Tonotopic distribution and inferior colliculus projection pattern of inhibitory and excitatory cell types in the lateral superior olive of Mongolian gerbils
Sound localization critically relies on brainstem neurons that compare information from the two ears. The conventional role of the lateral superior olive (LSO) is extraction of intensity differences; however, it is increasingly clear that relative timing, especially of transients, is also an important function. Cellular diversity within the LSO that is not well understood may underlie its multiple roles. There are glycinergic inhibitory and glutamatergic excitatory principal neurons in the LSO, however, there is some disagreement regarding their relative distribution and projection pattern. Here we employ in situ hybridization to definitively identify transmitter types combined with retrograde labeling of projections to the inferior colliculus (IC) to address these questions. Excitatory LSO neurons were more numerous (76%) than inhibitory ones. A smaller proportion of inhibitory neurons were IC-projecting (45% vs. 64% for excitatory) suggesting that inhibitory LSO neurons may have more projections to other regions such the lateral lemniscus or more distributed IC projections. Inhibitory LSO neurons almost exclusively projected ipsilaterally making up a sizeable proportion (41%) of the transmitter type-labeled ipsilateral IC projection from LSO and exhibited a moderate low frequency bias (10% difference H-L). Two thirds of excitatory neurons projected contralaterally and had a slight high frequency bias (4%). One third of excitatory LSO neurons projected ipsilaterally to the IC and these cells were strongly biased toward the low frequency limb of the LSO (37%). This projection appears to be species specific in animals with good low frequency hearing suggesting that it may be a specialization for such ability.
Jeffrey G Mellott
Matasha Dhar
Amir Mafi
Nick Tokar
Bradley D Winters
J Comp Neurol
. 2022 Feb;530(2):506-517. doi: 10.1002/cne.25226. Epub 2021 Aug 11.
2022
English
Inhibitory NPY Neurons Provide a Large and Heterotopic Commissural Projection in the Inferior Colliculus
Located in the midbrain, the inferior colliculus (IC) plays an essential role in many auditory computations, including speech processing and sound localization. The right and left sides of the IC are interconnected by a dense fiber tract, the commissure of the IC (CoIC), that provides each IC with one of its largest sources of input (i.e., the contralateral IC). Despite its prominence, the CoIC remains poorly understood. Previous studies using anterograde and retrograde tract-tracing showed that IC commissural projections are predominately homotopic and tonotopic, targeting mirror-image locations in the same frequency region in the contralateral IC. However, it is unknown whether specific classes of neurons, particularly inhibitory neurons which constitute ~10%-40% of the commissural projection, follow this pattern. We, therefore, examined the commissural projections of Neuropeptide Y (NPY) neurons, the first molecularly identifiable class of GABAergic neurons in the IC. Using retrograde tracing with Retrobeads (RB) in NPY-hrGFP mice of both sexes, we found that NPY neurons comprise ~11% of the commissural projection. Moreover, focal injections of Retrobeads showed that NPY neurons in the central nucleus of the IC exhibit a more divergent and heterotopic commissural projection pattern than non-NPY neurons. Thus, commissural NPY neurons are positioned to provide lateral inhibition to the contralateral IC. Through this circuit, sounds that drive activity in limited regions on one side of the IC likely suppress activity across a broader region in the contralateral IC.
Justin D Anair
Marina A Silveira
Pooyan Mirjalili
Nichole L Beebe
Brett R Schofield
Michael T Roberts
Front Neural Circuits
. 2022 May 26;16:871924. doi: 10.3389/fncir.2022.871924. eCollection 2022.
2022
English
Tonotopic distribution and inferior colliculus projection pattern of inhibitory and excitatory cell types in the lateral superior olive of Mongolian gerbils.
Sound localization critically relies on brainstem neurons that compare information from the two ears. The conventional role of the lateral superior olive (LSO) is extraction of intensity differences; however, it is increasingly clear that relative timing, especially of transients, is also an important function. Cellular diversity within the LSO that is not well understood may underlie its multiple roles. There are glycinergic inhibitory and glutamatergic excitatory principal neurons in the LSO, however, there is some disagreement regarding their relative distribution and projection pattern. Here we employ in situ hybridization to definitively identify transmitter types combined with retrograde labeling of projections to the inferior colliculus (IC) to address these questions. Excitatory LSO neurons were more numerous (76%) than inhibitory ones. A smaller proportion of inhibitory neurons were IC-projecting (45% vs. 64% for excitatory) suggesting that inhibitory LSO neurons may have more projections to other regions such the lateral lemniscus or more distributed IC projections. Inhibitory LSO neurons almost exclusively projected ipsilaterally making up a sizeable proportion (41%) of the transmitter type-labeled ipsilateral IC projection from LSO and exhibited a moderate low frequency bias (10% difference H-L). Two thirds of excitatory neurons projected contralaterally and had a slight high frequency bias (4%). One third of excitatory LSO neurons projected ipsilaterally to the IC and these cells were strongly biased toward the low frequency limb of the LSO (37%). This projection appears to be species specific in animals with good low frequency hearing suggesting that it may be a specialization for such ability.
Mellott JG; Dhar M; Mafi A; Tokar N; Winters BD
The Journal of Comparative Neurology
2021
2021-08-11
© 2021 Wiley Periodicals LLC.
Journal Article
<table width="91" style="border-collapse:collapse;width:68pt;"><colgroup><col width="91" style="width:68pt;" /></colgroup><tbody><tr style="height:15pt;"><td width="91" height="20" class="xl18" style="width:68pt;height:15pt;"><a href="http://doi.org/10.1002/cne.25226">http://doi.org/10.1002/cne.25226</a></td>
</tr></tbody></table>
Tonotopic distribution and inferior colliculus projection pattern of inhibitory and excitatory cell types in the lateral superior olive of Mongolian gerbils.
auditory; GlyT2; inferior colliculus; lateral superior olive; tonotopy; vGlut2
Sound localization critically relies on brainstem neurons that compare information from the two ears. The conventional role of the lateral superior olive (LSO) is extraction of intensity differences; however, it is increasingly clear that relative timing, especially of transients, is also an important function. Cellular diversity within the LSO that is not well understood may underlie its multiple roles. There are glycinergic inhibitory and glutamatergic excitatory principal neurons in the LSO, however, there is some disagreement regarding their relative distribution and projection pattern. Here we employ in situ hybridization to definitively identify transmitter types combined with retrograde labeling of projections to the inferior colliculus (IC) to address these questions. Excitatory LSO neurons were more numerous (76%) than inhibitory ones. A smaller proportion of inhibitory neurons were IC-projecting (45% vs. 64% for excitatory) suggesting that inhibitory LSO neurons may have more projections to other regions such the lateral lemniscus or more distributed IC projections. Inhibitory LSO neurons almost exclusively projected ipsilaterally making up a sizeable proportion (41%) of the transmitter type-labeled ipsilateral IC projection from LSO and exhibited a moderate low frequency bias (10% difference H-L). Two thirds of excitatory neurons projected contralaterally and had a slight high frequency bias (4%). One third of excitatory LSO neurons projected ipsilaterally to the IC and these cells were strongly biased toward the low frequency limb of the LSO (37%). This projection appears to be species specific in animals with good low frequency hearing suggesting that this may be a specialization for such ability. This article is protected by copyright. All rights reserved. (© 2021 Wiley Periodicals, Inc.)
