpin difficulties in processing environmental sounds
(Gordon-Salant and Fitzgibbons,
1993; Strouse et al.,
1998). The impact of aging on temporal processing has been
behaviorally assessed in humans and in laboratory animals by varying the width
of a silent gap embedded in a continuous acoustic background
(Schneider et al., 1994;
Snell, 1997;
Schneider et al., 1998;
Schneider and Hamstra, 1999;
He et al., 1999;
Lister et al., 2002;
Barsz et al., 2002;
Ison and Allen, 2003;
Turner et al., 2005c). In
addition, human studies show age-related decline in the ability to extract
visual signals from a cluttered visual background
(Cremer and Zeef, 1987).
Age-related changes in mammalian central auditory pathways
Inhibitory circuits throughout the auditory neuraxis are responsible for
important survival functions. These include coding the localization of sound
in space, as well as extraction and coding of salient communication signals.
Processing environmental sounds is necessary for successful predation or
avoiding predation. Certain species of Chiropterans (bats) use many of these
same circuits for echolocation to navigate their environment and locate
insects (Pollak et al., 1977;
Simmons, 1989;
Portfors and Sinex, 2005;
Vater et al., 2003;
Portfors and Sinex, 2005).
For example, behavioral studies in bats, kangaroo rats, insects and fish show
the importance of the auditory system for survival in the wild. This, in turn,
suggests that an age-related degradation of acoustic signal processing
(sensory function) could play as important a role as motor decline in loss of
normal adult behavioral success within an animal's natural habitat
(Webster and Webster, 1971;
Cumming, 1996;
Anderson et al., 1998;
Sisneros and Bass, 2005;
Hollen and Manser, 2006).
Increasingly, recent studies suggest that a selective loss of normal adult
inhibitory neurotransmission may subserve this loss of sensory function. This
review is focused on aging in inhibitory neurotransmitter systems; however, it
is important to understand that age-related changes occur in other
neurotransmitter systems, including serotonergic
(Tadros et al., 2007a),
cholinergic (Caspary et al.,
1990) and excitant amino acids
(Banay-Schwartz et al., 1989a;
Banay-Schwartz et al., 1989b;
Tadros et al., 2007b).
Accurate temporal processing depends on the ability of inhibitory circuits
to sharpen responses to rapidly time-varying signals
(Walton et al., 1997;
Walton et al., 1998;
Krishna and Semple, 2000;
Frisina, 2001;
Caspary et al., 2002;
Liang et al., 2002). Rapidly
time-varying signals play an important role in communication and socialization
among mammals. For either predator or prey, the loss of these abilities would
prove detrimental to survival. The present review will focus on age-related
changes in inhibitory neurotransmission involved in circuits within the CN,
the SOC, the IC and the A1 (Fig.
1). Major age-related pre- and postsynaptic changes and
age-related functional changes in these structures are summarized in
Table 1. Age-related changes
are reviewed in the context of coding salient species-specific sounds,
localization cues and echolocation. The neurochemical and functional
literature reviewed below is primarily from two rat strains [Fischer-344
(F344) and Fischer Brown-Norway F1 hybrid (FBN)] unless otherwise noted. The
two strains differ in the nature of their age-related loss of cochlear inner
and outer hair cells, with the FBN strain approximating the pattern of hair
cell loss seen for the wild type, Brown Norway rat
(Fig. 2A)
(Keithley et al., 1992;
Turner and Caspary, 2005).
Fig. 2 displays the modest
age-related inner hair cell changes for both strains while outer hair cell
changes are more extensive (Fig.
2A), and likely subserve the 20–30 dB parallel age-related
shift in functional threshold measures using the auditory brainstem-evoked
response (Fig. 2B). The two
strains differ in hearing sensitivity (Fig.
2B) and their 50% mortality rate (F344 at 24 months and FBN at 32
months). Central age-related hearing changes have also been extensively
studied in mice, whose upper frequency of hearing is higher compared to rats,
with cut-off frequencies listed up into the 60 kHz range for some strains of
mice (Ehret, 1975;
Kulig and Willott, 1984).
|
|
Cochlear nuclei and superior olivary complex
The first central auditory `relay stations' are the DCN and VCN (for a
review, see Young and Oertel,
2004). In young adult animals, the VCN codes both time and
intensity features of sound (Rhode and
Smith, 1986a), sending projections to the second major group of
nuclei on the auditory neuraxis, the SOC
(Warr, 1966). As with all
lemniscal auditory structures (primary ascending auditory pathway), these
structures are tonotopically arranged. Low frequency sounds may be coded by a
firing pattern that approximates the frequency of the acoustic signal,
phase-locking, while higher frequencies are coded spatially
(Sullivan, 1985;
Rhode and Smith, 1986a;
Rhode and Smith, 1986b;
Pollak et al., 2002).
Response properties of many neurons code both the fine structure and the
envelope of communication signals and environmental sounds. Accurate temporal
representations of environmental sounds are required for accurate localization
of both low- and high-frequency sounds
(Joris and Yin, 2007).
Localization of sounds in the horizontal plane is necessary to avoid predation
or to successfully localize prey. Localization of high frequency sounds is
thought to involve left vs right comparison of interaural intensity
differences, which primarily occurs in the LSO
(Batra et al., 1997;
Tollin and Yin, 2002).
