Search

Tinnitus affects roughly 15%–20% of the population while severely impacting 10% of those afflicted. Tinnitus pathology is multifactorial, generally initiated by damage to the auditory periphery, resulting in a cascade of maladaptive plastic changes at multiple levels of the central auditory neuraxis as well as limbic and non‐auditory cortical centres. Using a well‐established condition‐suppression model of tinnitus, we measured tinnitus‐related changes in the microcircuits of excitatory/inhibitory neurons onto layer 5 pyramidal neurons (PNs), as well as changes in the excitability of vasoactive intestinal peptide (VIP) neurons in primary auditory cortex (A1). Patch‐clamp recordings from PNs in A1 slices showed tinnitus‐related increases in spontaneous excitatory postsynaptic currents (sEPSCs) and decreases in spontaneous inhibitory postsynaptic currents (sIPSCs). Both measures could be correlated to the rat's behavioural evidence of tinnitus. Tinnitus‐related changes in PN excitability were independent of changes in A1 excitatory or inhibitory cell numbers. VIP neurons, part of an A1 local circuit that can control the excitation of layer 5 PNs via disinhibitory mechanisms, showed significant tinnitus‐related increases in excitability that directly correlated with the rat's behavioural tinnitus score. That PN and VIP changes directly correlated to tinnitus behaviour suggests an important role in A1 tinnitus pathology. Tinnitus‐related A1 changes were similar to findings in studies of neuropathic pain in somatosensory cortex suggesting a common pathology of these troublesome perceptual impairments. Improved understanding between excitatory, inhibitory and disinhibitory sensory cortical circuits can serve as a model for testing therapeutic approaches to the treatment of tinnitus and chronic pain. Key points: We identified tinnitus‐related changes in synaptic function of specific neuronal subtypes in a reliable animal model of tinnitus.The findings show direct and indirect tinnitus‐related losses of normal inhibitory function at A1 layer 5 pyramidal cells, and increased VIP excitability.The findings are similar to what has been shown for neuropathic pain suggesting that restoring normal inhibitory function at synaptic inputs onto A1 pyramidal neurons (PNs) could conceptually reduce tinnitus discomfort. [ABSTRACT FROM AUTHOR]

Tinnitus impacts between 10-20% of the population. Individuals most troubled by their tinnitus have their attention bound to and are distracted by, their tinnitus percept. While numerous treatments to ameliorate tinnitus have been tried, no therapeutic approach has been clinically accepted. The present study used an established condition-suppression noise-exposure rat model of tinnitus to: (1) examine tinnitus-related changes in nAChR function of layer 5 pyramidal (PNs) and of vasoactive intestinal peptide (VIP) neurons in primary auditory cortex (A1) and (2) examine how the partial desensitizing nAChR agonists, sazetidine-A and varenicline, can act as potential therapeutic agents in the treatment of tinnitus. We posited that tinnitus-related changes in layer 5 nAChR responses may underpin the decline in attentional resources previously observed in this animal model (Brozoski et al., 2019). In vitro whole-cell patch-clamp studies previously revealed a significant tinnitus-related loss in nAChR-evoked excitatory postsynaptic currents from A1 layer 5 PNs. In contrast, VIP neurons from animals with behavioral evidence of tinnitus showed significantly increased nAChR-evoked excitability. Here we hypothesize that sazetidine-A and varenicline have therapeutic benefits for subjects who cannot divert their attention away from the phantom sound in their heads. We found that sazetidine-A or varenicline normalized tinnitusrelated reductions in GABAergic input currents onto A1 layer 5 PNs. We then tested sazetidine-A and varenicline for the management of tinnitus using our tinnitus animal model. Subcutaneous injection of sazetidine-A or varenicline, 1 h prior to tinnitus testing, significantly decreased the rat's behavioral evidence of tinnitus in a dose-dependent manner. Collectively, these results support the need for additional clinical investigations of partial desensitizing nAChR agonists sazetidine-A and varenicline for the treatment of tinnitus. [ABSTRACT FROM AUTHOR]

Ageing and challenging signal‐in‐noise conditions are known to engage the use of cortical resources to help maintain speech understanding. Extensive corticothalamic projections are thought to provide attentional, mnemonic and cognitive‐related inputs in support of sensory inferior colliculus (IC) inputs to the medial geniculate body (MGB). Here we show that a decrease in modulation depth, a temporally less distinct periodic acoustic signal, leads to a jittered ascending temporal code, changing MGB unit responses from adapting responses to responses showing repetition enhancement, posited to aid identification of important communication and environmental sounds. Young‐adult male Fischer Brown Norway rats, injected with the inhibitory opsin archaerhodopsin T (ArchT) into the primary auditory cortex (A1), were subsequently studied using optetrodes to record single‐units in MGB. Decreasing the modulation depth of acoustic stimuli significantly increased repetition enhancement. Repetition enhancement was blocked by optical inactivation of corticothalamic terminals in MGB. These data support a role for corticothalamic projections in repetition enhancement, implying that predictive anticipation could be used to improve neural representation of weakly modulated sounds. Key points: In response to a less temporally distinct repeating sound with low modulation depth, medial geniculate body (MGB) single units show a switch from adaptation towards repetition enhancement.Repetition enhancement was reversed by blockade of MGB inputs from the auditory cortex.Collectively, these data argue that diminished acoustic temporal cues such as weak modulation engage cortical processes to enhance coding of those cues in auditory thalamus. [ABSTRACT FROM AUTHOR]