Mellott JG; Dhar M; Mafi A; Tokar N; Winters BD
The Journal of Comparative Neurology
2021
2021-08-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1002/cne.25226" target="_blank" rel="noreferrer noopener">10.1002/cne.25226</a>
Group II metabotropic glutamate receptors modulate sound evoked and spontaneous activity in the mouse inferior colliculus.
auditory; GABAergic; LY354740; mGluR2/3; neuromodulation; non-GABAergic
Little is known about the functions of group II metabotropic glutamate receptors (mGluRs2/3) in the inferior colliculus (IC)-a midbrain structure that is a major integration region of the central auditory system. We investigated how these receptors modulate sound-evoked and spontaneous firing in the mouse IC in vivo We first performed immunostaining and tested hearing thresholds to validate VGAT-ChR2 transgenic mice on a mixed CBA/CaJ x C57BL/6J genetic background. Transgenic animals allowed for optogenetic cell type identification. Extracellular single neuron recordings were obtained before and after pharmacological mGluR2/3 activation. We observed increased sound-evoked firing-as assessed by the rate-level functions-in a subset of both GABAergic and non-GABAergic IC neurons following mGluR2/3 pharmacological activation. These neurons also displayed elevated spontaneous excitability and were distributed throughout the IC area tested, suggesting a widespread mGluR2/3 distribution in the mouse IC.Significance Glutamate is the primary excitatory neurotransmitter in the brain. It binds to both ionotropic and metabotropic glutamate receptors. Fast ionotropic receptors generate rapid synaptic transmission, whereas slower metabotropic glutamate receptors (mGluRs) modulate this synaptic transmission. Here, we discovered that activation of group II mGluRs enhances sound-evoked and spontaneous neuronal firing in the inferior colliculus-the hub of the central auditory system. We used transgenic mice which allowed for identification of excitatory and inhibitory neurons and found that both these cell types are modulated by group II mGluRs. Our results provide better understanding of mGluR modulatory roles, which is crucial in opening avenues for using mGluR-targeting drugs to treat hearing disorders.
Kristaponyte I; Beebe NL; Young JW; Shanbhag SJ; Schofield BR; Galazyuk AV
eNeuro
2020
2020-12-14
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1523/ENEURO.0328-20.2020" target="_blank" rel="noreferrer noopener">10.1523/ENEURO.0328-20.2020</a>
Mechanisms underlying enhancement of spontaneous glutamate release by group I mGluRs at a central auditory synapse
SYNAPTIC vesicles; auditory; mGluR; MNTB; EPSC; spontaneous glutamate release; voltage-gated sodium channel; DIRECTIONAL hearing; GLUTAMIC acid; MEMBRANE potential; SYNAPSES
One emerging concept in neuroscience states that synaptic vesicles and the molecular machinery underlying spontaneous transmitter release are different from those underlying action potential-driven synchronized transmitter release. Differential neuromodulation of these two distinct release modes by metabotropic glutamate receptors (mGluRs) constitutes critical supporting evidence. However, the mechanisms underlying such a differential modulation are not understood. Here, we investigated the mechanisms of the modulation by group I mGluRs (mGluR I) on spontaneous glutamate release in the medial nucleus of the trapezoid body (MNTB), an auditory brainstem nucleus critically involved in sound localization. Whole-cell patch recordings from brainstem slices of mice of both sexes were performed. Activation of mGluR I by 3,5-DHPG (200 μM) produced an inward current at -60 mV, and increased spontaneous glutamate release in MNTB neurons. Pharmacological evidence indicated involvement of both mGluR1 and mGluR5, which was further supported for mGluR5 by immunolabeling results. The modulation was eliminated by blocking NaV channels (tetrodotoxin, 1 μM), persistent Na+ current (INaP) (Riluzole, 10 μM), or CaV channels (CdCl2, 100 µM). Presynaptic calyx recordings revealed that 3,5-DHPG shifted the activation of INaP to more hyperpolarized voltages and increased INaP at resting membrane potential. Our data indicate that mGluR I enhance spontaneous glutamate release via regulation of INaP and subsequent Ca2+-dependent processes under rest condition. [ABSTRACT FROM AUTHOR]
Kang P;Wang X;Yuan W;Dainan L;Hai H;Yong L
Journal Of Neuroscience
2020
2020-09-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
Cholinergic projections from the pedunculopontine tegmental nucleus contact excitatory and inhibitory neurons in the inferior colliculus
rat; acetylcholine; auditory; brain-stem; plasticity; cells; modulation; neuromodulation; pathways; midbrain; hearing; arousal; acetylcholine-receptors; auditory input; choline acetyltransferase; gabaergic neurons; viral tracing; volume transmission; viral tracing
The inferior colliculus processes nearly all ascending auditory information. Most collicular cells respond to sound, and for a majority of these cells, the responses can be modulated by acetylcholine (ACh). The cholinergic effects are varied and, for the most part, the underlying mechanisms are unknown. The major source of cholinergic input to the inferior colliculus is the pedunculopontine tegmental nucleus (PPT), part of the pontomesencephalic tegmentum known for projections to the thalamus and roles in arousal and the sleep-wake cycle. Characterization of PPT inputs to the inferior colliculus has been complicated by the mixed neurotransmitter population within the PPT. Using selective viral-tract tracing techniques in a ChAT-Cre Long Evans rat, the present study characterizes the distribution and targets of cholinergic projections from PPT to the inferior colliculus. Following the deposit of viral vector in one PPT, cholinergic axons studded with boutons were present bilaterally in the inferior colliculus, with the greater density of axons and boutons ipsilateral to the injection site. On both sides, cholinergic axons were present throughout the inferior colliculus, distributing boutons to the central nucleus, lateral cortex, and dorsal cortex. In each inferior colliculus (IC) subdivision, the cholinergic PPT axons appear to contact both GABAergic and glutamatergic neurons. These findings suggest cholinergic projections from the PPT have a widespread influence over the IC, likely affecting many aspects of midbrain auditory processing. Moreover, the effects are likely to be mediated by direct cholinergic actions on both excitatory and inhibitory circuits in the inferior colliculus.