Neurons that compare low frequency sounds from both sides of the head are
mostly located in the MSO. The relative size and importance of the LSO and MSO
cell groups are directly related to the frequency range of particular species
and their particular diurnal habitats
(Warr, 1982). In order to
minimize temporal jitter in the SOC system, projection neurons in VCN receive
both intrinsic and extrinsic inputs, primarily from glycinergic neurons, which
dampen excitatory responses and allow VCN neurons to accurately follow small
latency shifts and code rapidly time-varying signals over a wide range of
signal intensities (Frisina et al.,
1990a; Caspary and Finlayson,
1991).
Age-related changes in cochlear nuclei
Age-related changes in the cochlear nuclei suggest a compensatory
down-regulation of inhibition following an age-related loss of peripheral
input (Turner and Caspary,
2005) and have been recently reviewed
(Frisina and Walton, 2001).
These age-related changes include reduction of glycine levels in both DCN and
VCN (Banay-Schwartz et al.,
1989b), along with changes in the subunit make-up of the
pentameric, heteromeric glycine receptor (GlyR)
(Krenning et al., 1998;
Caspary et al., 2002).
Age-related GlyR subunit changes in VCN suggest an age-related return to a
more developmental form of the GlyRs with a down-regulation of the
1 and up-regulation of the 2 subunit
(Krenning et al., 1998).
Age-related subunit mRNA changes are found throughout the cochlear nuclei,
resulting in the loss of strychnine binding observed in the DCN of both aged
rats and mice (Milbrandt and Caspary,
1995; Willott et al.,
1997). Functionally, the DCN appears to have a role in the
extraction of signals in noise (Gibson et
al., 1985), while also coding spectral notches to locate sounds in
the vertical plane (Nelken and Young,
1996). Similar to communication sounds, the envelope of amplitude
and frequency modulated signals are coded by DCN projection neurons
(Frisina et al., 1994;
Nelken and Young, 1996;
Imig et al., 2000). Many of
the major response types within the cochlear nuclei receive intrinsic
glycinergic endings from vertical and cartwheel cells in the DCN and
D-stellate cells in the VCN (for a review, see
Oertel and Young, 2004).
Strychnine blockade of GlyRs within DCN and VCN increases discharge rate,
primarily, within the excitatory response area and reduces synchrony of
temporal coded events (Wickesberg and
Oertel, 1990; Caspary et al.,
1994; Backoff et al.,
1999). Response properties recorded from aged DCN projection
neurons resemble responses observed in young adult animals from the same DCN
neurons with their GlyRs blocked. Fusiform cells display age-related increases
in maximum discharge rate and changes in temporal responses, consistent with a
loss of glycinergic inhibition (Caspary et
al., 2005). The reduced damping seen in the response properties of
aged DCN fusiform cells would likely affect the ability to extract salient
signals from a cluttered acoustic environment and degrade envelope coding of
communication signals. Since DCN output neurons project to the contralateral
IC, age-related changes would be reflected in the responses of the fusiform
cell projection targets in the IC
(Ramachandran et al., 1999;
Frisina and Walton, 2001).
Age-related changes in the superior olivary complex
As noted above, the subnuclei of the superior olivary complex are highly
specialized for the localization of sound in space. For the most part,
environmental high-frequency sounds are coded by interaural intensity
differences. Circuits leading from the VCN on one side enter the LSO directly,
while inputs from the contralateral side, synapse first in the medial nucleus
of the trapezoid body, which converts the excitatory glutamatergic message
into an inhibitory glycinergic message at a short latency, high fidelity
synapse known as the endbulb of Held
(Moore and Caspary, 1983).
Glycinergic inputs impinge on LSO neurons, completing a circuit that is
exquisitely suited for spatial localization using interaural intensity
(Finlayson and Caspary, 1991).
Relatively few aging studies have been carried out in the SOC. A selective
loss of inhibitory input from the MNTB to the LSO would hamper localization in
the ipsilateral hemifield. Casey and Feldman
(Casey and Feldman, 1982;
Casey and Feldman, 1988) found
that MNTB neurons were selectively lost in two strains of aged rat. However,
functional studies found only small changes in the slope of interaural
intensity difference functions in the F344 rat
(Finlayson and Caspary, 1993).
Two additional aging studies in mouse and gerbil also found relatively small
age-related changes in the SOC (O'Neill
et al., 1997; Frisina,
2001; Gleich et al.,
2004). SOC studies do show age-related changes in potassium
channels and calcium binding proteins in cells of origin of a descending
pathway from the SOC to the cochlea (Zettle et al., 2007).
Inferior colliculus
The IC is a mandatory relay station on the ascending auditory pathway
(Oliver and Heurta, 1992;
Pollak et al., 2002;
Malmierca, 2003;
Morest and Oliver, 1984).