The presence of novel or degraded communication sounds likely results in activation of basal forebrain cholinergic neurons increasing release of ACh onto presynaptic and postsynaptic nAChRs in primary auditory cortex (Al). nAChR subtypes include high-affinity heteromeric nAChRs commonly composed of α4 and (S2 subunits and low-affinity homomeric nAChRs composed of α7 subunits. In young male FBN rats, we detail the following: (1) the distribution/expression of nAChR subunit transcripts in excitatory (VGluTl) and inhibitory (VGAT) neurons across Al layers; (2) heteromeric nAChR binding across Al layers; and (3) nAChR excitability in Al layer (L) 5 cells. In aged rats, we detailed the impact of aging on Al nAChR subunit expression across layers, heteromeric nAChR receptor binding, and nAChR excitability of Al L5 cells. A majority of Al cells coexpressed transcripts for β2 and α4 with or without ot7, while dispersed subpopulations expressed β2 and α7 or a 7 alone. nAChR subunit transcripts were expressed in young excitatory and inhibitory neurons across L2-L6. Transcript abundance varied across layers, and was highest for β2 and α4. Significant age-related decreases in nAChR subunit transcript expression (message) and receptor binding (protein) were observed in L2-6, most pronounced in infragranular layers. Iti vitro patch-clamp recordings from L5B pyramidal output neurons showed age-related nAChR subunit-selective reductions in postsynaptic responses to ACh. Age-related losses of nAChR subunits likely impact ways in which Al neurons respond to ACh release. While the elderly require additional resources to disambiguate degraded speech codes, resources mediated by nAChRs may be compromised with aging. [ABSTRACT FROM AUTHOR]

Key points: Temporal imprecision leads to deficits in the comprehension of signals in cluttered acoustic environments, and the elderly are shown to use cognitive resources to disambiguate these signals.To mimic ageing in young rats, we delivered sound signals that are temporally degraded, which led to temporally imprecise neural codes.Instead of adaptation to repeated stimuli, with degraded signals, there was a relative increase in firing rates, similar to that seen in aged rats.We interpret this increase with repetition as a repair mechanism for strengthening the internal representations of degraded signals by the higher‐order structures. To better understand speech in challenging environments, older adults increasingly use top‐down cognitive and contextual resources. The medial geniculate body (MGB) integrates ascending inputs with descending predictions to dynamically gate auditory representations based on salience and context. A previous MGB single‐unit study found an increased preference for predictable sinusoidal amplitude modulated (SAM) stimuli in aged rats relative to young rats. The results suggested that the age‐degraded/jittered up‐stream acoustic code may engender an increased preference for predictable/repeating acoustic signals, possibly reflecting increased use of top‐down resources. In the present study, we recorded from units in young‐adult MGB, comparing responses to standard SAM with those evoked by less salient SAM (degraded) stimuli. We hypothesized that degrading the SAM stimulus would simulate the degraded ascending acoustic code seen in the elderly, increasing the preference for predictable stimuli. Single units were recorded from clusters of advanceable tetrodes implanted above the MGB of young‐adult awake rats. Less salient SAM significantly increased the preference for predictable stimuli, especially at higher modulation frequencies. Rather than adaptation, higher modulation frequencies elicited increased numbers of spikes with each successive trial/repeat of the less salient SAM. These findings are consistent with previous findings obtained in aged rats suggesting that less salient acoustic signals engage the additional use of top‐down resources, as reflected by an increased preference for repeating stimuli that enhance the representation of complex environmental/communication sounds. Key points: Temporal imprecision leads to deficits in the comprehension of signals in cluttered acoustic environments, and the elderly are shown to use cognitive resources to disambiguate these signals.To mimic ageing in young rats, we delivered sound signals that are temporally degraded, which led to temporally imprecise neural codes.Instead of adaptation to repeated stimuli, with degraded signals, there was a relative increase in firing rates, similar to that seen in aged rats.We interpret this increase with repetition as a repair mechanism for strengthening the internal representations of degraded signals by the higher‐order structures. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) is a potent neuromodulator capable of modifying patterns of acoustic information flow. In auditory cortex, cholinergic systems have been shown to increase salience/gain while suppressing extraneous information. However, the mechanism by which cholinergic circuits shape signal processing in the auditory thalamus (medial geniculate body, MGB) is poorly understood. The present study, in male Fischer Brown Norway rats, seeks to determine the location and function of presynaptic neuronal nicotinic ACh receptors (nAChRs) at the major inputs to MGB and characterize how nAChRs change during aging. In vitro electrophysiological/optogenetic methods were used to examine responses of MGB neurons after activation of nAChRs during a paired-pulse paradigm. Presynaptic nAChR activation increased responses evoked by stimulation of excitatory corticothalamic and inhibitory tectothalamic terminals. Conversely, nAChR activation appeared to have little effect on evoked responses from inhibitory thalamic reticular nucleus and excitatory tectothalamic terminals. In situ hybridization data showed nAChR subunit transcripts in GABAergic inferior colliculus neurons and glutamatergic auditory cortical neurons supporting the present slice findings. Responses to nAChR activation at excitatory corticothalamic and inhibitory tectothalamic inputs were diminished by aging. These findings suggest that cholinergic input to the MGB increases the strength of tectothalamic inhibitory projections, potentially improving the signal-to-noise ratio and signal detection while increasing corticothalamic gain, which may facilitate top-down identification of stimulus identity. These mechanisms appear to be affected negatively by aging, potentially diminishing speech perception in noisy environments. Cholinergic inputs to the MGB appear to maximize sensory processing by adjusting both top-down and bottom-up mechanisms in conditions of attention and arousal. [ABSTRACT FROM AUTHOR]

