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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: 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., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

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 RAN SAM signals with 16% preferring SEQ SAM. Compared with young awake units, there was a significant increase of aged awake units preferring SEQ SAM (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., Significance Statement: Older individuals compensate for impaired ascending acoustic information by increasing use of cortical cognitive and attentional resources. The interplay between ascending and descending influences in the thalamus may serve to enhance the salience of speech signals that are degraded as they ascend to the cortex. The present findings demonstrate that medial geniculate body units from awake rats show an age-related preference for predictable modulated signals relative to randomly presented signals, especially at higher, more challenging modulation frequencies. Conversely, units from anesthetized animals, with little top-down influences, strongly preferred randomly presented modulated sequences. These results suggest a neuronal substrate for an age-related increase in experience/attentional-based influences in processing temporally complex auditory information in the auditory thalamus., (Copyright © 2016 the authors 0270-6474/16/3610696-11$15.00/0.)

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 GABA(A) receptors (GABA(A)Rs) and long-lasting (tonic) inhibition via high-affinity (extrasynaptic) GABA(A)Rs, 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 GABA(A)R-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 GABA(A)R 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 GABA(A)R density and a 50.4% reduction in GABA(A)R-mediated tonic whole cell Cl(-) currents in the aged MGB. Synaptic GABA(A)R-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-clamp method. Results demonstrate selective significant age-dependent deficits in the tonic inhibitory tone within the MGB. These data suggest that selective GABA(A)R 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.

Background: Neural inhibition plays an important role in auditory processing and attentional gating. Extrasynaptic GABA(A) receptors (GABA(A)R), containing α(4)and δ GABA(A)R 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 GABA(A) receptor constructs to elucidate the presence of extrasynaptic GABA(A)Rs using both a quantitative receptor binding assay and patch-clamp electrophysiology in thalamic brain slices. Intense [(3)H]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 GABA(A)Rs capable of mediating a tonic inhibitory Cl(-) current., Conclusions/significance: Potent tonic inhibitory GABA(A)R 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 δ-subunit containing GABA(A)Rs may represent a novel pharmacological target for the treatment of auditory pathologies including temporal processing disorders or tinnitus.

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]

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]

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]

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]

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]

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]

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]