Noftz WA; Beebe NL; Mellott JG; Schofield BR
Frontiers in Neural Circuits
2020
2020-07-16
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.3389/fncir.2020.00043" target="_blank" rel="noreferrer noopener">10.3389/fncir.2020.00043</a>
Knockdown Of Leptin A Expression Dramatically Alters Zebrafish Development
atlantic salmon; Auditory; bhlh genes; bone; carp cyprinus-carpio; cell fate specification; central-nervous-system; cloning; danio-rerio; differentiation; Endocrinology & Metabolism; gene; metabolism; n-cadherin; receptor; sensory ganglia; Visual; visual-system
Using morpholino antisense oligonucleotide (MO) technology, we blocked leptin A or leptin receptor expression in embryonic zebrafish, and analyzed consequences of leptin A knock-down on fish development. Embryos injected with leptin A or leptin receptor MOs (leptin A or leptin receptor morphants) had smaller bodies and eyes, undeveloped inner ear, enlarged pericardial cavity, curved body and/or tail and larger yolk compared to control embryos of the same stages. The defects persisted in 6-9 days old larvae. We found that blocking leptin A function had little effect on the development of early brain (1 day old), but differentiation of both the morphant dorsal brain and retinal cells was severely disrupted in older (2 days old) embryos. Despite the enlarged pericardial cavity, differentiation of cardiac cells appeared to be similar to control embryos. Formation of the morphants' inner ear is also severely disrupted, which corroborates existing reports of leptin receptor expression in inner ear of both zebrafish and mammals. Co-injection of leptin A MO and recombinant leptin results in partial rescue of the wild-type phenotype. Our results suggest that leptin A plays distinct roles in zebrafish development. (c) 2012 Elsevier Inc. All rights reserved.
Liu Q; Dalman M; Chen Y; Akhter M; Brahmandam S; Patel Y; Lowe J; Thakkar M; Gregory A V; Phelps D; Riley C; Londraville R L
General and Comparative Endocrinology
2012
2012-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.ygcen.2012.07.011" target="_blank" rel="noreferrer noopener">10.1016/j.ygcen.2012.07.011</a>
A novel class of inferior colliculus principal neurons labeled in vasoactive intestinal peptide-Cre mice
auditory; Inferior colliculus; mouse; neural circuits; neuron types; neuroscience; optogenetics; VIP
Located in the midbrain, the inferior colliculus (IC) is the hub of the central auditory system. Although the IC plays important roles in speech processing, sound localization, and other auditory computations, the organization of the IC microcircuitry remains largely unknown. Using a multifaceted approach in mice, we have identified vasoactive intestinal peptide (VIP) neurons as a novel class of IC principal neurons. VIP neurons are glutamatergic stellate cells with sustained firing patterns. Their extensive axons project to long-range targets including the auditory thalamus, auditory brainstem, superior colliculus, and periaqueductal gray. Using optogenetic circuit mapping, we found that VIP neurons integrate input from the contralateral IC and the dorsal cochlear nucleus. The dorsal cochlear nucleus also drove feedforward inhibition to VIP neurons, indicating that inhibitory circuits within the IC shape the temporal integration of ascending inputs. Thus, VIP neurons are well-positioned to influence auditory computations in a number of brain regions.
Goyer David; Silveira Marina A; George Alexander P; Beebe Nichole L; Edelbrock Ryan M; Malinski Peter T; Schofield Brett R; Roberts Michael T
eLife
2019
2019-04
<a href="http://doi.org/10.7554/eLife.43770" target="_blank" rel="noreferrer noopener">10.7554/eLife.43770</a>
Effects of artifact rejection and Bayesian weighting on the auditory brainstem response during quiet and active behavioral conditions.
Adult; Female; Male; College; Analysis of Variance; Students; Artifacts; Evoked Potentials; Human; Descriptive Statistics; Repeated Measures; Post Hoc Analysis; Comparative Studies; T-Tests; Auditory; Brainstem; Noise – Prevention and Control
PURPOSE: To evaluate the effects of 2 noise reduction techniques on the auditory brainstem response (ABR). METHOD: ABRs of 20 normal hearing adults were recorded during quiet and active behavioral conditions using 2 stimulus intensity levels. Wave V amplitudes and residual noise root-mean-square values were measured following the offline application of artifact rejection and Bayesian weighting. Repeated measures analysis of variance and Bonferroni adjusted pairwise t tests were utilized to evaluate significant main effects and interactions between the 2 noise reduction techniques. RESULTS: ABRs recorded during the quiet behavioral condition resulted in minimal differences in wave V amplitude and noise reduction improvement, suggesting that the 2 techniques were equally effective under ideal recording situations. During the active behavioral condition, however, the techniques differed significantly in the ability to preserve the evoked potential and reduce noise. Consequently, strict artifact rejection levels resulted in an inherent underestimation of wave V amplitudes when compared with the Bayesian approach. CONCLUSION: Artifact rejection had a detrimental effect on waveform morphology of the ABR. This could lead to difficulty in ABR interpretation when patients are active and ultimately result in diagnostic errors.
Sanchez JT; Gans D
American Journal of Audiology
2006
2006-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1044/1059-0889(2006/019)" target="_blank" rel="noreferrer noopener">10.1044/1059-0889(2006/019)</a>
Simultaneous presentation of facial nerve neuroma and otosclerosis.
Adult; Humans; Male; Magnetic Resonance Imaging; Functional Laterality; Evoked Potentials; Audiometry; Cranial Nerve Neoplasms/diagnosis/*pathology/surgery; Deafness/diagnosis/etiology; Facial Nerve/*pathology/surgery; Neuroma/diagnosis/*pathology/surgery; Otosclerosis/*complications/diagnosis/*physiopathology; Tinnitus/etiology; Auditory; Brain Stem
Otosclerosis often occurs as a unilateral mixed or conductive hearing loss. In the absence of retrocochlear findings, otologists usually do not pursue further diagnostic testing. A patient who presented to the Warren Otologic Group with a unilateral mixed hearing loss is discussed. He was followed for 1 year with the intent of scheduling a stapedectomy. Two weeks prior to the surgical date, the patient developed a sudden hearing loss and was admitted to the hospital for treatment. Magnetic resonance imaging demonstrated a tiny, enhancing mass in the lateral internal auditory canal, measuring 7 mm in diameter. At surgery, the tumor was found to originate at the union of the nervus intermedius and the facial nerve. The simultaneous occurrence of facial nerve neuroma and otosclerosis is discussed, with emphasis on a thorough evaluation of all unilateral mixed hearing losses, including those attributable to otosclerosis.
Rizer F M; Guthikonda M; Lippy W H; Schuring A G
The American journal of otology
1994
1994-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Ultrastructural characterization of GABAergic and excitatory synapses in the inferior colliculus.
auditory; inhibition; circuit; gamma-aminobutyric acid; ultrastructure
In the inferior colliculus (IC) cells integrate inhibitory input from the brainstem and excitatory input from both the brainstem and auditory cortex. In order to understand how these inputs are integrated by IC cells identification of their synaptic arrangements is required. We used electron microscopy to characterize GABAergic synapses in the dorsal cortex, central nucleus, and lateral cortex of the IC (ICd, ICc, and IClc) of guinea pigs. Throughout the IC, GABAergic synapses are characterized by pleomorphic vesicles and symmetric junctions. Comparisons of GABAergic synapses with excitatory synapses revealed differences (in some IC subdivisions) between the distributions of these synapse types onto IC cells. For excitatory cells in the IClc and ICd GABAergic synapses are biased toward the somas and large dendrites, whereas the excitatory boutons are biased toward spines and small dendrites. This arrangement could allow for strong inhibitory gating of excitatory inputs. Such differences in synaptic distributions were not observed in the ICc, where the two classes of bouton have similar distributions along the dendrites of excitatory cells. Interactions between excitatory and GABAergic inputs on the dendrites of excitatory ICc cells may be more restricted (i.e., reflecting local dendritic processing) than in the other IC subdivisions. Comparisons across IC subdivisions revealed evidence for two classes of GABAergic boutons, a small GABAergic (SG) class that is present throughout the IC and a large GABAergic (LG) class that is almost completely restricted to the ICc. In the ICc, LG, and SG boutons differ in their targets. SG boutons contact excitatory dendritic shafts most often, but also contact excitatory spines and somas (excitatory and GABAergic). LG synapses make comparatively fewer contacts on excitatory shafts, and make comparatively more contacts on excitatory spines and on somas (excitatory and GABAergic). LG boutons likely have a lemniscal origin.