Age-related changes of inhibition within the IC would likely impair the
ability of the animal to further refine the localization of an environmental
sound source from information received from the SOC, nuclei of the lateral
lemnisci, and DCN (Vater et al.,
1992; Litovsky and Delgutte,
2002; Escabi et al.,
2003; Pecka et al.,
2007; Palmer et al.,
2007). In addition, inhibition plays a role in processing acoustic
delay information as well as strict temporal processing
(Pollak et al., 2002). Delay
coding is critical for echolocation in bats and may play a role in processing
periodic vs aperiodic segments in communication signals. IC circuits
utilizing both GABAergic and glycinergic inhibition have been shown to be
important in coding selective communication calls in animals and are
critically involved in delay circuits in bats
(Yan and Suga, 1996;
Portfors and Wenstrup, 2001;
Klug et al., 2002). The IC
receives excitatory glutamatergic inputs directly from the DCN as well as a
major ascending projection from the SOC (for a review, see
Kelly and Caspary, 2005).
Extrinsic GABAergic projections to the IC arise bilaterally from the dorsal
nuclei of the lateral lemniscus, while glycinergic inputs originate from the
ventral nucleus of the lateral lemniscus and the LSO. In addition, intrinsic
GABAergic neurons are located throughout both the central nucleus and the
shell nuclei of the IC. IC neurons also receive a major excitatory descending
projection from the auditory cortex
(Winer et al., 1998;
Winer et al., 2002;
Winer, 2006).
As is the case for age-related changes described below, it is not known
whether age-related inhibitory changes in IC are the result of de
novo aging changes within the central nervous system or are the direct
result of a gradual loss of peripheral input or both. In response to
superthreshold acoustic stimulation, noise-exposed animals (modest damage to
the auditory periphery) show altered evoked responses in the IC and auditory
cortex, providing a functional picture suggestive of hyperexcitability
(Willott and Lu, 1982;
Popelár et al., 1987;
Salvi et al., 1990;
Gerken et al., 1991;
Syka et al., 1994;
Szczepaniak and Møller,
1995; Wang et al.,
1996; Syka and Rybalko,
2000; Aizawa and Eggermont,
2007). Neurochemical findings in support of these functional
changes reveal that damage to the auditory periphery results in a selective
down-regulation of normal adult inhibitory GABAergic function in the IC.
Surface-recorded evoked potentials from the IC of noise-exposed rats show
reduced sensitivity to bicuculline blockade
(Szczepaniak and Møller,
1995). Deafness resulted in decreased GABA release in
vivo and decreased numbers of IC neurons showing electrically evoked
suppression of unit activity (Bledsoe et
al., 1995). IC GAD levels were reduced 2–30 days following
noise exposure (Abbott et al.,
1999; Milbrandt et al.,
2000). GABA uptake and release following ossicle removal or
cochlear ablation resulted in complex long-term changes in GABA and glycine
neurochemistry (Suneja et al.,
1998). Collectively, these studies suggest that decreased acoustic
input at the auditory periphery results in significant changes in GABA
neurotransmission in normal adult IC.
|
;
Palombi and Caspary, 1996b;
Palombi and Caspary, 1996c;
Palombi and Caspary, 1996d;
Shaddock-Palombi et al.,
2001). Similar physiological changes occur in C57 and CBA mice
(Willott, 1986;
Willott et al., 1988;
Willott et al., 1991;
McFadden and Willott, 1994;
Walton et al., 1998;
Walton et al., 2002;
Simon et al., 2004).
A number of measures of presynaptic GABA neurotransmission show age-related
changes in the mammalian IC. GABA levels, GABA immunostaining, GAD activity
and GABAA and GABAB receptor binding all decrease in the
aged rodent IC (Banay-Schwartz et al.,
1989a; Banay-Schwartz et al.,
1989b; Caspary et al.,
1990; Gutiérrez et al.,
1994; Raza et al.,
1994; Milbrandt et al.,
1994; Milbrandt et al.,
1996). The IC neuropil shows an age-related rearrangement of
synaptic endings onto soma and proximal dendrites
(Helfert et al., 1999).
Possibly in response to age-related presynaptic changes, age-related
postsynaptic changes occur in the mammalian IC GABAA receptor. The
GABAA receptor is a heterogeneous family of ligand-gated
Cl– ion channel receptors, which receive input from
GABA-releasing inhibitory circuits. GABAA receptors exist as
pentameric subunit complexes made up of combinations of 19 possible
GABAA receptor subunits, which can be activated/allosterically
modulated by numerous pharmacological agents
(Sieghart, 1992a;
Sieghart, 1992b;
Wafford et al., 1993;
Sieghart, 1995;
Rabow et al., 1995;
Möhler et al., 2002).
Thus, changes in the make-up of the GABAA receptor would alter the
function of sensory coding in the aged IC. In the IC, both GABAA
receptor subunit message and protein levels show age-related changes, with a
significant down-regulation of the adult 1 subunit in favor
of an up-regulation of the 3 GABAA receptor
subunit (Gutiérrez et al.,
1994; Milbrandt et al.,
1997; Caspary et al.,
1999). In situ hybridization and western blot studies
show significant age-related up-regulation of the 
1 subunit
(Fig. 3) suggestive of a
compensatory age-related increase in the affinity for GABA
(Milbrandt et al., 1997;
Caspary et al., 1999).
Coexpression of the 1 subunit with 1 and
β2 subunits in oocytes produces a GABAA receptor
complex, which fluxes more Cl– ions per mmol GABA than
wild-type 2 subunit containing receptor constructs
(Ducic et al., 1995). Receptor
binding studies found significant age-related enhancement of GABA's ability to
modulate binding at the picrotoxin GABAA receptor site
(Fig. 4)
(Milbrandt et al., 1996).