Key points Neuronal nicotinic acetylcholine receptors (nAChRs) play a fundamental role in the attentional circuitry throughout the mammalian CNS. , In the present study, we report a novel finding that ageing negatively impacts nAChR efficacy in auditory thalamus, and this is probably the result of a loss of nAChR density ( Bmax) and changes in the subunit composition of nAChRs., Our data support the hypothesis that age-related maladaptive changes involving nAChRs within thalamocortical circuits partially underpin the difficulty that elderly adults experience with respect to attending to speech and other salient acoustic signals., Abstract The flow of auditory information through the medial geniculate body (MGB) is regulated, in part, by cholinergic projections from the pontomesencephalic tegmentum. The functional significance of these projections is not fully established, although they have been strongly implicated in the allocation of auditory attention. Using in vitro slice recordings, we have analysed postsynaptic function and pharmacology of neuronal nicotinic ACh receptors (nAChRs) in young adult and the aged rat MGB. We find that ACh produces significant excitatory postsynaptic actions on young MGB neurons, probably mediated by β2-containing heteromeric nAChRs. Radioligand binding studies show a significant age-related loss of heteromeric nAChR receptor number, which supports patch clamp data showing an age-related loss in ACh efficacy in evoking postsynaptic responses. Use of the β2-selective nAChR antagonist, dihydro-β-erythroidine, suggests that loss of cholinergic efficacy may also be the result of an age-related subunit switch from high affinity β2-containing nAChRs to low affinity β4-containing nAChRs, in addition to the loss of total nAChR number. This age-related nAChR dysfunction may partially underpin the attentional deficits that contribute to the loss of speech understanding in the elderly. [ABSTRACT FROM AUTHOR]

Tinnitus is defined as a phantom sound (ringing in the ears), and can significantly reduce the quality of life for those who suffer its effects. Ten to fifteen percent of the general adult population report symptoms of tinnitus with 1–2% reporting that tinnitus negatively impacts their quality of life. Noise exposure is the most common cause of tinnitus and the military environment presents many challenging high-noise situations. Military noise levels can be so intense that standard hearing protection is not adequate. Recent studies suggest a role for inhibitory neurotransmitter dysfunction in response to noise-induced peripheral deafferentation as a key element in the pathology of tinnitus. The auditory thalamus, or medial geniculate body (MGB), is an obligate auditory brain center in a unique position to gate the percept of sound as it projects to auditory cortex and to limbic structures. Both areas are thought to be involved in those individuals most impacted by tinnitus. For MGB, opposing hypotheses have posited either a tinnitus-related pathologic decrease or pathologic increase in GABAergic inhibition. In sensory thalamus, GABA mediates fast synaptic inhibition via synaptic GABA A receptors (GABA A Rs) as well as a persistent tonic inhibition via high-affinity extrasynaptic GABA A Rs and slow synaptic inhibition via GABA B Rs. Down-regulation of inhibitory neurotransmission, related to partial peripheral deafferentation, is consistently presented as partially underpinning neuronal hyperactivity seen in animal models of tinnitus. This maladaptive plasticity/Gain Control Theory of tinnitus pathology (see Auerbach et al., 2014 ; Richardson et al., 2012) is characterized by reduced inhibition associated with increased spontaneous and abnormal neuronal activity, including bursting and increased synchrony throughout much of the central auditory pathway. A competing hypothesis suggests that maladaptive oscillations between the MGB and auditory cortex, thalamocortical dysrhythmia, predict tinnitus pathology (De Ridder et al., 2015). These unusual oscillations/rhythms reflect net increased tonic inhibition in a subset of thalamocortical projection neurons resulting in abnormal bursting. Hyperpolarizing de-inactivation of T-type Ca2+ channels switches thalamocortical projection neurons into burst mode. Thalamocortical dysrhythmia originating in sensory thalamus has been postulated to underpin neuropathies including tinnitus and chronic pain. Here we review the relationship between noise-induced tinnitus and altered inhibition in the MGB. [ABSTRACT FROM AUTHOR]