Nakamoto Kyle T; Mellott Jeffrey G; Killius Jeanette; Storey-Workley Megan E; Sowick Colleen S; Schofield Brett R
Frontiers in neuroanatomy
2014
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3389/fnana.2014.00108" target="_blank" rel="noreferrer noopener">10.3389/fnana.2014.00108</a>
Perineuronal nets and GABAergic cells in the inferior colliculus of guinea pigs.
GABA; auditory; plasticity; extracellular matrix; inhibition; midbrain
Perineuronal nets (PNs) are aggregates of extracellular matrix that have been associated with neuronal plasticity, critical periods, fast-spiking cells and protection from oxidative stress. Although PNs have been reported in the auditory system in several species, there is disagreement about the distribution of PNs within the inferior colliculus (IC), an important auditory hub in the midbrain. Furthermore, PNs in many brain areas are preferentially associated with GABAergic cells, but whether such an association exists in the IC has not been addressed. We used Wisteria floribunda agglutinin staining and immunohistochemistry in guinea pigs to examine PNs within the IC. PNs are present in all IC subdivisions and are densest in the central portions of the IC. Throughout the IC, PNs are preferentially associated with GABAergic cells. Not all GABAergic cells are surrounded by PNs, so the presence of PNs can be used to subdivide IC GABAergic cells into "netted" and "non-netted" categories. Finally, PNs in the IC, like those in other brain areas, display molecular heterogeneity that suggests a multitude of functions.
Foster Nichole L; Mellott Jeffrey G; Schofield Brett R
Frontiers in neuroanatomy
2014
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3389/fnana.2013.00053" target="_blank" rel="noreferrer noopener">10.3389/fnana.2013.00053</a>
Cholinergic and non-cholinergic projections from the pedunculopontine and laterodorsal tegmental nuclei to the medial geniculate body in Guinea pigs.
GABA; auditory; thalamus; sleep; acetylcholine; arousal; glutamate
The midbrain tegmentum is the source of cholinergic innervation of the thalamus and has been associated with arousal and control of the sleep/wake cycle. In general, the innervation arises bilaterally from the pedunculopontine tegmental nucleus (PPT) and the laterodorsal tegmental nucleus (LDT). While this pattern has been observed for many thalamic nuclei, a projection from the LDT to the medial geniculate body (MG) has been questioned in some species. We combined retrograde tracing with immunohistochemistry for choline acetyltransferase (ChAT) to identify cholinergic projections from the brainstem to the MG in guinea pigs. Double-labeled cells (retrograde and immunoreactive for ChAT) were found in both the PPT (74%) and the LDT (26%). In both nuclei, double-labeled cells were more numerous on the ipsilateral side. About half of the retrogradely labeled cells were immunonegative, suggesting they are non-cholinergic. The distribution of these immunonegative cells was similar to that of the immunopositive ones: more were in the PPT than the LDT and more were on the ipsilateral than the contralateral side. The results indicate that both the PPT and the LDT project to the MG, and suggest that both cholinergic and non-cholinergic cells contribute substantially to these projections.
Motts Susan D; Schofield Brett R
Frontiers in neuroanatomy
2010
2010
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<a href="http://doi.org/10.3389/fnana.2010.00137" target="_blank" rel="noreferrer noopener">10.3389/fnana.2010.00137</a>
Brief Stimulus Exposure Fully Remediates Temporal Processing Deficits Induced by Early Hearing Loss.
Female; Male; Animals; Age Factors; *auditory cortex; *development; *gap detection; *hearing loss; *remediation; *temporal coding; Acoustic Stimulation/*methods; Auditory Cortex/*physiology/*physiopathology; Auditory Perception/*physiology; Gerbillinae; Hearing Loss/*physiopathology; Brain Stem/*physiology; Evoked Potentials; Auditory
In childhood, partial hearing loss can produce prolonged deficits in speech perception and temporal processing. However, early therapeutic interventions targeting temporal processing may improve later speech-related outcomes. Gap detection is a measure of auditory temporal resolution that relies on the auditory cortex (ACx), and early auditory deprivation alters intrinsic and synaptic properties in the ACx. Thus, early deprivation should induce deficits in gap detection, which should be reflected in ACx gap sensitivity. We tested whether earplugging-induced, early transient auditory deprivation in male and female Mongolian gerbils caused correlated deficits in behavioral and cortical gap detection, and whether these could be rescued by a novel therapeutic approach: brief exposure to gaps in background noise. Two weeks after earplug removal, animals that had been earplugged from hearing onset throughout auditory critical periods displayed impaired behavioral gap detection thresholds (GDTs), but this deficit was fully reversed by three 1 h sessions of exposure to gaps in noise. In parallel, after earplugging, cortical GDTs increased because fewer cells were sensitive to short gaps, and gap exposure normalized this pattern. Furthermore, in deprived animals, both first-spike latency and first-spike latency jitter increased, while spontaneous and evoked firing rates decreased, suggesting that deprivation causes a wider range of perceptual problems than measured here. These cortical changes all returned to control levels after gap exposure. Thus, brief stimulus exposure, perhaps in a salient context such as the unfamiliar placement into a testing apparatus, rescued impaired gap detection and may have potential as a remediation tool for general auditory processing deficits.SIGNIFICANCE STATEMENT Hearing loss in early childhood leads to impairments in auditory perception and language processing that can last well beyond the restoration of hearing sensitivity. Perceptual deficits can be improved by training, or by acoustic enrichment in animal models, but both approaches involve extended time and effort. Here, we used a novel remediation technique, brief periods of auditory stimulus exposure, to fully remediate cortical and perceptual deficits in gap detection induced by early transient hearing loss. This technique also improved multiple cortical response properties. Rescue by this efficient exposure regime may have potential as a therapeutic tool to remediate general auditory processing deficits in children with perceptual challenges arising from early hearing loss.
Green David B; Mattingly Michelle M; Ye Yi; Gay Jennifer D; Rosen Merri J
The Journal of neuroscience : the official journal of the Society for Neuroscience
2017
2017-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1523/JNEUROSCI.0916-17.2017" target="_blank" rel="noreferrer noopener">10.1523/JNEUROSCI.0916-17.2017</a>
Extracellular Molecular Markers and Soma Size of Inhibitory Neurons: Evidence for Four Subtypes of GABAergic Cells in the Inferior Colliculus.