Modulation of GABAA receptor binding at this site using
bath-application of GABA resulted in an age-related, dose-dependent shift to
the left in the GABA modulation curve (Fig.
4) (Milbrandt et al.,
1996). This dose–response shift in the binding assay further
supports the observed age-related subunit changes.
|
In addition, a direct measure of age-related subunit efficacy was obtained
by examining the ability of GABA to flux Cl– ions into
microsac/synaptosome preparations from rat IC. GABA influx was significantly
increased in samples from aged rat IC, confirming oocyte expression studies
noted above (Caspary et al.,
1999). These findings differ with previous whole brain synaptosome
chloride uptake studies, which found reduced Cl– uptake with
aging (Concas et al., 1988).
Age-related GABAA receptor changes may reflect a partial
postsynaptic compensation for the significant age-related loss in presynaptic
GABA release.
|
Primary auditory cortex
Primary auditory cortex (A1) is generally considered necessary for
perception and interpretation of the stimulus. Acoustic information reaching
A1 has been extensively processed/coded at lower levels of the auditory
neuraxis and generally no longer directly resembles the acoustic stimulus in
time, intensity or spatial relationship when observed in the discharge
properties of A1 neurons (Schreiner et
al., 2000; Nelken,
2004). A1 receives its major ascending projection from the medial
geniculate body (MGB) projecting to A1 layer IV
(Brodal, 1981;
Winer and Lee, 2007). Inputs
from the contralateral auditory cortex and nonauditory inputs impinge on
layers II and VI with descending and intracortical outputs from layer V
(Winer et al., 1998;
Winer, 2006).
Functionally, A1 has a tonotopic map of the cochlea and a map of binaural
properties with excitation and inhibition from the different hemifields
represented on orthogonal stripes (Purves
et al., 2007). Different regions of primary auditory cortex may be
specialized for processing frequency combinations or may selectively code
frequency or amplitude modulations
(Schreiner et al., 2000).
Acoustic processing in non-primary auditory cortex is not well understood, but
is likely involved in higher-order processing of scenes and communication
signals (Esser et al., 1997;
Nelkin, 2004). Specifically, the ability to process temporal sequences of
sound, similar to those found in communication signals, is lost following
ablation of auditory cortex in cats and primates
(Neff, 1977;
Hupfer et al., 1977). Thus,
without the auditory cortex, primates cannot discriminate conspecific
communication sounds from each other
(Hupfer et al., 1977).
Increased neural noise in the aged cortex due to loss of GABAergic inhibition
would likely impair normal adult coding functions.
Age-related changes in primary auditory cortex
Aging in mice with high frequency hearing loss showed tonotopic
reorganization of A1 similar to that observed with small lesions of the
cochlea in adult animals (Willott et al.,
1993; Irvine et al.,
2000). In rats, aging was associated with deterioration of
temporal processing speed in A1 neurons, which was not present in lower
structures such as the inferior colliculus and auditory thalamus
(Mendelson and Ricketts, 2001;
Lee et al., 2002;
Mendelson and Lui, 2004).
These electrophysiological studies suggest that aging is associated with
degraded spectral and temporal properties of the auditory cortex, which might
play a role in accurate processing of communication signals.
In a recent aging study in rat A1
(Turner et al., 2005a), aging
was found to be associated with a number of changes in response properties.
First, the distribution of receptive field shapes was altered in aging. A
percentage of classic V/U-shaped, receptive fields
(Fig. 5A), more commonly seen
in young A1 neurons were replaced by more complex receptive fields
(Fig. 5B) seen in aged A1
neurons. Second, more on-stimulus firing was seen for Complex receptive
fields, which were generally associated with inhibited firing in young-adult
Complex neurons. Third, receptive field maps from aged rats, regardless of
shape, were less reliable across three successive repetitions of the same
stimulus. Fourth, aging in Complex receptive field maps, but not V/U maps, was
associated with an increased discharge rate in response to extracellular
current pulse stimulation (Fig.
5C).
|
;
Turner et al., 2005b) and are
likely to have distinctly different projection patterns
(Hefti and Smith, 2000;
Hefti and Smith, 2003).
V/U-shaped receptive field neurons are more closely associated with larger
pyramidal cells that form the descending projections to the brainstem
(Games and Winer, 1988;
Winer et al., 1998;
Winer and Prieto, 2001;
Turner et al., 2005a). In
contrast, neurons with the Complex maps are associated with smaller layer V
pyramidal neurons thought to exhibit an intracortical projection pattern and
are more likely to receive direct inhibitory inputs
(Hefti and Smith, 2000;
Hefti and Smith, 2003;
Turner et al., 2005a;
Turner et al., 2005b).
The relative reduction of V/U-shaped maps and increase in Complex maps
could have significant implications for auditory processing in aged animals.
