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1.  Hearing Loss Prevents the Maturation of GABAergic Transmission in the Auditory Cortex 
Cerebral Cortex (New York, NY)  2008;18(9):2098-2108.
Inhibitory neurotransmission is a critical determinant of neuronal network gain and dynamic range, suggesting that network properties are shaped by activity during development. A previous study demonstrated that sensorineural hearing loss (SNHL) in gerbils leads to smaller inhibitory potentials in L2/3 pyramidal neurons in the thalamorecipient auditory cortex, ACx. Here, we explored the mechanisms that account for proper maturation of γ-amino butyric acid (GABA)ergic transmission. SNHL was induced at postnatal day (P) 10, and whole-cell voltage-clamp recordings were obtained from layer 2/3 pyramidal neurons in thalamocortical slices at P16–19. SNHL led to an increase in the frequency of GABAzine-sensitive (antagonist) spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs), accompanied by diminished amplitudes and longer durations. Consistent with this, the amplitudes of minimum-evoked IPSCs were also reduced while their durations were longer. The α1- and β2/3 subunit–specific agonists zolpidem and loreclezole increased control but not SNHL sIPSC durations. To test whether SNHL affected the maturation of GABAergic transmission, sIPSCs were recorded at P10. These sIPSCs resembled the long SNHL sIPSCs. Furthermore, zolpidem and loreclezole were ineffective in increasing their durations. Together, these data strongly suggest that the presynaptic release properties and expression of key postsynaptic GABAA receptor subunits are coregulated by hearing.
doi:10.1093/cercor/bhm233
PMCID: PMC2517109  PMID: 18222937
α1 and β2/3 subunits; auditory cortex; development; GABAA receptor; hearing impairment
2.  Rescue of Inhibitory Synapse Strength following Developmental Hearing Loss 
PLoS ONE  2013;8(1):e53438.
Inhibitory synapse dysfunction may contribute to many developmental brain disorders, including the secondary consequences of sensory deprivation. In fact, developmental hearing loss leads to a profound reduction in the strength of inhibitory postsynaptic currents (IPSCs) in the auditory cortex, and this deficit persists into adulthood. This finding is consistent with the general theory that the emergence of mature synaptic properties requires activity during development. Therefore, we tested the prediction that inhibitory strength can be restored following developmental hearing loss by boosting GABAergic transmission in vivo. Conductive or sensorineural hearing loss was induced surgically in gerbils prior to hearing onset and GABA agonists were then administered for one week. IPSCs were subsequently recorded from pyramidal neurons in a thalamocortical brain slice preparation. Administration of either a GABAA receptor a1 subunit specific agonist (zolpidem), or a selective GABA reuptake inhibitor (SGRI), rescued IPSC amplitude in hearing loss animals. Furthermore, this restoration persisted in adults, long after drug treatment ended. In contrast, a GABAB receptor agonist baclofen did not restore inhibitory strength. IPSCs could also be restored when SGRI administration began 3 weeks after sensory deprivation. Together, these results demonstrate long-lasting restoration of cortical inhibitory strength in the absence of normal experience. This suggests that in vivo GABAA receptor activation is sufficient to promote maturation, and this principle may extend to other developmental disorders associated with diminished inhibitory function.
doi:10.1371/journal.pone.0053438
PMCID: PMC3543446  PMID: 23326429
3.  Hearing Loss Alters the Subcellular Distribution of Presynaptic GAD and Postsynaptic GABAA Receptors in the Auditory Cortex 
Cerebral Cortex (New York, NY)  2008;18(12):2855-2867.
We have shown previously that auditory experience regulates the maturation of excitatory synapses in the auditory cortex (ACx). In this study, we used electron microscopic immunocytochemistry to determine whether the heightened excitability of the ACx following neonatal sensorineural hearing loss (SNHL) also involves pre- or postsynaptic alterations of GABAergic synapses. SNHL was induced in gerbils just prior to the onset of hearing (postnatal day 10). At P17, the gamma-aminobutyri acid type A (GABAA) receptor's β2/3-subunit (GABAAβ2/3) clusters residing at plasma membranes in layers 2/3 of ACx was reduced significantly in size (P < 0.05) and number (P < 0.005), whereas the overall number of immunoreactive puncta (intracellular + plasmalemmal) remained unchanged. The reduction of GABAAβ2/3 was observed along perikaryal plasma membranes of excitatory neurons but not of GABAergic interneurons. This cell-specific change can contribute to the enhanced excitability of SNHL ACx. Presynaptically, GABAergic axon terminals were significantly larger but less numerous and contained 47% greater density of glutamic acid decarboxylase immunoreactivity (P < 0.05). This suggests that GABA synthesis may be upregulated by a retrograde signal arising from lowered levels of postsynaptic GABAAR. Thus, both, the pre- and postsynaptic sides of inhibitory synapses that form upon pyramidal neurons of the ACx are regulated by neonatal auditory experience.
doi:10.1093/cercor/bhn044
PMCID: PMC2583158  PMID: 18403398
β2/3 subunits; deafness; development; electron microscopy; immunocytochemistry
4.  A Comparison of Auditory Perception in Hearing-Impaired and Normal-Hearing Listeners: An Auditory Scene Analysis Study 
Background
Auditory scene analysis (ASA) is the process by which the auditory system separates individual sounds in natural-world situations. ASA is a key function of auditory system, and contributes to speech discrimination in noisy backgrounds. It is known that sensorineural hearing loss (SNHL) detrimentally affects auditory function in complex environments, but relatively few studies have focused on the influence of SNHL on higher level processes which are likely involved in auditory perception in different situations.