Female; GABA; Male; Animals; auditory; Guinea Pigs; plasticity; Auditory Pathways/cytology/*physiology; Biomarkers; Cell Size; Extracellular Space/*physiology; gamma-Aminobutyric Acid/*physiology; Glutamate Decarboxylase/metabolism; Inferior Colliculi/cytology/*physiology; inhibition; Neuronal Plasticity/physiology; Neurons/*physiology/ultrastructure; perineuronal net; Vesicular Glutamate Transport Protein 2/metabolism; VGLUT2
UNLABELLED: Inhibition plays an important role in shaping responses to stimuli throughout the CNS, including in the inferior colliculus (IC), a major hub in both ascending and descending auditory pathways. Subdividing GABAergic cells has furthered the understanding of inhibition in many brain areas, most notably in the cerebral cortex. Here, we seek the same understanding of subcortical inhibitory cell types by combining staining for two types of extracellular markers–perineuronal nets (PNs) and perisomatic rings of terminals expressing vesicular glutamate transporter 2 (VGLUT2)–to subdivide IC GABAergic cells in adult guinea pigs. We found four distinct groups of GABAergic cells in the IC: (1) those with both a PN and a VGLUT2 ring; (2) those with only a PN; (3) those with only a VGLUT2 ring; and (4) those with neither marker. In addition, these four GABAergic subtypes differ in their soma size and distribution among IC subdivisions. Functionally, the presence or absence of VGLUT2 rings indicates differences in inputs, whereas the presence or absence of PNs indicates different potential for plasticity and temporal processing. We conclude that these markers distinguish four GABAergic subtypes that almost certainly serve different roles in the processing of auditory stimuli within the IC. SIGNIFICANCE STATEMENT: GABAergic inhibition plays a critical role throughout the brain. Identification of subclasses of GABAergic cells (up to 15 in the cerebral cortex) has furthered the understanding of GABAergic roles in circuit modulation. Inhibition is also prominent in the inferior colliculus, a subcortical hub in auditory pathways. Here, we use two extracellular markers to identify four distinct groups of GABAergic cells. Perineuronal nets and perisomatic rings of glutamatergic boutons are present in many subcortical areas and often are associated with inhibitory cells, but they have rarely been used to identify inhibitory subtypes. Our results further the understanding of inhibition in the inferior colliculus and suggest that these extracellular molecular markers may provide a key to distinguishing inhibitory subtypes in many subcortical areas.
Beebe Nichole L; Young Jesse W; Mellott Jeffrey G; Schofield Brett R
The Journal of neuroscience : the official journal of the Society for Neuroscience
2016
2016-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1523/JNEUROSCI.0217-16.2016" target="_blank" rel="noreferrer noopener">10.1523/JNEUROSCI.0217-16.2016</a>
Roles of inhibition in complex auditory responses in the inferior colliculus: inhibited combination-sensitive neurons.
Acoustic Stimulation; Action Potentials/drug effects/physiology; Afferent/drug effects/*physiology; Animals; Auditory; Auditory Pathways/drug effects/*physiology; Bicuculline/pharmacology; Brain Stem/drug effects/*physiology; Chiroptera; Electrophysiology; Evoked Potentials; GABA-A Receptor Antagonists; GABA-A/physiology; Glycine/antagonists & inhibitors/physiology; Inferior Colliculi/*physiology; Neural Inhibition/drug effects/*physiology; Neurons; Receptors; Strychnine/pharmacology
We studied the functional properties and underlying neural mechanisms associated with inhibitory combination-sensitive neurons in the mustached bat's inferior colliculus (IC). In these neurons, the excitatory response to best frequency tones was suppressed by lower frequency signals (usually in the range of 12-30 kHz) in a time-dependant manner. Of 143 inhibitory units, the majority (71%) were type I, in which low-frequency sounds evoked inhibition only. In the remainder, however, the low-frequency inhibitory signal also evoked excitation. Of these, excitation preceded the inhibition in type E/I units (16%), whereas in type I/E units (13%), excitation followed the inhibition. Type E/I and I/E units were distinct in the tuning and threshold sensitivity of low-frequency responses, whereas type I units overlapped the other types in these features. In 71 neurons, antagonists to receptors for glycine [strychnine (STRY)] or GABA [bicuculline (BIC)] were applied microiontophoretically. These antagonists failed to eliminate combination-sensitive inhibition in 92% (STRY), 93% (BIC), and 87% (BIC + STRY) of the type I units tested. However, inhibition was reduced in many neurons. Results were similar for type E/I and I/E inhibitory neurons. The results indicate that there are distinct populations of combination-sensitive inhibited neurons in the IC and that these populations are at least partly independent of glycine or GABAA receptors in the IC. We propose that these populations originate in different brain stem auditory nuclei, that they may be modified by interactions within the IC, and that they may perform different spectrotemporal analyses of vocal signals.
Nataraj Kiran; Wenstrup Jeffrey J
Journal of neurophysiology
2006
2006-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/jn.01148.2005" target="_blank" rel="noreferrer noopener">10.1152/jn.01148.2005</a>
Auditory responses in the cochlear nucleus of awake mustached bats: precursors to spectral integration in the auditory midbrain.
Acoustic Stimulation/methods; Action Potentials/*physiology; Animals; Auditory; Brain Mapping; Brain Stem/*physiology; Chiroptera/*physiology; Cochlear Nucleus/*physiology; Evoked Potentials; Mesencephalon/physiology; Nerve Net/*physiology; Pitch Perception/*physiology; Wakefulness/physiology
In the cochlear nucleus (CN) of awake mustached bats, single- and two-tone stimuli were used to examine how responses in major CN subdivisions contribute to spectrotemporal integrative features in the inferior colliculus (IC). Across CN subdivisions, the proportional representation of frequencies differed. A striking result was the substantial number of units tuned to frequencies \textless23 kHz. Across frequency bands, temporal response patterns, latency, and spontaneous discharge differed. For example, the 23- to 30-kHz representation, which comprises the fundamental of the sonar call, had an unusually high proportion of units with onset responses (39%) and low spontaneous rates (53%). Units tuned to 58-59 kHz, corresponding to the sharply tuned cochlear resonance, had slightly but significantly longer latencies than other bands. In units tuned to frequencies \textgreater30 kHz, 31% displayed a secondary excitatory peak, usually between 10 and 22 kHz. The secondary peak may originate in cochlear mechanisms for some units, but in others it may result from convergent input onto CN neurons. In 20% of units tested with two-tone stimuli, suppression of best frequency (BF) responses was tuned at least an octave below BF. These properties may underlie similar IC responses. However, other forms of spectral interaction present in IC were absent in CN: we found no facilitatory combination-sensitive interactions and very few combination-sensitive inhibitory interactions of the dominant IC type in which inhibition was tuned to 23-30 kHz. Such interactions arise above CN. Distinct forms of spectral integration thus originate at different levels of the ascending auditory pathway.
Marsh Robert A; Nataraj Kiran; Gans Donald; Portfors Christine V; Wenstrup Jeffrey J
Journal of neurophysiology
2006
2006-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/jn.00634.2005" target="_blank" rel="noreferrer noopener">10.1152/jn.00634.2005</a>
A function for binaural integration in auditory grouping and segregation in the inferior colliculus.