The loss of the tips of the tuning curves with aging and hearing loss, in
combination with a reduction in the more finely tuned V/U-shaped receptive
fields, would impact descending pathways. Similarly, the relative increase in
the poorly tuned Complex receptive fields, as well as their reduced inhibitory
response to sound, might serve to introduce more noise into A1 and cortical
coding of sound in general. Together, receptive field changes observed in the
two major types of aged auditory cortex neurons could translate into degraded
coding of acoustic signals, especially in complex acoustic environments. The
degree to which these electrophysiological changes seen in aging are
associated with specific neurochemical changes related to GABA
neurotransmission has been addressed in a series of studies. As noted above,
age-related changes within the auditory brainstem included pre- and
postsynaptic changes in the neurochemistry of the inhibitory
neurotransmitters, GABA and glycine. As was the case for the inferior
colliculus, there were significant age-related reductions in the level of both
the message and protein for GAD in the rat A1
(Ling et al., 2005). The
largest age-related changes in GAD message were found in A1 layer II
(GAD67: –40%) (Ling et
al., 2005). Although GAD message changes related to aging have
been observed in other cortical regions, including hippocampus, protein
changes in parietal cortex were small when compared to GAD protein changes in
A1 (Fig. 6)
(Stanley and Shetty, 2004;
Ling et al., 2005). Taken
together, the findings from A1 suggest a systematic age-related disruption in
GABA neurotransmission that is associated with specific changes in how neurons
in A1 code sensory signals.
Overview and future research
A search of the background literature for this review quickly revealed that
little systematic neuroethological research has examined age-related hearing
loss and its impact on survival in the wild. While the importance of auditory
and visual acuity has been shown to have great survival value for a number of
different species (Webster and Webster,
1971; Cumming,
1996; Anderson et al.,
1998; Sisneros and Bass,
2005; Hollen and Manser,
2006), the impact of sensory aging on predator/prey relationships
in a natural habitat has not been well studied. Many years ago, Webster and
Webster demonstrated that altering the nature of the middle ear of the
kangaroo rat changed hearing sensitivity in such a way that the adult kangaroo
rats were more susceptible to predation by snakes in a restricted natural
habitat (Webster and Webster,
1971). Similar studies designed to examine the impact of aging in
the wild have not been carried out. Studies designed to examine the impact of
aging, in species that survive into old age in the wild, are sorely needed.
Additional sensory studies might investigate how compensatory plastic changes
at one brain nucleus within a circuit would impact on other nuclei, and how
homeostatic plasticity of aging might differentially affect changes in
temporal reliability relative to changes in the place code. Future studies
will need to model the impact of age-related changes across the entire
ascending and descending auditory pathways, mapping the plastic adjustments
with both positive and negative consequences throughout the system. It is
generally assumed that many mammalian species do not survive into old age in
the wild. However, few systematic aging studies have been done for most
species in the wild. The present studies suggest that it is important to
consider the impact of age-related sensory dysfunction on survival, rather
than simply focus on the impact of aging on normal adult motor function.
Conclusions
Studies reviewed above suggest there is an age-related net down-regulation
of glycinergic and GABAergic inhibition throughout the auditory central
nervous system. Behavioral studies in humans and animals suggest (1) an
age-related loss of GAP detection, a measure of temporal processing
(Barsz et al., 2002); (2) an
age-related loss of localization of sound in space
(Warren et al., 1978;
Brown, 1984); and (3) an
age-related loss in the ability to discriminate complex communication signals
(Gordon-Salant and Fitzgibbons,
1993; Frisina and Frisina,
1997; Gordon-Salant and
Fitzgibbons, 2001; Hamann et
al., 2004; He et al.,
2007). Diminished dampening due to a decrease of tonic inhibition,
reduced accuracy of binaural cues due to a loss of time-locked inhibition, and
an increase in neural noise due to a loss of tonic inhibition, all observed in
aged populations at different levels of the central auditory process, help
explain the significant auditory deficits observed in aged animals.
List of abbreviations
Acknowledgments
We would like to thank Judy Bryan, Jennifer Parrish, Patricia Jett and Hongning Wang for their time and efforts toward the editing of this review. This review and studies were supported by the National Institutes of Health, Institute on Deafness and other Communicative Disorders DC 000151-27 to D.M.C.
References
Abbott, S. D., Hughes, L. F., Bauer, C. A., Salvi, R. and Caspary, D. M. (1999). Detection of glutamate decarboxylase isoforms in rat inferior colliculus following acoustic exposure. Neuroscience 93,1375 -1381.[CrossRef][Medline]
Aizawa, N. and Eggermont, J. J. (2007). Mild noise-induced hearing loss at young age affects temporal modulation transfer functions in adult cat primary auditory cortex. Hear. Res. 223,71 -82.[CrossRef][Medline]
Akhtar, N. D. and Land, P. W. (1991). Activity-dependent regulation of glutamic acid decarboxylase in the rat barrel cortex: effects of neonatal versus adult sensory deprivation. J. Comp. Neurol. 307,200 -213.[CrossRef][Medline]
Anderson, S., Rydell, J. and Svenson, M. G. E. (1998). Light, predation and the lekking behaviour of the ghost swift Hepialus humuli (L.) (Lepidoptera: Hepialidae). Proc. R. Soc. Lond. B Biol. Sci. 265,1345 -1351.