Objectives
The purpose of the current study was to compare the auditory system ability of normally hearing and SNHL subjects using the ASA examination.
Materials and Methods
A total of 40 right-handed adults (age range: 18 - 45 years) participated in this study. The listeners were divided equally into control and mild to moderate SNHL groups. ASA ability was measured using an ABA-ABA sequence. The frequency of the "A" was kept constant at 500, 1000, 2000 or 4000 Hz, while the frequency of the "B" was set at 3 to 80 percent above the" A" tone. For ASA threshold detection, the frequency of the B stimulus was decreased until listeners reported that they could no longer hear two separate sounds.
Results
The ASA performance was significantly better for controls than the SNHL group; these differences were more obvious at higher frequencies. We found no significant differences between ASA ability as a function of tone durations in both groups.
Conclusions
The present study indicated that SNHL may cause a reduction in perceptual separation of the incoming acoustic information to form accurate representations of our acoustic world.
doi:10.5812/ircmj.9477
PMCID: PMC3971787  PMID: 24719695
Auditory Scene Analysis; Sensorineural Hearing Loss; Hearing
5.  Sensorineural Hearing Loss and Neural Correlates of Temporal Acuity in the Inferior Colliculus of the C57bl/6 Mouse 
Perception of complex sounds depends on the encoding of the dynamic and static structures within the ongoing stimulus by the auditory system. Aging has been associated with deficits in both areas, thus, the difficulty that the elderly have in speech comprehension could due to hearing loss, or to a loss of temporal sensitivity, or some combination of both. We investigated the effects of sensorineural hearing loss (SNHL) on neural correlates of temporal resolution by recording the responses of inferior colliculus neurons to a gap detection paradigm. We used C57BL/6 (C57) strain of laboratory mouse, which carries the Ahl deafness gene that initiates a progressive high frequency SNHL beginning at about 2 months of age and rapidly progresses to total deafness by 18 months. We compared gap encoding from inferior collicular neurons from young, normal-hearing C57 mice and middle-aged, hearing-impaired, C57 mice, quantifying minimal gap threshold, and recovery functions. The proportion of unit types, spontaneous rates and degree of monotonicity were comparable between young and middle-aged C57 mice. As expected, single unit thresholds were elevated by 30–40 dB in middle-aged C57 mice. However, no significant differences in mean minimal gap thresholds or in the slopes of the gap recovery functions were found between the two age groups. Thus, the results suggest that moderate high frequency SNHL does not affect temporal processing as measured by the gap detection paradigm.
doi:10.1007/s10162-007-0101-z
PMCID: PMC2536807  PMID: 17994264
presbycusis; gap detection; inferior colliculus; hearing loss; mouse
6.  Linear Transformation of Thalamocortical input by Intracortical Excitation 
Nature neuroscience  2013;16(9):10.1038/nn.3494.
Neurons in thalamorecipient layers of sensory cortices integrate thalamocortical and intracortical inputs. Although their functional properties can be inherited from the convergence of thalamic inputs, the roles of intracortical circuits in thalamocortical transformation of sensory information remain unclear. Here, by reversibly silencing intracortical excitatory circuits with optogenetic activation of parvalbumin-positive inhibitory neurons in mouse primary visual cortex, we compared visually-evoked thalamocortical input with total excitation in the same layer 4 pyramidal neurons. We found that intracortical excitatory circuits preserve the orientation and direction tuning of thalamocortical excitation, with a linear amplification of thalamocortical signals by about threefold. The spatial receptive field of thalamocortical input is slightly elongated, and is expanded by intracortical excitation in an approximately proportional manner. Thus, intracortical excitatory circuits faithfully reinforce the representation of thalamocortical information, and may influence the size of the receptive field by recruiting additional inputs.
doi:10.1038/nn.3494
PMCID: PMC3855439  PMID: 23933750
7.  Developmental plasticity of auditory cortical inhibitory synapses 
Hearing research  2011;279(1-2):140-148.
Functional inhibitory synapses form in auditory cortex well before the onset of normal hearing. However, their properties change dramatically during normal development, and many of these maturational events are delayed by hearing loss. Here, we review recent findings on the developmental plasticity of inhibitory synapse strength, kinetics, and GABAA receptor localization in auditory cortex. Although hearing loss generally leads to a reduction of inhibitory strength, this depends on the type of presynaptic interneuron. Furthermore, plasticity of inhibitory synapses also depends on the postsynaptic target. Hearing loss leads reduced GABAA receptor localization to the membrane of excitatory, but not inhibitory neurons. A reduction in normal activity in development can also affect the use-dependent plasticity of inhibitory synapses. Even moderate hearing loss can disrupt inhibitory short- and long-term synaptic plasticity. Thus, the cortex did not compensate for the loss of inhibition in the brainstem, but rather exacerbated the response to hearing loss by further reducing inhibitory drive. Together, these results demonstrate that inhibitory synapses are exceptionally dynamic during development, and deafness-induced perturbation of inhibitory properties may have a profound impact on auditory processing.