Human aging studies suggest that an increased use of top-down knowledge-based resources would compensate for degraded upstream acoustic information to accurately identify important temporally rich signals. Sinusoidal amplitude-modulated (SAM) stimuli have been used to mimic the fast-changing temporal features in speech and species-specific vocalizations. Single units were recorded from auditory thalamus [medial geniculate body (MGB)] of young awake, aged awake, young anesthetized, and aged anesthetized rats. SAM stimuli were modulated between 2 and 1024 Hz with the modulation frequency ( fm) changed randomly (RAN) across trials or sequentially (SEQ) after several repeated trials. Units were found to be RAN-preferring, SEQ-preferring, or nonselective based on total firing rate. Significant anesthesia and age effects were found. The majority (86%) of young anesthetized units preferred RAN SAM stimuli; significantly fewer young awake units (51%, p<0.0001) preferred RANSAM signals with16%preferringSEQSAM.Compared with young awake units, there was a significant increase of aged awake units preferring SEQSAM(30%, p<0.05).We examined RAN versus SEQ differences across fms by measuring selective fm areas under the rate modulation transfer function curve. The largest age-related differences from awake animals were found for mid-to-high fms in MGB units, with young units preferring RAN SAM while aged units showed a greater preference for SEQ-presented SAM. Together, these findings suggest that aged MGB units/animals employ increased top-down mediated stimulus context to enhance processing of "expected" temporally rich stimuli, especially at more challenging higher fms. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests a role for inhibitory neurotransmitter dysfunction in the pathology of tinnitus. Opposing hypotheses proposed either a pathologic decrease or increase of GABAergic inhibition in medial geniculate body (MGB). In thalamus,GABAmediates fast synaptic inhibition via synaptic GABAA receptors (GABAARs) and persistent tonic inhibition via high-affinity extrasynaptic GABAARs. Given that extrasynaptic GABAARs control the firing mode of thalamocortical neurons, we examined tonic GABAAR currents inMGBneurons in vitro, using the following three groups of adult rats: unexposed control (Ctrl); sound exposed with behavioral evidence of tinnitus (Tin); and sound exposed with no behavioral evidence of tinnitus (Non-T). Tonic GABAAR currents were evoked using the selective agonist gaboxadol. Months after a tinnitus-inducing sound exposure, gaboxadol-evoked tonic GABAAR currents showed significant tinnitus-related increases contralateral to the sound exposure. In situ hybridization studies found increased mRNA levels for GABAAR δ-subunits contralateral to the sound exposure. Tin rats showed significant increases in the number of spikes per burst evoked using suprathreshold-injected current steps. In summary, we found little evidence of tinnitus-related decreases in GABAergic neurotransmission. Tinnitus and chronic pain may reflect thalamocortical dysrhythmia, which results from abnormal theta-range resonant interactions between thalamus and cortex, due to neuronal hyperpolarization and the initiation of low-threshold calcium spike bursts (Walton and Llina's, 2010). In agreement with this hypothesis, we found tinnitus-related increases in tonic extrasynaptic GABAAR currents, in action potentials/evoked bursts, and in GABAAR δ-subunit gene expression. These tinnitus-related changes in GABAergic function may be markers for tinnitus pathology in the MGB. [ABSTRACT FROM AUTHOR]

Tinnitus is an auditory percept without an environmental acoustic correlate. Contemporary tinnitus models hypothesize tinnitus to be a consequence of maladaptive plasticity-induced disturbance of excitation-inhibition homeostasis, possibly convergent onmedial geniculate body (MGB, auditory thalamus) and related neuronal networks. The MGB is an obligate acoustic relay in a unique position to gate auditory signals to higher-order auditory and limbic centres. Tinnitus-related maladaptive plastic changes of MGB-related neuronal networks may affect the gating function of MGB and enhance gain in central auditory and non-auditory neuronal networks, resulting in tinnitus. The present study examined the discharge properties of MGB neurons in the sound-exposure gap inhibition animal model of tinnitus. MGB single unit responses were obtained from awake unexposed controls and sound-exposed adult rats with behavioural evidence of tinnitus. MGB units in animals with tinnitus exhibited enhanced spontaneous firing, altered burst properties and increased rate-level function slope when driven by broadband noise and tones at the unit's characteristic frequency. Elevated patterns of neuronal activity and altered bursting showed a significant positive correlation with animals' tinnitus scores. Altered activity of MGB neurons revealed additional features of auditory system plasticity associated with tinnitus, whichmay provide a testable assay for future therapeutic and diagnostic development. [ABSTRACT FROM AUTHOR]