Backoff, P. M., Palombi, P. S. and Caspary, D. M. (1999). GABA- and glycinergic inputs shape coding of AM in chinchilla cochlear nucleus. Hear. Res. 134, 77-88.[CrossRef][Medline]
Banay-Schwartz, M., Lajtha, A. and Palkovits, M. (1989a). Changes with aging in the levels of amino acids in rat CNS structural elements. I. Glutamate and related amino acids. Neurochem. Res. 14,555 -562.[CrossRef][Medline]
Banay-Schwartz, M., Lajtha, A. and Palkovits, M. (1989b). Changes with aging in the levels of amino acids in rat CNS structural elements. II. Taurine and small neutral amino acids. Neurochem. Res. 14,563 -570.[CrossRef][Medline]
Barsz, K., Ison, J. R., Snell, K. B. and Walton, J. P. (2002). Behavioral and neural measures of auditory temporal acuity in aging humans and mice. Neurobiol. Aging 23,565 -578.[CrossRef][Medline]
Batra, R., Kuwada, S. and Fitzpatrick, D. C.
(1997). Sensitivity to interaural temporal disparities of low-
and high-frequency neurons in the superior olivary complex. I. Heterogeneity
of responses. J. Neurophysiol.
78,1222
-1236.
Bergman, M., Blumenfeld, V. G., Cascardo, D., Dash, B., Levitt, H. and Margulies, M. K. (1976). Age-related decrement in hearing for speech. Sampling and longitudinal studies. J. Gerontol. 31,533 -538.[Medline]
Betts, L. R., Sekuler, A. B. and Bennett, P. J. (2007). The effects of aging on orientation discrimination. Vision Res. 47,1769 -1780.[CrossRef][Medline]
Bledsoe, S. C., Jr, Nagase, S., Miller, J. M. and Altschuler, R. A. (1995). Deafness-induced plasticity in the mature central auditory system. Neuroreport 7, 225-229.[Medline]
Brodal, A. (1981). The auditory system. InNeurological Anatomy in Relation to Clinical Medicine. 3rd edn , pp. 602-639. New York: Oxford University Press.
Brown, C. H. (1984). Directional hearing in aging rats. Exp. Aging Res. 10, 35-38.[Medline]
Carr, C. E., Maler, L. and Taylor, B. (1986). A time-comparison circuit in the electric fish midbrain. II. Functional morphology. J. Neurosci. 6,1372 -1383.[Abstract]
Casey, M. A. and Feldman, M. L. (1982). Aging in the rat medial nucleus of the trapezoid body. I. Light microscopy. Neurobiol. Aging 3,187 -195.[CrossRef][Medline]
Casey, M. A. and Feldman, M. L. (1988). Age-related loss of synaptic terminals in the rat medial nucleus of the trapezoid body. Neuroscience 24,189 -194.[CrossRef][Medline]
Caspary, D. (1972). Classification of subpopulations of neurons in the cochlear nuclei of the kangaroo rat. Exp. Neurol. 37,131 -151.[CrossRef][Medline]
Caspary, D. M. and Finlayson, P. G. (1991). Superior olivary complex: functional neuropharmacology of the principal cell types. In Neurobiology of Hearing, Vol. II: The Central Auditory System (ed. R. A. Altschuler, D. W. Hoffman, R. P. Bobbin and B. Clopton), pp. 141-162. New York: Raven Press.
Caspary, D. M., Raza, A., Lawhorn Armour, B. A., Pippin, J. and
Arneri
, S. P. (1990). Immunocytochemical and
neurochemical evidence for age-related loss of GABA in the inferior
colliculus: implications for neural presbycusis. J.
Neurosci. 10,2363
-2372.[Abstract]
Caspary, D. M., Backoff, P. M., Finlayson, P. G. and Palombi, P.
S. (1994). Inhibitory inputs modulate discharge rate within
frequency receptive fields of anteroventral cochlear nucleus neurons.
J. Neurophysiol. 72,2124
-2133.
Caspary, D. M., Holder, T. M., Hughes, L. F., Milbrandt, J. C., McKernan, R. M. and Naritoku, D. K. (1999). Age-related changes in GABAA receptor subunit composition and function in rat auditory system. Neuroscience 93,307 -312.[CrossRef][Medline]
Caspary, D. M., Salvi, R. J., Helfert, R. H., Brozoski, T. J. and Bauer, C. A. (2001). Neuropharmacology of noise induced hearing loss in brainstem auditory structures. In Noise Induced Hearing Loss: Mechanisms of Damage and Means of Prevention (ed. D. Henderson, D. Prasher, R. Kopke, R. J. Salvi and R. Hamernik), pp.169 -186. London: NRN Publications.
Caspary, D. M., Palombi, P. S. and Hughes, L. F. (2002). GABAergic inputs shape responses to amplitude modulated stimuli in the inferior colliculus. Hear. Res. 168,163 -173.[CrossRef][Medline]
Caspary, D. M., Schatteman, T. A. and Hughes, L. F.
(2005). Age-related changes in the inhibitory response properties
of dorsal cochlear nucleus output neurons: role of inhibitory inputs.
J. Neurosci. 25,10952
-10959.