doi:10.1016/j.heares.2011.03.015
PMCID: PMC3135718  PMID: 21463668
development; deafness; inhibitory interneuron; short-term depression; long-term potentiation; auditory cortex
8.  Linking the response properties of cells in auditory cortex with network architecture: co-tuning vs. lateral inhibition 
The frequency-intensity receptive fields (RF) of neurons in primary auditory cortex (AI) are heterogeneous. Some neurons have V-shaped RFs while others have enclosed ovoid RFs. Moreover, there is a wide range of temporal response profiles ranging from phasic to tonic firing. The mechanisms underlying this diversity of receptive field properties are yet unknown. Here we study the characteristics of thalamocortical (TC) and intracortical connectivity that give rise to the individual cell responses. Using a mouse auditory TC slice preparation, we found that the amplitude of synaptic responses in AI varies non-monotonically with the intensity of the stimulation in the medial geniculate nucleus (MGv). We constructed a network model of MGv and AI that was simulated using either rate model cells or in vitro neurons through an iterative procedure that used the recorded neural responses to reconstruct network activity. We compared the receptive fields and firing profiles obtained with networks configured either to have co-tuned excitatory and inhibitory inputs or relatively broad, lateral inhibitory inputs. Each of these networks yielded distinct response properties consistent with those documented in vivo with natural stimuli. The co-tuned network produced V-shaped RFs, phasic-tonic firing profiles, and predominantly monotonic rate-level functions. The lateral inhibitory network produced enclosed RFs with narrow frequency tuning, a variety of firing profiles, and robust non-monotonic rate-level functions. We conclude that both types of circuits must be present in order to account for the wide variety of responses observed in vivo.
doi:10.1523/JNEUROSCI.1789-08.2008
PMCID: PMC2729467  PMID: 18784296
primary auditory cortex; frequency tuning; intensity tuning; lateral inhibition; computational model; network dynamics; thalamocortical transformation
9.  Layer specific experience-dependent rewiring of thalamocortical circuits 
Thalamocortical circuits are central to sensory and cognitive processing. Recent work suggests that the thalamocortical inputs onto L4 and L6, the main input layers of neocortex, are activated differently by visual stimulation. Whether these differences depend on layer specific organization of thalamocortical circuits; or on specific properties of synapses onto receiving neurons is unknown. Here we combined optogenetic stimulation of afferents from the visual thalamus and paired recording electrophysiology in L4 and L6 of rat primary visual cortex to determine the organization and plasticity of thalamocortical synapses. We show that thalamocortical inputs onto L4 and L6 differ in synaptic dynamics and sensitivity to visual drive. We also demonstrate that the two layers differ in the organization of thalamocortical and recurrent intracortical connectivity. In L4, a significantly larger proportion of excitatory neurons responded to light activation of thalamocortical terminal fields than in L6. The local microcircuit in L4 showed a higher degree of recurrent connectivity between excitatory neurons than the microcircuit in L6. In addition, L4 recurrently connected neurons were driven by thalamocortical inputs of similar magnitude indicating the presence of local subnetworks that may be activated by the same axonal projection. Finally, brief manipulation of visual drive reduced the amplitude of light-evoked thalamocortical synaptic currents selectively onto L4. These data are the first direct indication that thalamocortical circuits onto L4 and L6 support different aspects of cortical function through layer specific synaptic organization and plasticity.
doi:10.1523/JNEUROSCI.4423-12.2013
PMCID: PMC3613853  PMID: 23447625
synaptic plasticity; experience; LGN; thalamocortical; optogenetics; microcircuitry; visual cortex
10.  Plasticity in the Developing Auditory Cortex: Evidence from Children with Sensorineural Hearing Loss and Auditory Neuropathy Spectrum Disorder 
The developing auditory cortex is highly plastic. As such, the cortex is both primed to mature normally and at risk for re-organizing abnormally, depending upon numerous factors that determine central maturation. From a clinical perspective, at least two major components of development can be manipulated: 1) input to the cortex and 2) the timing of cortical input. Children with sensorineural hearing loss (SNHL) and auditory neuropathy spectrum disorder (ANSD) have provided a model of early deprivation of sensory input to the cortex, and demonstrated the resulting plasticity and development that can occur upon introduction of stimulation. In this article, we review several fundamental principles of cortical development and plasticity and discuss the clinical applications in children with SNHL and ANSD who receive intervention with hearing aids and/or cochlear implants.