*Auditory Perception; Animals; Auditory; binaural integration; Evoked Potentials; Female; Guinea Pigs; harmonic complex; Inferior Colliculi/cytology/*physiology; inferior colliculus; Male; Neurons/physiology; pitch
Responses of neurons to binaural, harmonic complex stimuli in urethane-anesthetized guinea pig inferior colliculus (IC) are reported. To assess the binaural integration of harmonicity cues for sound segregation and grouping, responses were measured to harmonic complexes with different fundamental frequencies presented to each ear. Simultaneously gated harmonic stimuli with fundamental frequencies of 125 Hz and 145 Hz were presented to the left and right ears, respectively, and recordings made from 96 neurons with characteristic frequencies \textgreater2 kHz in the central nucleus of the IC. Of these units, 70 responded continuously throughout the stimulus and were excited by the stimulus at the contralateral ear. The stimulus at the ipsilateral ear excited (EE: 14%; 10/70), inhibited (EI: 33%; 23/70), or had no significant effect (EO: 53%; 37/70), defined by the effect on firing rate. The neurons phase locked to the temporal envelope at each ear to varying degrees depending on signal level. Many of the cells (predominantly EO) were dominated by the response to the contralateral stimulus. Another group (predominantly EI) synchronized to the contralateral stimulus and were suppressed by the ipsilateral stimulus in a phasic manner. A third group synchronized to the stimuli at both ears (predominantly EE). Finally, a group only responded when the waveform peaks from each ear coincided. We conclude that these groups of neurons represent different "streams" of information but exhibit modifications of the response rather than encoding a feature of the stimulus, like pitch.
Nakamoto Kyle T; Shackleton Trevor M; Magezi David A; Palmer Alan R
Journal of neurophysiology
2015
2015-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/jn.00472.2014" target="_blank" rel="noreferrer noopener">10.1152/jn.00472.2014</a>
Late maturation of backward masking in auditory cortex.
auditory; cortex; detection; development; masking
Speech perception relies on the accurate resolution of brief, successive sounds that change rapidly over time. Deficits in the perception of such sounds, indicated by a reduced ability to detect signals during auditory backward masking, strongly relate to language processing difficulties in children. Backward masking during normal development has a longer maturational trajectory than many other auditory percepts, implicating the involvement of central auditory neural mechanisms with protracted developmental time courses. Despite the importance of this percept, its neural correlates are not well described at any developmental stage. We therefore measured auditory cortical responses to masked signals in juvenile and adult Mongolian gerbils and quantified the detection ability of individual neurons and neural populations in a manner comparable with psychoacoustic measurements. Perceptually, auditory backward masking manifests as higher thresholds for detection of a short signal followed by a masker than for the same signal in silence. Cortical masking was driven by a combination of suppressed responses to the signal and a reduced dynamic range available for signal detection in the presence of the masker. Both coding elements contributed to greater masked threshold shifts in juveniles compared with adults, but signal-evoked firing suppression was more pronounced in juveniles. Neural threshold shifts were a better match to human psychophysical threshold shifts when quantified with a longer temporal window that included the response to the delayed masker, suggesting that temporally selective listening may contribute to age-related differences in backward masking. NEW & NOTEWORTHY In children, auditory detection of backward masked signals is immature well into adolescence, and detection deficits correlate with problems in speech processing. Our auditory cortical recordings reveal immature backward masking in adolescent animals that mirrors the prolonged development seen in children. This is driven by both signal-evoked suppression and dynamic range reduction. An extended window of analysis suggests that differences in temporally focused listening may contribute to late maturing thresholds for backward masked signals.
Mattingly Michelle M; Donell Brittany M; Rosen Merri J
Journal of neurophysiology
2018
2018-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/jn.00114.2018" target="_blank" rel="noreferrer noopener">10.1152/jn.00114.2018</a>
Effects of artifact rejection and bayesian weighting on the auditory brainstem response during quiet and active behavioral conditions.
*Artifacts; *Bayes Theorem; Adult; Auditory; Brain Stem/*physiology; Evoked Potentials; Female; Humans; Male; Motor Activity/*physiology; Noise; Rest/physiology
PURPOSE: To evaluate the effects of 2 noise reduction techniques on the auditory brainstem response (ABR). METHOD: ABRs of 20 normal hearing adults were recorded during quiet and active behavioral conditions using 2 stimulus intensity levels. Wave V amplitudes and residual noise root-mean-square values were measured following the offline application of artifact rejection and Bayesian weighting. Repeated measures analysis of variance and Bonferroni adjusted pairwise t tests were utilized to evaluate significant main effects and interactions between the 2 noise reduction techniques. RESULTS: ABRs recorded during the quiet behavioral condition resulted in minimal differences in wave V amplitude and noise reduction improvement, suggesting that the 2 techniques were equally effective under ideal recording situations. During the active behavioral condition, however, the techniques differed significantly in the ability to preserve the evoked potential and reduce noise. Consequently, strict artifact rejection levels resulted in an inherent underestimation of wave V amplitudes when compared with the Bayesian approach. CONCLUSION: Artifact rejection had a detrimental effect on waveform morphology of the ABR. This could lead to difficulty in ABR interpretation when patients are active and ultimately result in diagnostic errors.
Sanchez Jason Tait; Gans Donald
American Journal of Audiology
2006
2006-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1044/1059-0889(2006/019)" target="_blank" rel="noreferrer noopener">10.1044/1059-0889(2006/019)</a>
Excitatory and facilitatory frequency response areas in the inferior colliculus of the mustached bat.
Acoustic Stimulation; Animal; Animals; Auditory; Auditory Perception/*physiology; Brain Stem; Chiroptera/*physiology; Echolocation; Evoked Potentials; Inferior Colliculi/*physiology; Neurons/physiology; Vocalization
In the mustached bat's central nucleus of the inferior colliculus (ICC), many neurons display facilitatory or inhibitory responses when presented with two tones of distinctly different frequencies. Our previous studies have focused on spectral interactions between specific frequency bands contained in the bat's sonar vocalization. In this study, we describe excitatory and facilitatory frequency response areas across all frequencies in the mustached bat's audible range. We show that many neurons in the ICC have more extensive frequency interactions than previously documented. We recorded responses of 96 single units to single tones and combinations of two tones. Best frequencies of the units ranged from 59-15 kHz. Forty-one units had a single, excitatory frequency response area. The rest of the units had more complex frequency tuning that included multiple excitatory frequency response areas and facilitatory frequency response areas. Some of the facilitatory frequency interactions were between one sound with energy in a sonar frequency band and a second sound with energy in a non-sonar frequency band. We also found that neurons could be facilitated by more than one additional frequency band. Our findings of extensive frequency interactions in the ICC of the mustached bat suggest that some neurons may be well suited for the analysis of complex sounds, possibly including social communication sounds.
Portfors Christine V; Wenstrup Jeffrey J
Hearing research
2002
2002-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0378-5955(02)00376-3" target="_blank" rel="noreferrer noopener">10.1016/s0378-5955(02)00376-3</a>
Auditory nerve fiber differences in the normal and neurofilament deficient Japanese quail.