Key points Neurons in the medial geniculate body (MGB), the auditory thalamus, give stronger responses to rare sounds than to repetitive sounds, a phenomenon referred to as stimulus-specific adaptation (SSA)., The present study sought to elucidate how the inhibitory thalamic circuitry acting at GABAA receptors affects the generation and/or modulation of SSA from recordings of single unit responses from MGB. Microiontophoretic application of GABAergic agonists selectively increased SSA indices, whereas application of antagonists selectively reduced SSA values., We found that GABAA-mediated inhibition did not generate the SSA response but regulated the magnitude of SSA sensitivity in a gain control manner., These findings advance our understanding of the role of inhibition in coding deviance detection in the MGB., Abstract Stimulus-specific adaptation (SSA), which describes adaptation to repeated sounds concurrent with the maintenance of responsiveness to uncommon ones, may be an important neuronal mechanism for the detection of and attendance to rare stimuli or for the detection of deviance. It is well known that GABAergic neurotransmission regulates several different response properties in central auditory system neurons and that GABA is the major inhibitory neurotransmitter acting in the medial geniculate body (MGB). The mechanisms underlying SSA are still poorly understood; therefore, the primary aim of the present study was to examine what role, if any, MGB GABAergic circuits play in the generation and/or modulation of SSA. Microiontophoretic activation of GABAA receptors (GABAARs) with GABA or with the selective GABAAR agonist gaboxadol significantly increased SSA (computed with the common SSA index, CSI) by decreasing responses to common stimuli while having a lesser effect on responses to novel stimuli. In contrast, GABAAR blockade using gabazine resulted in a significant decrease in SSA. In all cases, decreases in the CSI during gabazine application were accompanied by an increase in firing rate to the stimulus paradigm. The present findings, in conjunction with those of previous studies, suggest that GABAA-mediated inhibition does not generate the SSA response, but can regulate the level of SSA sensitivity in a gain control manner. The existence of successive hierarchical levels of processing through the auditory system suggests that the GABAergic circuits act to enhance mechanisms to reduce redundant information. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central auditory system. Sensory thalamic structures show high levels of non-desensitizing extrasynaptic GABAA receptors (GABAARs) and a reduction in the redundancy of coded information. The present study compared the inhibitory potency of GABA acting at GABAARs between the inferior colliculus (IC) and the medial geniculate body (MGB) using quantitative in vivo, in vitro, and ex vivo experimental approaches. In vivo single unit studies compared the ability of half maximal inhibitory concentrations of GABA to inhibit sound-evoked temporal responses, and found that GABA was two to three times (P < 0.01) more potent at suppressing MGB single unit responses than IC unit responses. In vitro whole cell patch-clamp slice recordings were used to demonstrate that gaboxadol, a δ-subunit selective GABAAR agonist, was significantly more potent at evoking tonic inhibitory currents from MGB neurons than IC neurons (P < 0.01). These electrophysiological findings were supported by an in vitro receptor binding assay which used the picrotoxin analog [³H]TBOB to assess binding in the GABAAR chloride channel. MGB GABAARs had significantly greater total open chloride channel capacity relative to GABAARs in IC (P < 0.05) as shown by increased total [³H]TBOB binding. Finally, a comparative ex vivo measurement compared endogenous GABA levels and suggested a trend towards higher GABA concentrations in MGB than in IC. Collectively, these studies suggest that, per unit GABA, high affinity extrasynaptic and synaptic GABAARs confer a significant inhibitory GABAAR advantage to MGB neurons relative to IC neurons. This increased GABA sensitivity likely underpins the vital filtering role of auditory thalamus. [ABSTRACT FROM AUTHOR]

Novel stimulus detection by single neurons in the auditory system, known as stimulus-specific adaptation (SSA), appears to function as a real-time filtering/gating mechanism in processing acoustic information. Particular stimulus paradigms allowing for quantification of a neuron's ability to detect novel or deviant stimuli have been used to examine SSA in the inferior colliculus, medial geniculate body (MGB), and auditory cortex of anesthetized rodents. However, the study of SSA in awake animals is limited to auditory cortex. The present study used individually advanceable tetrodes to record single-unit responses from auditory thalamus (MGB) of awake young adult and aged Fischer Brown Norway (FBN) rats to 1) examine the presence of SSA in the MGB of awake rats and 2) determine whether SSA is altered by aging in MGB. MGB single units in awake FBN rats displayed SSA in response to two stimulus paradigms: the oddball paradigm and a random blocked/ interleaved presentation of a set of frequencies. SSA levels were modestly, but nonsignificantly, increased in the nonlemniscal regions of the MGB and at lower stimulus intensities, where 27 of 57 (47%) young adult MGB units displayed SSA. The present findings provide the initial description of SSA in the MGB of awake rats and support SSA as being qualitatively independent of arousal level or anesthetized state. Finally, contrary to previous studies in auditory cortex of anesthetized rats, MGB units in aged rats showed SSA levels indistinguishable from SSA levels in young adult rats, suggesting that SSA in MGB was not impacted by aging in an awake preparation. [ABSTRACT FROM AUTHOR]