doi:10.3766/jaaa.23.6.3
PMCID: PMC3733172  PMID: 22668761
Auditory neuropathy spectrum disorder; central auditory maturation; cortical auditory evoked potential; cochlear implants; hearing aids; experience-dependent plasticity; cochlear nerve deficiency
11.  Functional excitatory microcircuits in neonatal cortex connect thalamus and layer 4 
The functional connectivity of the cerebral cortex is shaped by experience during development, especially during a critical period early in life. In the prenatal and neonatal cortex, transient neuronal circuits are formed by a population of subplate neurons (SPNs). However, SPNs are absent in the adult cortex. While SPNs are crucial for normal development of the cerebral cortex and of thalamocortical synapses, little is known about how they are integrated in the developing thalamocortical circuit. We therefore investigated SPNs in vitro in thalamocortical slices of A1 and medial geniculate nucleus (MGN) in mouse from postnatal day 1 (P1) to P13. We found that SPNs can fire action potentials at P1 and that their intrinsic membrane properties are mature after P5. We find that SPNs receive functional excitatory inputs from the MGN as early as P2. The MGN projections to SPNs strengthen between P2 and P13 and are capable of inducing action potentials in SPNs. Selective activation of SPNs by photostimulation produced EPSCs in layer 4 neurons, demonstrating a functional excitatory connection. Thus SPNs are tightly integrated into the developing thalamocortical circuit and would be a reliable relay of early spontaneous and sound evoked activity. The role of SPNs in development likely results from their strong excitatory projection to layer 4 which might function to regulate activity dependent processes that enable mechanisms required for the functional maturation and plasticity of the developing cortex and thereby contribute to the development of normal cortical organization.
doi:10.1523/JNEUROSCI.4471-09.2009
PMCID: PMC3539415  PMID: 20007472
Auditory cortex; subplate; neonatal; development
12.  Envelope Coding in Auditory Nerve Fibers Following Noise-Induced Hearing Loss 
Recent perceptual studies suggest that listeners with sensorineural hearing loss (SNHL) have a reduced ability to use temporal fine-structure cues, whereas the effects of SNHL on temporal envelope cues are generally thought to be minimal. Several perceptual studies suggest that envelope coding may actually be enhanced following SNHL and that this effect may actually degrade listening in modulated maskers (e.g., competing talkers). The present study examined physiological effects of SNHL on envelope coding in auditory nerve (AN) fibers in relation to fine-structure coding. Responses were compared between anesthetized chinchillas with normal hearing and those with a mild–moderate noise-induced hearing loss. Temporal envelope coding of narrowband-modulated stimuli (sinusoidally amplitude-modulated tones and single-formant stimuli) was quantified with several neural metrics. The relative strength of envelope and fine-structure coding was compared using shuffled correlogram analyses. On average, the strength of envelope coding was enhanced in noise-exposed AN fibers. A high degree of enhanced envelope coding was observed in AN fibers with high thresholds and very steep rate-level functions, which were likely associated with severe outer and inner hair cell damage. Degradation in fine-structure coding was observed in that the transition between AN fibers coding primarily fine structure or envelope occurred at lower characteristic frequencies following SNHL. This relative fine-structure degradation occurred despite no degradation in the fundamental ability of AN fibers to encode fine structure and did not depend on reduced frequency selectivity. Overall, these data suggest the need to consider the relative effects of SNHL on envelope and fine-structure coding in evaluating perceptual deficits in temporal processing of complex stimuli.
doi:10.1007/s10162-010-0223-6
PMCID: PMC2975881  PMID: 20556628
temporal coding; sensorineural hearing loss; phase locking; modulation coding
13.  Pharmacological isolation of postsynaptic currents mediated by NR2A- and NR2B-containing NMDA receptors in the anterior cingulate cortex 
Molecular Pain  2007;3:11.
NMDA receptors (NMDARs) are involved in excitatory synaptic transmission and plasticity associated with a variety of brain functions, from memory formation to chronic pain. Subunit-selective antagonists for NMDARs provide powerful tools to dissect NMDAR functions in neuronal activities. Recently developed antagonist for NR2A-containing receptors, NVP-AAM007, triggered debates on its selectivity and involvement of the NMDAR subunits in bi-directional synaptic plasticity. Here, we re-examined the pharmacological properties of NMDARs in the anterior cingulate cortex (ACC) using NVP-AAM007 as well as ifenprodil, a selective antagonist for NR2B-containing NMDARs. By alternating sequence of drug application and examining different concentrations of NVP-AAM007, we found that the presence of NVP-AAM007 did not significantly affect the effect of ifenprodil on NMDAR-mediated EPSCs. These results suggest that NVP-AAM007 shows great preference for NR2A subunit and could be used as a selective antagonist for NR2A-containing NMDARs in the ACC.
doi:10.1186/1744-8069-3-11
PMCID: PMC1871573  PMID: 17470281
14.  Development of Inhibitory Timescales in Auditory Cortex 
Cerebral Cortex (New York, NY)  2010;21(6):1351-1361.
The time course of inhibition plays an important role in cortical sensitivity, tuning, and temporal response properties. We investigated the development of L2/3 inhibitory circuitry between fast-spiking (FS) interneurons and pyramidal cells (PCs) in auditory thalamocortical slices from mice between postnatal day 10 (P10) and P29. We found that the maturation of the intrinsic and synaptic properties of both FS cells and their connected PCs influence the timescales of inhibition. FS cell firing rates increased with age owing to decreased membrane time constants, shorter afterhyperpolarizations, and narrower action potentials. Between FS–PC pairs, excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) changed with age. The latencies, rise, and peak times of the IPSPs, as well as the decay constants of both EPSPs and IPSPs decreased between P10 and P29. In addition, decreases in short-term depression at excitatory PC–FS synapses resulted in more sustained synaptic responses during repetitive stimulation. Finally, we show that during early development, the temporal properties that influence the recruitment of inhibition lag those of excitation. Taken together, our results suggest that the changes in the timescales of inhibitory recruitment coincide with the development of the tuning and temporal response properties of auditory cortical networks.