Caspary, D. M., Hughes, L. F., Schatteman, T. A. and Turner, J. G. (2006). Age-related changes in the response properties of cartwheel cells in rat dorsal cochlear nucleus. Hear. Res. 216-217,207 -215.[CrossRef][Medline]
Concas, A., Pepitoni, S., Atsoggiu, T., Toffano, G. and Biggio, G. (1988). Aging reduces the GABA-dependent 36Cl– flux in rat brain membrane vesicles. Life Sci. 43,1761 -1771.[CrossRef][Medline]
Cremer, R. and Zeef, E. J. (1987). What kind of noise increases with age? J. Gerontol. 42,515 -518.[Medline]
Cumming, G. S. (1996). Mantis movements by night and the interactions of sympatric bats and mantises. Can. J. Zool. 74,1771 -1774.[CrossRef]
Divenyi, P. L. and Haupt, K. M. (1997a). Audiological correlates of speech understanding deficits in elderly listeners with mild-to-moderate hearing loss. II. Correlation analysis. Ear Hear. 18,100 -113.[CrossRef][Medline]
Divenyi, P. L. and Haupt, K. M. (1997b). Audiological correlates of speech understanding deficits in elderly listeners with mild-to-moderate hearing loss. III. Factor representation. Ear Hear. 18,189 -201.[CrossRef][Medline]
Dubno, J. R., Lee, F. S., Matthaws, L. J. and Mills, J. H.
(1997). Age-related and gender-related changes in monaural speech
recognition. J. Speech Lang. Hear. Res.
40,444
-452.
Duci, I., Caruncho, H. J., Zhu, W. J., Vicini, S. and
Costa, E. (1995). gamma-Aminobutyric acid gating of
Cl– channels in recombinant GABAA receptors.
J. Pharmacol. Exp. Ther.
272,438
-445.
Ehret, G. (1975). Frequency and intensity difference limens and nonlinearities in the ear of the house mouse (Mus musculus). J. Comp. Physiol. A 102,321 -336.[CrossRef]
Escabi, M. A., Miller, L. M., Read, H. L. and Schreiner, C.
E. (2003). Naturalistic auditory contrast improves
spectrotemporal coding in the cat inferior colliculus. J.
Neurosci. 23,11489
-11504.
Esser, K. H., Condon, C. J., Suga, N. and Kanwal, J. S.
(1997). Syntax processing by auditory cortical neurons in the
FM-FM area of the mustached bat Pteronotus parnellii. Proc. Natl.
Acad. Sci. USA 94,14019
-14024.
Evans, E. F. and Nelson, P. G. (1973). On the functional relationship between the dorsal and ventral divisions of the cochlear nucleus of the cat. Exp. Brain Res. 17,428 -442.[Medline]
Finlayson, P. G. and Caspary, D. M. (1991).
Low-frequency neurons in the lateral superior olive exhibit phase-sensitive
binaural inhibition. J. Neurophysiol.
65,598
-605.
Finlayson, P. G. and Caspary, D. M. (1993). Response properties in young and old Fischer-344 rat lateral superior olive neurons: a quantitative approach. Neurobiol. Aging 14,127 -139.[CrossRef][Medline]
Frisina, D. R. and Frisina, R. D. (1997). Speech recognition in noise and presbycusis: relations to possible neural mechanisms. Hear. Res. 106,95 -104.[CrossRef][Medline]
Frisina, R. D. (2001). Anatomical and neurochemocal bases of presbycusis. In Functional Neurobiology of Aging (ed. P. R. Hof and C. V. Mobbs), pp.531 -547. New York: Academic Press.
Frisina, R. D. and Walton, J. P. (2001). Aging of the mouse central auditory system. In Handbook of Mouse Auditory Research: From Behavior to Molecular Biology (ed. J. P. Willott), pp. 339-379. New York: CRC Press.
Frisina, R. D., Smith, R. L. and Chamberlain, S. C. (1990a). Encoding of amplitude modulation in the gerbil cochlear nucleus. I. A hierarchy of enhancement. Hear. Res. 44, 99-122.[CrossRef][Medline]
Frisina, R. D., Smith, R. L. and Chamberlain, S. C. (1990b). Encoding of amplitude modulation in the gerbil cochlear nucleus: II. Possible neural mechanisms. Hear. Res. 44,123 -141.[CrossRef][Medline]
Frisina, R. D., Walton, J. P. and Karcich, K. J. (1994). Dorsal cochlear nucleus single neurons can enhance temporal processing capabilities in background noise. Exp. Brain Res. 102,160 -164.[Medline]
Fuchs, J. L. and Salazar, E. (1998). Effects of whisker trimming on GABA(A) receptor binding in the barrel cortex of developing and adult rats. J. Comp. Neurol. 395,209 -216.[CrossRef][Medline]
Games, K. D. and Winer, J. A. (1988). Layer V in rat auditory cortex: projections to the inferior colliculus and contralateral cortex. Hear. Res. 34, 1-25.[CrossRef][Medline]
Gerken, G. M., Solecki, J. M. and Boettcher, F. A. (1991). Temporal integration of electrical stimulation of auditory nuclei in normal-hearing and hearing-impaired cat. Hear. Res. 53,101 -112.[CrossRef][Medline]
Gibson, D. J., Young, E. D. and Costalupes, J. A.
(1985). Similarity of dynamic range adjustment in auditory nerve
and cochlear nuclei. J. Neurophysiol.