Abstract: Auditory cortex (AI) shows age-related decreases in pre-synaptic markers for gamma-aminobutyric acid (GABA) and degraded AI neuronal response properties. Previous studies find age-related increases in spontaneous and driven activity, decreased spectral and directional sensitivity, and impaired novelty detection. The present study examined expression of GABAA receptor (GABAAR) subunit message, protein, and quantitative GABAAR binding in young, middle-aged, and aged rat AI, with comparisons with adjoining parietal cortex. Significant loss of GABAAR α1 subunit message across AI layers was observed in middle-aged and aged rats and α1 subunit protein levels declined in layers II and III. Age-related increases in GABAAR α3 subunit message and protein levels were observed in certain AI layers. GABAAR subunits, including β1, β2, γ1, γ2s, and γ2L, primarily, but not exclusively, showed age-related declines at the message and protein levels. The ability of GABA to modulate [3H]t-butylbicycloorthobenzoate binding in the chloride channel showed age-related decreases in peak binding and changes in desensitization kinetics. Collectively, age-related changes in GABAAR subunit composition would alter the magnitude and temporal properties of inhibitory synaptic transmission and could underpin observed age-related functional changes seen in the elderly. [Copyright &y& Elsevier]

Age-related deficits in detecting and understanding speech, which can lead to social withdrawal and isolation, have been linked to changes in the central auditory system. Many of these central age-related changes involve altered mechanisms of inhibitory neurotransmission, essential for accurate and reliable auditory processing. In sensory thalamus, GABA mediates fast (phasic) inhibition via synaptic GABAA receptors (GABAARs) and long-lasting (tonic) inhibition via high-affinity (extrasynaptic) GABAARs, which provide a majority of the overall inhibitory tone in sensory thalamus. Due to a delicate balance between excitation and inhibition, alteration of normal thalamic inhibitory function with age and a reduction of tonic GABAAR-mediated inhibition may disrupt normal adult auditory processing, sensory gating, thalamocortical rhythmicity, and slow-wave sleep. The present study examines age-related homeostatic plasticity of GABAAR function in auditory thalamus or the medial geniculate body (MGB). Using thalamic slices from young adult (3-8 months) and aged (28 -32 months) rats, these studies found a 45.5% reduction in GABAAR density and a 50.4% reduction in GABAAR-mediated tonic whole cell Cl- currents in the aged MGB. Synaptic GABAAR-mediated inhibition appeared differentially affected in aged lemniscal and nonlemniscal MGB. Except for resting membrane potential, basic properties were unaltered with age, including neuronal Cl ~ homeostasis determined using the gramicidin perforated patch-damp method. Results demonstrate selective significant age-dependent deficits in the tonic inhibitory tone within the MGB. These data suggest that selective GABAAR subtype agonists or modulators might be used to augment MGB inhibitory neurotransmission, improving speech understanding, sensory gating, and slow-wave sleep for a subset of elderly individuals. [ABSTRACT FROM AUTHOR]

Flavoprotein autofluorescence imaging was used to examine auditory cortical synaptic responses in aged animals with behavioral evidence of tinnitus and hearing loss. Mice were exposed to noise trauma at 1 -3 months of age and were assessed for behavioral evidence of tinnitus and hearing loss immediately after the noise trauma and again at --24-30 months of age. Within 2 months of the final behavioral assessment, auditory cortical synaptic transmission was examined in brain slices using electrical stimulation of putative thalamocortical afférents, and flavoprotein autofluorescence imaging was used to measure cortical activation. Noise-exposed animals showed a 68% increase in amplitude of cortical activation compared with controls (p = 0.008), and these animals showed a diminished sensitivity to GABAAergic blockade (p = 0.008, using bath-applied 200nΜ SR 95531 [6-Imino-3-(4-methoxyphenyl)-l(6H)-p yridazinebutanoic acid hydrobromide] ). The strength of cortical activation was significantly correlated to the degree of tinnitus behavior, assessed via a loss of gap detection in a startle paradigm. The decrease in GABAA sensitivity was greater in the regions of the cortex farther away from the stimulation site, potentially reflecting a greater sensitivity of corticocortical versus thalamocortical projections to the effects of noise trauma. Finally, there was no relationship between auditory cortical activation and activation of the somatosensory cortex in the same slices, suggesting that the increases in auditory cortical activation were not attributable to a generalized hyperexcitable state in noise-exposed animals. These data suggest that noise trauma can cause long-lasting changes in the auditory cortical physiology and may provide specific targets to ameliorate the effects of chronic tinnitus. [ABSTRACT FROM AUTHOR]