doi:10.1093/cercor/bhq214
PMCID: PMC3097987  PMID: 21068186
circuitry; fast-spiking interneuron; pyramidal cell; synaptic integration
15.  Temporal Coding by Cochlear Nucleus Bushy Cells in DBA/2J Mice with Early Onset Hearing Loss 
The bushy cells of the anterior ventral cochlear nucleus (AVCN) preserve or improve the temporal coding of sound information arriving from auditory nerve fibers (ANF). The critical cellular mechanisms entailed in this process include the specialized nerve terminals, the endbulbs of Held, and the membrane conductance configuration of the bushy cell. In one strain of mice (DBA/2J), an early-onset hearing loss can cause a reduction in neurotransmitter release probability, and a smaller and slower spontaneous miniature excitatory postsynaptic current (EPSC) at the endbulb synapse. In the present study, by using a brain slice preparation, we tested the hypothesis that these changes in synaptic transmission would degrade the transmission of timing information from the ANF to the AVCN bushy neuron. We show that the electrical excitability of bushy cells in hearing-impaired old DBA mice was different from that in young, normal-hearing DBA mice. We found an increase in the action potential (AP) firing threshold with current injection; a larger AP afterhyperpolarization; and an increase in the number of spikes produced by large depolarizing currents. We also tested the temporal precision of bushy cell responses to high-frequency stimulation of the ANF. The standard deviation of spikes (spike jitter) produced by ANF-evoked excitatory postsynaptic potentials (EPSPs) was largely unaffected in old DBA mice. However, spike entrainment during a 100-Hz volley of EPSPs was significantly reduced. This was not a limitation of the ability of bushy cells to fire APs at this stimulus frequency, because entrainment to trains of current pulses was unaffected. Moreover, the decrease in entrainment is not attributable to increased synaptic depression. Surprisingly, the spike latency was 0.46 ms shorter in old DBA mice, and was apparently attributable to a faster conduction velocity, since the evoked excitatory postsynaptic current (EPSC) latency was shorter in old DBA mice as well. We also tested the contribution of the low-voltage-activated K+ conductance (gKLV) on the spike latency by using dynamic clamp. Alteration in gKLV had little effect on the spike latency. To test whether these changes in DBA mice were simply a result of continued postnatal maturation, we repeated the experiments in CBA mice, a strain that shows normal hearing thresholds through this age range. CBA mice exhibited no reduction in entrainment or increased spike jitter with age. We conclude that the ability of AVCN bushy neurons to reliably follow ANF EPSPs is compromised in a frequency-dependent fashion in hearing-impaired mice. This effect can be best explained by an increase in spike threshold.
doi:10.1007/s10162-006-0052-9
PMCID: PMC1785302  PMID: 17066341
auditory; spike reliability; entrainment; deafness; endbulb of Held
16.  Temporal Coding by Cochlear Nucleus Bushy Cells in DBA/2J Mice with Early Onset Hearing Loss 
The bushy cells of the anterior ventral cochlear nucleus (AVCN) preserve or improve the temporal coding of sound information arriving from auditory nerve fibers (ANF). The critical cellular mechanisms entailed in this process include the specialized nerve terminals, the endbulbs of Held, and the membrane conductance configuration of the bushy cell. In one strain of mice (DBA/2J), an early-onset hearing loss can cause a reduction in neurotransmitter release probability, and a smaller and slower spontaneous miniature excitatory postsynaptic current (EPSC) at the endbulb synapse. In the present study, by using a brain slice preparation, we tested the hypothesis that these changes in synaptic transmission would degrade the transmission of timing information from the ANF to the AVCN bushy neuron. We show that the electrical excitability of bushy cells in hearing-impaired old DBA mice was different from that in young, normal-hearing DBA mice. We found an increase in the action potential (AP) firing threshold with current injection; a larger AP afterhyperpolarization; and an increase in the number of spikes produced by large depolarizing currents. We also tested the temporal precision of bushy cell responses to high-frequency stimulation of the ANF. The standard deviation of spikes (spike jitter) produced by ANF-evoked excitatory postsynaptic potentials (EPSPs) was largely unaffected in old DBA mice. However, spike entrainment during a 100-Hz volley of EPSPs was significantly reduced. This was not a limitation of the ability of bushy cells to fire APs at this stimulus frequency, because entrainment to trains of current pulses was unaffected. Moreover, the decrease in entrainment is not attributable to increased synaptic depression. Surprisingly, the spike latency was 0.46 ms shorter in old DBA mice, and was apparently attributable to a faster conduction velocity, since the evoked excitatory postsynaptic current (EPSC) latency was shorter in old DBA mice as well. We also tested the contribution of the low-voltage-activated K+ conductance (gKLV) on the spike latency by using dynamic clamp. Alteration in gKLV had little effect on the spike latency. To test whether these changes in DBA mice were simply a result of continued postnatal maturation, we repeated the experiments in CBA mice, a strain that shows normal hearing thresholds through this age range. CBA mice exhibited no reduction in entrainment or increased spike jitter with age. We conclude that the ability of AVCN bushy neurons to reliably follow ANF EPSPs is compromised in a frequency-dependent fashion in hearing-impaired mice. This effect can be best explained by an increase in spike threshold.