*Mutation; Animals; Auditory; Axons/ultrastructure; Brain Stem; Cochlear Nerve/*pathology/*physiopathology; Coturnix/genetics; Electron; Evoked Potentials; Microscopy; Myelin Sheath/ultrastructure; Nerve Fibers/pathology/physiology; Neurofilament Proteins/*deficiency/*genetics
A primary axonal disease affecting the central and peripheral nervous system was discovered in a mutant strain of the Japanese quail, named quiver (Quv). We have previously demonstrated altered auditory evoked potentials in the neurofilament (NF) deficient quail. In this current study we attempt to find relationships between the auditory evoked potential results and the histo-pathological abnormalities of the auditory neurons. No abnormalities in the external auditory meatus and tympanic cavity were observed in either Quv or control quails and the ganglion cell bodies and their nuclei appeared normal by light microscopy. The myelin staining pattern was found to be similar in both strains with hematoxylin and eosin and Kluver-Barrera staining. The frequency histograms of fiber and axonal diameters of myelinated fibers showed an unimodal pattern in both strains. In Quv quails myelinated fibers and their axoplasm were smaller in diameter than in controls resulting in smaller neural tissue mass. In electron microscopic observation the axons of the Quv quail were composed of mitochondria and microtubules and smooth endoplasmic reticuli. In Quv quail electron micrographs of cochlear nerve myelinated fibers NFs were not seen in the axons and the neuronal cell bodies. Our current findings indicate that the previously reported reduction of conduction velocity of auditory evoked potentials may be due to smaller fiber and/or axonal diameter. The g-ratio, myelin thickness and fiber circularity were found to be the same for both strains. In conclusion, loss of axonal cytoskeletal elements (NFs) correlates well with our electrophysiological findings. Reduced conduction velocity and severely distorted auditory evoked potentials in NF deficient quails seem to be primarily due to axonal hypotrophy.
Sheykholeslami K; Kaga K; Mizutani M
Hearing research
2001
2001-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0378-5955(01)00326-4" target="_blank" rel="noreferrer noopener">10.1016/s0378-5955(01)00326-4</a>
Binaural interaction of bone-conducted auditory brainstem responses in children with congenital atresia of the external auditory canal.
Adolescent; Audiometry; Auditory; Bilateral/congenital/physiopathology; Bone Conduction/*physiology; Brain Stem/*physiology; Child; Conductive/congenital/physiopathology; Ear; Ear Canal/*abnormalities/physiopathology; Evoked Potentials; Evoked Response; Hearing Loss; Humans; Middle/abnormalities; Preschool; Pure-Tone; Temporal Bone/abnormalities
Bilateral bone-conducted auditory brainstem responses (BC-ABRs) were recorded in children with atresia of the external auditory canal bilaterally (AECB) in order to compare the response characteristics to normal hearing adults. The binaural interaction component (BIC) of the ABR occurs when the sum of the monaural-evoked ABR amplitudes are different in amplitude when compared to the binaural-evoked ABR amplitude. Previous electrophysiological work from our lab has shown that children with AECB lateralize bone-conducted (BC) sound. Furthermore, we have found in normal-hearing adults that BICs exist using BC clicks. In adults, BC-BIC occurred in the latency region corresponding to waves IV-VI, whereas for children with AECB corresponding peak latencies occurred earlier. Same as normal-hearing adults, BC-ABR IV-V complex peak amplitudes for sum of the BC-monaural right and
Sheykholeslami Kianoush; Habiby Kermany Mohammad; Sebastein Schmerber; Kaga Kimitaka
International journal of pediatric otorhinolaryngology
2003
2003-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0165-5876(03)00197-6" target="_blank" rel="noreferrer noopener">10.1016/s0165-5876(03)00197-6</a>
An operant-based detection method for inferring tinnitus in mice.
*Conditioning; *Disease Models; *Inferior colliculus; *Mouse model; *Noise-induced hearing loss; *Operant conditioning; *Sodium salicylate; *Tinnitus; Acoustic Stimulation; Analysis of Variance; Animal; Animals; Auditory; Avoidance Learning; Brain Stem/physiology; Electroshock; Equipment Design; Evoked Potentials; Female; Inbred C57BL; Inferior Colliculi/physiopathology; Male; Mice; Motor Activity; Neurons/physiology; Operant; Otoacoustic Emissions; Sodium Salicylate; Spontaneous/physiology; Tinnitus/*diagnosis/physiopathology; Tissue Culture Techniques; Voltage-Sensitive Dye Imaging
BACKGROUND: Subjective tinnitus is a hearing disorder in which a person perceives sound when no external sound is present. It can be acute or chronic. Because our current understanding of its pathology is incomplete, no effective cures have yet been established. Mouse models are useful for studying the pathophysiology of tinnitus as well as for developing therapeutic treatments. NEW METHOD: We have developed a new method for determining acute and chronic tinnitus in mice, called sound-based avoidance detection (SBAD). The SBAD method utilizes one paradigm to detect tinnitus and another paradigm to monitor possible confounding factors, such as motor impairment, loss of motivation, and deficits in learning and memory. RESULTS: The SBAD method has succeeded in monitoring both acute and chronic tinnitus in mice. Its detection ability is further validated by functional studies demonstrating an abnormal increase in neuronal activity in the inferior colliculus of mice that had previously been identified as having tinnitus by the SBAD method. COMPARISON WITH EXISTING METHODS: The SBAD method provides a new means by which investigators can detect tinnitus in a single mouse accurately and with more control over potential confounding factors than existing methods. CONCLUSION: This work establishes a new behavioral method for detecting tinnitus in mice. The detection outcome is consistent with functional validation. One key advantage of mouse models is they provide researchers the opportunity to utilize an extensive array of genetic tools. This new method could lead to a deeper understanding of the molecular pathways underlying tinnitus pathology.
Zuo Hongyan; Lei Debin; Sivaramakrishnan Shobhana; Howie Benjamin; Mulvany Jessica; Bao Jianxin
Journal of neuroscience methods
2017
2017-11
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<a href="http://doi.org/10.1016/j.jneumeth.2017.08.029" target="_blank" rel="noreferrer noopener">10.1016/j.jneumeth.2017.08.029</a>
Noise-induced cochlear synaptopathy: Past findings and future studies.
*Auditory Perception; *Hearing; *Hearing loss; *Molecular approach; *Preclinical model; *Spiral ganglion; *Synaptic loss; *Synaptic Transmission; Animals; Auditory; Hair Cells; Hearing Loss; Hearing Tests; Humans; Inner/*pathology; Noise-Induced/diagnosis/*pathology/physiopathology/psychology; Noise/*adverse effects; Predictive Value of Tests; Psychoacoustics; Spiral Ganglion/*pathology/physiopathology; Synapses/*pathology
For decades, we have presumed the death of hair cells and spiral ganglion neurons are the main cause of hearing loss and difficulties understanding speech in noise, but new findings suggest synapse loss may be the key contributor. Specifically, recent preclinical studies suggest that the synapses between inner hair cells and spiral ganglion neurons with low spontaneous rates and high thresholds are the most vulnerable subcellular structures, with respect to insults during aging and noise exposure. This cochlear synaptopathy can be "hidden" because this synaptic loss can occur without permanent hearing threshold shifts. This new discovery of synaptic loss opens doors to new research directions. Here, we review a number of recent studies and make suggestions in two critical future research directions. First, based on solid evidence of cochlear synaptopathy in animal models, it is time to apply molecular approaches to identify the underlying molecular mechanisms; improved understanding is necessary for developing rational, effective therapies against this cochlear synaptopathy. Second, in human studies, the data supporting cochlear synaptopathy are indirect although rapid progress has been made. To fully identify changes in function that are directly related this hidden synaptic damage, we argue that a battery of tests including both electrophysiological and behavior tests should be combined for diagnosis of "hidden hearing loss" in clinical studies. This new approach may provide a direct link between cochlear synaptopathy and perceptual difficulties.