Background: Neural inhibition plays an important role in auditory processing and attentional gating. Extrasynaptic GABAA receptors (GABAAR), containing α4 and δ GABAAR subunits, are thought to be activated by GABA spillover outside of the synapse following release resulting in a tonic inhibitory Cl- current which could account for up to 90% of total inhibition in visual and somatosensory thalamus. However, the presence of this unique type of inhibition has not been identified in auditory thalamus. Methodology/Principal Findings: The present study used gaboxadol, a partially selective potent agonist for δ-subunit containing GABAA receptor constructs to elucidate the presence of extrasynaptic GABAARs using both a quantitative receptor binding assay and patch-clamp electrophysiology in thalamic brain slices. Intense [³H]gaboxadol binding was found to be localized to the MGB while whole cell recordings from MGB neurons in the presence of gaboxadol demonstrated the expression of δ-subunit containing GABAARs capable of mediating a tonic inhibitory Cl2 current. Conclusions/Significance: Potent tonic inhibitory GABAAR responses mediated by extrasynaptic receptors may be important in understanding how acoustic information is processed by auditory thalamic neurons as it ascends to auditory cortex. In addition to affecting cellular behavior and possibly neurotransmission, functional extrasynaptic d-subunit containing GABAARs may represent a novel pharmacological target for the treatment of auditory pathologies including temporal processing disorders or tinnitus [ABSTRACT FROM AUTHOR]

Tinnitus is a phantom sound (ringing of the ears) that affects quality of life for millions around the world and is associated in most cases with hearing impairment. This symposium will consider evidence that deafferentation of tonotopically organized central auditory structures leads to increased neuron spontaneous firing rates and neural synchrony in the hearing loss region. This region covers the frequency spectrum of tinnitus sounds, which are optimally suppressed following exposure to band-limited noise covering the same frequencies. Cross-modal compensations in subcortical structures may contribute to tinnitus and its modulation by jaw-clenching and eye movements. Yet many older individuals with impaired hearing do not have tinnitus, possibly because age-related changes in inhibitory circuits are better preserved.Abrain network involving limbic and other nonauditory regions is active in tinnitus and may be driven when spectrotemporal information conveyed by the damaged ear does not match that predicted by central auditory processing. [ABSTRACT FROM AUTHOR]

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 (Al) 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 Al 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. [ABSTRACT FROM AUTHOR]

Abstract: Silicon-substrate multi-channel electrodes (multiprobes) have proven useful in a variety of electrophysiological tasks. When using multiprobes it is often useful to identify the site of each channel, e.g., when recording single-unit activity from a heterogeneous structure. Lesion marking of electrode sites has been used for many years. Electrolytic, or direct current (DC) lesions, have been used successfully to mark multiprobe sites in rat hippocampus [Townsend G, Peloquin P, Kloosterman F, Hetke JF, Leung LS. Recording and marking with silicon multichannel electrodes. Brain Res Brain Res Protoc 2002;9:122–9]. The present method used radio-frequency (rf) lesions to distinctly mark each of the 16 recording sites of 16-channel linear array multiprobes, in chinchilla inferior colliculus. A commercial radio-frequency lesioner was used as the current source, in conjunction with custom connectors adapted to the multiprobe configuration. In vitro bench testing was used to establish current–voltage–time parameters, as well as to check multiprobe integrity and radio-frequency performance. In in vivo application, visualization of individual-channel multiprobe recording sites was clear in 21 out of 33 sets of collicular serial-sections (i.e., probe tracks) obtained from acute experimental subjects, i.e., maximum post-lesion survival time of 2h. Advantages of the rf method include well-documented methods of in vitro calibration as well as low impact on probe integrity. The rf method of marking individual-channel sites should be useful in a variety of applications. [Copyright &y& Elsevier]

Age-related hearing loss frequently results in a loss in the ability to discriminate speech signals, especially in noise. This is attributable, in part, to a loss in temporal resolving power and ability to adjust dynamic range. Circuits in the adult dorsal cochlear nucleus (DCN) have been shown to preserve signal in background noise. Fusiform cells, major DCN output neurons, receive focused glycinergic inputs from tonotopically aligned vertical cells that also project to the ventral cochlear nucleus. Glycine-mediated inhibition onto fusiform cells results in decreased tone-evoked activity as intensity is increased at frequencies adjacent to characteristic frequency (CF). DCN output is thus shaped by glycinergic inhibition, which can be readily assessed in recordings from fusiform cells. Previous DCN studies suggest an age-related loss of markers for glycinergic neurotransmission. The present study postulated that response properties of aged fusiform cells would show a loss of inhibition, resembling conditions observed with glycine receptor blockade. The functional impact of aging was examined by comparing response properties from units meeting fusiform-cell criteria in young and aged rats. Fusiform cells in aged animals displayed significantly higher maximum discharge rates to CF tones than those recorded from young-adult animals. Fusiform cells of aged rats displayed significantly fewer nonmonotonic CF rate-level functions and an age-related change in temporal response properties. These findings are consistent with an age-related loss of glycinergic input, likely from vertical cells, and with findings from other sensory aging studies suggesting a selective age-related decrement in inhibitory amino acid neurotransmitter function. [ABSTRACT FROM AUTHOR]