doi:10.1007/s10162-006-0052-9
PMCID: PMC1785302  PMID: 17066341
auditory; spike reliability; entrainment; deafness; endbulb of Held
17.  Synaptic Mechanisms Underlying Functional Dichotomy between Intrinsic-Bursting and Regular-Spiking Neurons in Auditory Cortical Layer 5 
Corticofugal projections from the primary auditory cortex (A1) have been shown to play a role in modulating subcortical processing. However, functional properties of the corticofugal neurons and their synaptic circuitry mechanisms remain unclear. In this study, we performed in vivo whole-cell recordings from layer 5 (L5) pyramidal neurons in the rat A1 and found two distinct neuronal classes according to their functional properties. Intrinsic-bursting (IB) neurons, the L5 corticofugal neurons, exhibited early and rather unselective spike responses to a wide range of frequencies. The exceptionally broad spectral tuning of IB neurons was attributable to their broad excitatory inputs with long temporal durations and inhibitory inputs being more narrowly tuned than excitatory inputs. This uncommon pattern of excitatory–inhibitory interplay was attributed initially to a broad thalamocortical convergence onto IB neurons, which also receive temporally prolonged intracortical excitatory input as well as feedforward inhibitory input at least partially from more narrowly tuned fast-spiking inhibitory neurons. In contrast, regular-spiking neurons, which are mainly corticocortical, exhibited sharp frequency tuning similar to L4 pyramidal cells, underlying which are well-matched purely intracortical excitation and inhibition. The functional dichotomy among L5 pyramidal neurons suggests two distinct processing streams. The spectrally and temporally broad synaptic integration in IB neurons may ensure robust feedback signals to facilitate subcortical function and plasticity in a general manner.
doi:10.1523/JNEUROSCI.4810-12.2013
PMCID: PMC3714095  PMID: 23516297
18.  Intrinsic modulators of auditory thalamocortical transmission 
Hearing Research  2012;287(1-2):43-50.
Neurons in layer 4 of the primary auditory cortex receive convergent glutamatergic inputs from thalamic and cortical projections that activate different groups of postsynaptic glutamate receptors. Of particular interest in layer 4 neurons are the Group II metabotropic glutamate receptors (mGluRs), which hyperpolarize neurons postsynaptically via the downstream opening of GIRK channels. This pronounced effect on membrane conductance could influence the neuronal processing of synaptic inputs, such as those from the thalamus, essentially modulating information flow through the thalamocortical pathway. To examine how Group II mGluRs affect thalamocortical transmission, we used an in vitro slice preparation of the auditory thalamocortical pathways in the mouse to examine synaptic transmission under conditions where Group II mGluRs were activated. We found that both pre- and post-synaptic Group II mGluRs are involved in the attenuation of thalamocortical EPSP/Cs. Thus, thalamocortical synaptic transmission is suppressed via the presynaptic reduction of thalamocortical neurotransmitter release and the postsynaptic inhibition of the layer 4 thalamorecipient neurons. This could enable the thalamocortical pathway to autoregulate transmission, via either a gating or gain control mechanism, or both.
doi:10.1016/j.heares.2012.04.001
PMCID: PMC3383630  PMID: 22726616
19.  Histopathology of Nonsyndromic Autosomal Dominant Midfrequency Sensorineural Hearing Loss 
Background
Autosomal dominant, nonsyndromic, midfrequency sensorineural hearing loss (SNHL) is a well-known clinical entity. There are no reported histopathologic studies of temporal bones from individuals with such a hearing loss.
Objectives
To describe the otopathology in 2 affected individuals from 2 different kindreds with nonsyndromic, dominant, midfrequency SNHL.
Material and Methods
Both subjects belonged to multigenerational families with nonsyndromic, autosomal dominant SNHL showing a cookie-bite pattern. Temporal bones were removed at autopsy and studied by light microscopy. Cytocochleograms were constructed for hair cells, stria vascularis, and cochlear neuronal cells.
Results
Subject 1 (a 77-yr-old man) from Kindred A was diagnosed in early childhood with an SNHL that was progressive, reaching profound levels by adulthood. Both cochleae showed complete loss of inner and outer hair cells, moderate to severe diffuse atrophy of the stria vascularis, and severe loss of cochlear neurons, including the peripheral dendrites. The hearing loss in Subject 2 (an 82-yr-old man from Kindred B) began in late childhood, was slowly progressive, and involved the higher frequencies later in life. Histopathology showed loss of outer and inner hair cells in the basal turn of the cochlea, moderate to severe loss of stria vascularis, but relative preservation of peripheral dendrites and cochlear neurons.