53,940
-958.
Gleich, O., Weiss, M. and Strutz, J. (2004). Age-dependent changes in the lateral superior olive of the gerbil (Meriones unguiculatus). Hear. Res. 194, 47-59.[CrossRef][Medline]
Gordon-Salant, S. and Fitzgibbons, P. J. (1993). Temporal factors and speech recognition performance in young and elderly listeners. J. Speech Hear. Res. 36,1272 -1285.
Gordon-Salant, S. and Fitzgibbons, P. J.
(2001). Sources of age-related recognition difficulty for
time-compressed speech. J. Speech Lang. Hear. Res.
44,709
-719.
Grothe, B. and Sanes, D. H. (1994). Synaptic inhibition influences the temporal coding properties of medial superior olivary neurons: an in vitro study. J. Neurosci. 14,1701 -1709.[Abstract]
Gutierrez, A., Khan, Z. U. and De Blas, A. L. (1994). Immunocytochemical localization of gamma 2 short and gamma 2 long subunits of the GABAA receptor in the rat brain. J. Neurosci. 14,7168 -7179.[Abstract]
Hamann, I., Gleich, O., Klump, G. M., Kittel, M. C. and Strutz, J. (2004). Age-dependent changes of gap detection in the Mongolian gerbil (Meriones unguiculatus). J. Assoc. Res. Otolaryngol. 5,49 -57.[CrossRef][Medline]
Harnischfeger, G., Neuweiler, G. and Schlegel, P.
(1985). Interaural time and intensity coding in superior olivary
complex and inferior colliculus of the echolocating bat Molossus ater.J. Neurophysiol. 53,89
-109.
He, N. J., Horwitz, A. R., Dubno, J. R. and Mills, J. H. (1999). Psychometric functions for gap detection in noise measured from young and aged subjects. J. Acoust. Soc. Am. 106,966 -978.[CrossRef][Medline]
He, N. J., Mills, J. H. and Dubno, J. R. (2007). Frequency modulation detection: effects of age, psychophysical method, and modulation waveform. J. Acoust. Soc. Am. 122,467 -477.[CrossRef][Medline]
Hefti, B. J. and Smith, P. H. (2000). Anatomy,
physiology, and synaptic responses of rat layer V auditory cortical cells and
effects of intracellular GABA(GABA (A) blockade. J.
Neurophysiol. 83,2626
-2638.
Hefti, B. J. and Smith, P. H. (2003). Distribution and kinetic properties of GABAergic inputs to layer V pyramidal cells in rat auditory cortex. J. Assoc. Res. Otolaryngol. 4,106 -121.[CrossRef][Medline]
Helfert, R. H., Sommer, T. J., Meeks, J., Hofstetter, P. and Hughes, L. F. (1999). Age-related synaptic changes in the central nucleus of the inferior colliculus of Fischer-344 rats. J. Comp. Neurol. 406,285 -298.[CrossRef][Medline]
Hendry, S. H. and Jones, E. G. (1986). Reduction in number of immunostained GABAergic neurones in deprived-eye dominance columns of monkey area 17. Nature 320,750 -753.[CrossRef][Medline]
Hendry, S. H. and Jones, E. G. (1988). Activity-dependent regulation of GABA expression in the visual cortex of adult monkeys. Neuron 1,701 -712.[CrossRef][Medline]
Hollen, L. I. and Manser, M. B. (2006). Ontogeny of alarm call responses in meerkats, Suricata suricatta: the roles of age, sex and nearby conspecifics. Anim. Behav. 72,1345 -1353.[CrossRef]
Hua, T., Li, X., He, L., Zhou, Y., Wang, Y. and Leventhal, A. G. (2006). Functional degradation of visual cortical cells in old cats. Neurobiol. Aging 27,155 -162.[CrossRef][Medline]
Hupfer, K., Jurgens, U. and Ploog, D. (1977). The effect of superior temporal lesions on the recognition of species-specific calls in the squirrel monkey. Exp. Brain Res. 30, 75-87.[Medline]
Imig, T. J., Bibikov, N. G., Poirier, P. and Samson, F. K.
(2000). Directionality derived from pinna-cue spectral notches in
cat dorsal cochlear nucleus. J. Neurophysiol.
83,907
-925.
Irvine, D. R., Rajan, R. and McDermott, H. J. (2000). Injury-induced reorganization in adult auditory cortex and its perceptual consequences. Hear. Res. 147,188 -199.[CrossRef][Medline]
Irvine, D. R. F., Park, V. N. and McCormick, L.
(2001). Mechanisms underlying the sensitivity of neurons in the
lateral superior olive to interaural intensity differences. J.
Neurophysiol. 86,2647
-2666.
Ison, J. R. and Allen, P. (2003). A diminished rate of `physiological decay' at noise offset contributes to age-related changes in temporal acuity in the CBA mouse model of presbycusis. J. Acoust. Soc. Am. 114,522 -528.[CrossRef][Medline]
Jones, E. G. (1990). The role of afferent
activity in the maintenance of primate neocortical function. J.
Exp. Biol. 153,155
-176.
Joris, P. and Yin, T. C. (2007). A matter of time: internal delays in binaural processing. Trends Neurosci. 30,70 -78.[CrossRef][Medline]