The inferior colliculus (IC) is an important auditory processing center receiving inputs from lower brainstem nuclei, higher auditory and nonauditory structures, and contralateral IC. The IC, along with other auditory structures, is involved in coding information about the envelope of complex signals. Biologically relevant acoustic signals, including animal vocalizations and speech, are spectrally and temporally complex and display amplitude and frequency variations over time. Certain IC neurons respond selectively over a narrow range of modulation frequencies to sinusoidally amplitude modulated (SAM) stimuli. Responses to SAM stimuli can be measured in terms of discharge rate, with rate plotted against the modulation frequency to generate rate modulation transfer functions (rMTF). A role for the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), in shaping selective responses to SAM stimuli has been suggested. The present study examined the role of GABA in shaping responses to SAM stimuli in the IC of anesthetized chinchilla. Responses from 94 IC neurons were obtained before, during and after iontophoretic application of the GABAA receptor antagonist bicuculline methiodide. Complete responses to SAM stimuli were obtained from 55 extensively tested neurons, displaying band-pass (38) and low-pass rMTFs (17). For neurons showing band-pass rMTFs, GABAA receptor blockade selectively increased discharge rate at low modulation frequencies for 14 units, increased discharge near the best modulation frequency for 12 units. For neurons showing low-pass rMTFs, GABAA receptor blockade selectively increased discharge rate at low modulation frequencies for nine units. GABAA receptor blockade consistently reduced peak modulation gain, producing low-pass gain functions in a subset of IC neurons. In support of previous findings suggesting that selective temporal responses to SAM stimuli are coded in lower brainstem nuclei, temporal responses to SAM stimuli were relatively unaffected by GABAA receptor blockade. These findings support a role for GABA in shaping selective rate responses to SAM stimuli for a subset of chinchilla IC neurons. [Copyright &y& Elsevier]

Previous studies have shown that levels of binding for the strychnine-sensitive glycine receptor in the cochlear nucleus (CN) of Fischer(F344) rats decrease with age. Given the major role glycine plays in normal CN function, changes in glycine-receptor activity may contribute to central presbycusis. To further evaluate the impact of age on glycine receptors, in situ hybridization was used to assess, in three age groups of F344 rats, changes in levels of gene expression for four of its subunits. When compared with the 3-month-old rats, expression of mRNAs for α1 and β subunits in the anteroventral CN decreased significantly in the 18- and 27-month-old age groups, while mRNA expression for the α2 subunit increased. If protein expressions are similar, these subunit changes may alter the function of glycine receptors, thereby affecting binding to its ligands. [ABSTRACT FROM AUTHOR]

Measuring tinnitus in laboratory animals is difficult, involving weeks or months of operant training. Preliminary data suggest that rapid screening for tinnitus in rats can be accomplished using an unconditioned acoustic startle reflex. In control animals, a gap in an otherwise constant acoustic background inhibits a subsequent startle response to a sound impulse. If, however, the background signal is qualitatively similar to the animal’s tinnitus, poorer detection of the gap and less inhibition of the startle might be expected. Fourteen animals with putative tinnitus at 10 kHz and 13 control animals were tested for gap detection using three different background signals: broadband noise, and filtered bandpass noise centered either at 16 kHz (15.5–16.5 kHz) or at their suspected tinnitus locus of 10 kHz (9.5–10.5 kHz). As predicted, animals with evidence of tinnitus exhibited significantly worse gap detection at 10 kHz, and were not significantly different than control animals at 16 kHz and broadband noise. These results suggest a new methodology for rapidly detecting tinnitus in individual animals. Equipment donated by Hamilton-Kinder Inc Behavioral Testing Systems in the memory of SIU graduate Dorothy Jean Kinder (Walker). [Work supported by NIH grants AG023910-01 (JT), DC4830 (TB & CB), and DC00151 (DC).] [ABSTRACT FROM AUTHOR]

Neurons in the chinchilla lateral superior olivary nucleus (LSO) were studied as part of a broader study of neurotransmitters of the superior olivary complex (SOC) [Moore et al., Neurosci. Abs. 7, 389 (1981)]. Two hundred thirty neurons, localized to an area lateral to the medial superior olive, were classified according to their responses to monaural and binaural stimulation at characteristic frequency (CF). Forty-two percent of the neurons were monaurally excited (predominantly ipsilaterally) and binaurally inhibited. Eight percent of the neurons displayed excitation when either ear was stimulated and inhibition upon binaural stimulation. Sixteen percent were excited when either ear was stimulated and displayed a summated binaural response. A smaller population of neurons (5%) was excited by either ipsi- or contralateral stimulation and displayed an enhanced binaural response. Poststimulus time and interspike interval histograms were obtained for all conditions. Response patterns in the chinchilla are consistent with findings described for other previously studied species. [Work supported by NIH Grant NS15640, SIU CRC funds and Pearson Family Foundation.] [ABSTRACT FROM AUTHOR]