Conclusion
The main histopathologic abnormalities were loss of hair cells, stria vascularis, and cochlear neurons in 1 case and loss of hair cells and stria vascularis in the second case. Our results are consistent with the hypothesis that dysfunction and loss of hair cells may have been the primary histopathologic correlate for the midfrequency hearing losses in these 2 subjects.
doi:10.1097/MAO.0b013e3181778245
PMCID: PMC2587055  PMID: 18665028
Sensorineural hearing loss; Temporal bone histopathology; Genetic deafness
20.  Residual Inhibition Functions Overlap Tinnitus Spectra and the Region of Auditory Threshold Shift 
Animals exposed to noise trauma show augmented synchronous neural activity in tonotopically reorganized primary auditory cortex consequent on hearing loss. Diminished intracortical inhibition in the reorganized region appears to enable synchronous network activity that develops when deafferented neurons begin to respond to input via their lateral connections. In humans with tinnitus accompanied by hearing loss, this process may generate a phantom sound that is perceived in accordance with the location of the affected neurons in the cortical place map. The neural synchrony hypothesis predicts that tinnitus spectra, and heretofore unmeasured “residual inhibition functions” that relate residual tinnitus suppression to the center frequency of masking sounds, should cover the region of hearing loss in the audiogram. We confirmed these predictions in two independent cohorts totaling 90 tinnitus subjects, using computer-based tools designed to assess the psychoacoustic properties of tinnitus. Tinnitus spectra and residual inhibition functions for depth and duration increased with the amount of threshold shift over the region of hearing impairment. Residual inhibition depth was shallower when the masking sounds that were used to induce residual inhibition showed decreased correspondence with the frequency spectrum and bandwidth of the tinnitus. These findings suggest that tinnitus and its suppression in residual inhibition depend on processes that span the region of hearing impairment and not on mechanisms that enhance cortical representations for sound frequencies at the audiometric edge. Hearing thresholds measured in age-matched control subjects without tinnitus implicated hearing loss as a factor in tinnitus, although elevated thresholds alone were not sufficient to cause tinnitus.
doi:10.1007/s10162-008-0136-9
PMCID: PMC2580805  PMID: 18712566
residual inhibition; tinnitus spectra; neural synchrony; cortical reorganization
21.  The Role of Inflammatory Mediators in the Pathogenesis of Otitis Media and Sequelae 
This review deals with the characteristics of various inflammatory mediators identified in the middle ear during otitis media and in cholesteatoma. The role of each inflammatory mediator in the pathogenesis of otitis media and cholesteatoma has been discussed. Further, the relation of each inflammatory mediator to the pathophysiology of the middle and inner ear along with its mechanisms of pathological change has been described. The mechanisms of hearing loss including sensorineural hearing loss (SNHL) as a sequela of otitis media are also discussed. The passage of inflammatory mediators through the round window membrane into the scala tympani is indicated. In an experimental animal model, an application of cytokines and lipopolysaccharide (LPS), a bacterial toxin, on the round window membrane induced sensorineural hearing loss as identified through auditory brainstem response threshold shifts. An increase in permeability of the blood-labyrinth barrier (BLB) was observed following application of these inflammatory mediators and LPS. The leakage of the blood components into the lateral wall of the cochlea through an increase in BLB permeability appears to be related to the sensorineural hearing loss by hindering K+ recycling through the lateral wall disrupting the ion homeostasis of the endolymph. Further studies on the roles of various inflammatory mediators and bacterial toxins in inducing the sensorineumral hearing loss in otitis media should be pursued.
doi:10.3342/ceo.2008.1.3.117
PMCID: PMC2671742  PMID: 19434244
Otitis media; Inflammatory mediators; Cytokines; Chemokines; Cholesteatoma; Sensorineural hearing loss
22.  Effects of sensorineural hearing loss on temporal coding of harmonic and inharmonic tone complexes in the auditory nerve 
Listeners with sensorineural hearing loss (SNHL) often show poorer thresholds for fundamental-frequency (F0) discrimination, and poorer discrimination between harmonic and frequency-shifted (inharmonic) complex tones, than normal-hearing (NH) listeners—especially when these tones contain resolved or partially resolved components. It has been suggested that these perceptual deficits reflect reduced access to temporal-fine-structure (TFS) information, and could be due to degraded phase-locking in the auditory nerve (AN) with SNHL. In the present study, TFS and temporal-envelope (ENV) cues in single AN-fiber responses to bandpass-filtered harmonic and inharmonic complex tones were measured in chinchillas with either normal hearing or noise-induced SNHL. The stimuli were comparable to those used in recent psychophysical studies of F0 and harmonic/inharmonic discrimination. As in those studies, the rank of the center component was manipulated to produce different resolvability conditions, different phase relationships (cosine and random phase) were tested, and background noise was present. Neural TFS and ENV cues were quantified using cross-correlation coefficients computed using shuffled cross-correlograms between neural responses to REF (harmonic) and TEST (F0- or frequency-shifted) stimuli. In animals with SNHL, AN-fiber tuning curves showed elevated thresholds, broadened tuning, best-frequency shifts, and downward shifts in the dominant TFS response component; however, no significant degradation in the ability of AN fibers to encode TFS or ENV cues was found. Consistent with optimal-observer analyses, the results indicate that TFS and ENV cues depended only on the relevant frequency shift in Hz and thus were not degraded because phase-locking remained intact. These results suggest that perceptual “TFS-processing” deficits do not simply reflect degraded phase-locking at the level of the AN. To the extent that performance in F0 and harmonic/inharmonic discrimination tasks depend on TFS cues, it is likely through a more complicated (sub-optimal) decoding mechanism, which may involve “spatiotemporal” (place-time) neural representations.
doi:10.1007/978-1-4614-1590-9_13
PMCID: PMC3757517  PMID: 23716215
auditory nerve; temporal fine structure; temporal envelope; noise-induced hearing loss
23.  Synaptic Input Correlations Leading to Membrane Potential Decorrelation of Spontaneous Activity in Cortex 
The Journal of Neuroscience  2013;33(38):15075-15085.
Correlations in the spiking activity of neurons have been found in many regions of the cortex under multiple experimental conditions and are postulated to have important consequences for neural population coding. While there is a large body of extracellular data reporting correlations of various strengths, the subthreshold events underlying the origin and magnitude of signal-independent correlations (called noise or spike count correlations) are unknown. Here we investigate, using intracellular recordings, how synaptic input correlations from shared presynaptic neurons translate into membrane potential and spike-output correlations. Using a pharmacologically activated thalamocortical slice preparation, we perform simultaneous recordings from pairs of layer IV neurons in the auditory cortex of mice and measure synaptic potentials/currents, membrane potentials, and spiking outputs. We calculate cross-correlations between excitatory and inhibitory inputs to investigate correlations emerging from the network. We furthermore evaluate membrane potential correlations near resting potential to study how excitation and inhibition combine and affect spike-output correlations. We demonstrate directly that excitation is correlated with inhibition thereby partially canceling each other and resulting in weak membrane potential and spiking correlations between neurons. Our data suggest that cortical networks are set up to partially cancel correlations emerging from the connections between neurons. This active decorrelation is achieved because excitation and inhibition closely track each other. Our results suggest that the numerous shared presynaptic inputs do not automatically lead to increased spiking correlations.
doi:10.1523/JNEUROSCI.0347-13.2013
PMCID: PMC3776060  PMID: 24048838
24.  Formal auditory training in adult hearing aid users 
Clinics  2010;65(2):165-174.
INTRODUCTION
Individuals with sensorineural hearing loss are often able to regain some lost auditory function with the help of hearing aids. However, hearing aids are not able to overcome auditory distortions such as impaired frequency resolution and speech understanding in noisy environments. The coexistence of peripheral hearing loss and a central auditory deficit may contribute to patient dissatisfaction with amplification, even when audiological tests indicate nearly normal hearing thresholds.
OBJECTIVE
This study was designed to validate the effects of a formal auditory training program in adult hearing aid users with mild to moderate sensorineural hearing loss.
METHODS
Fourteen bilateral hearing aid users were divided into two groups: seven who received auditory training and seven who did not. The training program was designed to improve auditory closure, figure-to-ground for verbal and nonverbal sounds and temporal processing (frequency and duration of sounds). Pre- and post-training evaluations included measuring electrophysiological and behavioral auditory processing and administration of the Abbreviated Profile of Hearing Aid Benefit (APHAB) self-report scale.
RESULTS
The post-training evaluation of the experimental group demonstrated a statistically significant reduction in P3 latency, improved performance in some of the behavioral auditory processing tests and higher hearing aid benefit in noisy situations (p-value < 0,05). No changes were noted for the control group (p-value <0,05).
CONCLUSION
The results demonstrated that auditory training in adult hearing aid users can lead to a reduction in P3 latency, improvements in sound localization, memory for nonverbal sounds in sequence, auditory closure, figure-to-ground for verbal sounds and greater benefits in reverberant and noisy environments.
doi:10.1590/S1807-59322010000200008
PMCID: PMC2827703  PMID: 20186300
Hearing loss; Rehabilitation; Auditory Evoked Potentials; Neuronal Plasticity
25.  Neuromagnetic Indicators of Tinnitus and Tinnitus Masking in Patients with and without Hearing Loss 
Tinnitus is an auditory phenomenon characterised by the perception of a sound in the absence of an external auditory stimulus. Chronic subjective tinnitus is almost certainly maintained via central mechanisms, and this is consistent with observed measures of altered spontaneous brain activity. A number of putative central auditory mechanisms for tinnitus have been proposed. The influential thalamocortical dysrhythmia model suggests that tinnitus can be attributed to the disruption of coherent oscillatory activity between thalamus and cortex following hearing loss. However, the extent to which this disruption specifically contributes to tinnitus or is simply a consequence of the hearing loss is unclear because the necessary matched controls have not been tested. Here, we rigorously test several predictions made by this model in four groups of participants (tinnitus with hearing loss, tinnitus with clinically normal hearing, no tinnitus with hearing loss and no tinnitus with clinically normal hearing). Magnetoencephalography was used to measure oscillatory brain activity within different frequency bands in a ‘resting’ state and during presentation of a masking noise. Results revealed that low-frequency activity in the delta band (1–4 Hz) was significantly higher in the ‘tinnitus with hearing loss’ group compared to the ‘no tinnitus with normal hearing’ group. A planned comparison indicated that this effect was unlikely to be driven by the hearing loss alone, but could possibly be a consequence of tinnitus and hearing loss. A further interpretative linkage to tinnitus was given by the result that the delta activity tended to reduce when tinnitus was masked. High-frequency activity in the gamma band (25–80 Hz) was not correlated with tinnitus (or hearing loss). The findings partly support the thalamocortical dysrhythmia model and suggest that slow-wave (delta band) activity may be a more reliable correlate of tinnitus than high-frequency activity.
doi:10.1007/s10162-012-0340-5
PMCID: PMC3441951  PMID: 22791191
thalamocortical dysrhythmia; tinnitus masking; magnetoencephalography; cortical oscillations

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