Kobel Megan; Le Prell Colleen G; Liu Jennifer; Hawks John W; Bao Jianxin
Hearing research
2017
2017-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.heares.2016.12.008" target="_blank" rel="noreferrer noopener">10.1016/j.heares.2016.12.008</a>
Prepulse inhibition of the acoustic startle reflex vs. auditory brainstem response for hearing assessment.
*Audiometric functions; *Hearing loss; *Mouse; *Permanent threshold shift; *Sound exposure; *Temporary threshold shift; Acoustic Stimulation/*methods; Animal; Animals; Audiometry; Auditory; Auditory Threshold/*physiology; Brain Stem/*physiology; Evoked Potentials; Hearing; Inbred CBA; Male; Mice; Models; Noise; Prepulse Inhibition/*physiology; Pure-Tone/*methods; Reflex; Startle/*physiology
The high prevalence of noise-induced and age-related hearing loss in the general population has warranted the use of animal models to study the etiology of these pathologies. Quick and accurate auditory threshold determination is a prerequisite for experimental manipulations targeting hearing loss in animal models. The standard auditory brainstem response (ABR) measurement is fairly quick and translational across species, but is limited by the need for anesthesia and a lack of perceptual assessment. The goal of this study was to develop a new method of hearing assessment utilizing prepulse inhibition (PPI) of the acoustic startle reflex, a commonly used tool that measures detection thresholds in awake animals, and can be performed on multiple animals simultaneously. We found that in control mice PPI audiometric functions are similar to both ABR and traditional operant conditioning audiograms. The hearing thresholds assessed with PPI audiometry in sound exposed mice were also similar to those detected by ABR thresholds one day after exposure. However, three months after exposure PPI threshold shifts were still evident at and near the frequency of exposure whereas ABR thresholds recovered to the pre-exposed level. In contrast, PPI audiometry and ABR wave one amplitudes detected similar losses. PPI audiometry provides a high throughput automated behavioral screening tool of hearing in awake animals. Overall, PPI audiometry and ABR assessments of the auditory system are robust techniques with distinct advantages and limitations, which when combined, can provide ample information about the functionality of the auditory system.
Longenecker R J; Alghamdi F; Rosen M J; Galazyuk A V
Hearing research
2016
2016-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.heares.2016.06.006" target="_blank" rel="noreferrer noopener">10.1016/j.heares.2016.06.006</a>
Canertinib induces ototoxicity in three preclinical models.
Animals; Antineoplastic Agents/*adverse effects/pharmacology; Antitumor; Auditory; Canertinib; Carcinoma; Drug Screening Assays; Ear; Electrophysiology; ERBB; ErbB Receptors/*antagonists & inhibitors; Female; Hair Cells; Hearing Loss/*chemically induced; Hearing/*drug effects; Inbred C57BL; Inbred CBA; Lung Neoplasms/drug therapy; Male; Mice; Morpholines/*adverse effects/pharmacology; Neuregulin-1/metabolism; Non-small cell lung cancer; Non-Small-Cell Lung/drug therapy; NRG1; Ototoxicity; Outer hair cell; Outer/*drug effects; Signal Transduction/drug effects; Zebrafish
Neuregulin-1 (NRG1) ligand and its epidermal growth factor receptor (EGFR)/ERBB family regulate normal cellular proliferation and differentiation in many tissues including the cochlea. Aberrant NRG1 and ERBB signaling cause significant hearing impairment in mice. Dysregulation of the same signaling pathway in humans is involved in certain types of cancers such as breast cancer or non-small cell lung cancer (NSCLC). A new irreversible pan-ERBB inhibitor, canertinib, has been tested in clinical trials for the treatment of refractory NSCLC. Its possible ototoxicity was unknown. In this study, a significant dose-dependent canertinib ototoxicity was observed in a zebrafish model. Canertinib ototoxicity was further confirmed in two mouse models with different genetic backgrounds. The data strongly suggested an evolutionally preserved ERBB molecular mechanism underlying canertinib ototoxicity. Thus, these results imply that clinical monitoring of hearing loss should be considered for clinical testing of canertinib or other pan-ERBB inhibitors.
Tang Jian; Qian Yi; Li Hui; Kopecky Benjamin J; Ding Dalian; Ou Henry C; DeCook Rhonda; Chen Xiaojie; Sun Zhenyu; Kobel Megan; Bao Jianxin
Hearing research
2015
2015-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.heares.2015.07.002" target="_blank" rel="noreferrer noopener">10.1016/j.heares.2015.07.002</a>
Development of tinnitus in CBA/CaJ mice following sound exposure.
Animals; Auditory; Brain Stem; Evoked Potentials; Inbred CBA; Mice; Noise/*adverse effects; Reflex; Startle; Tinnitus/*etiology/physiopathology
Tinnitus, the perception of a sound without an external acoustic source, is a complex perceptual phenomenon affecting the quality of life in 17% of the adult population. Despite its ubiquity and morbidity, the pathophysiology of tinnitus is a work in progress, and there is no generally accepted cure or treatment. Development of a reliable common animal model is crucial for tinnitus research and may advance this field. The goal of this study was to develop a tinnitus mouse model. Tinnitus was induced in an experimental group of mice by an exposure to a loud (116 dB sound pressure level (SPL)) narrow band noise (one octave, centered at 16 kHz) during 1 h under anesthesia. The tinnitus was then assessed behaviorally by measuring gap induced suppression of the acoustic startle reflex. We found that a vast majority of the sound-exposed mice (86%) developed behavioral signs of tinnitus. This was a complex, long lasting, and dynamic process. On the day following exposure, all mice demonstrated signs of acute tinnitus over the entire range of sound frequencies used for testing (10-31 kHz). However, 2-3 months later, a behavioral evidence of tinnitus was evident only at a narrow frequency range (20-31 kHz) representing a presumed chronic condition. Extracellular recordings confirmed a significantly higher rate of spontaneous activity in inferior colliculus neurons in sound-exposed compared to control mice. Surprisingly, unilateral sound exposure suppresses startle responses in mice and they remained suppressed even 3 months post-exposure, whereas auditory brainstem response thresholds were completely recovered during 2 months following exposure. In summary, behavioral evidence of tinnitus can be reliably developed in mice by sound exposure, and tinnitus induction can be assessed by quantifying prepulse inhibition of the acoustic startle reflex.
Longenecker Ryan J; Galazyuk Alexander V
Journal of the Association for Research in Otolaryngology : JARO
2011
2011-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s10162-011-0276-1" target="_blank" rel="noreferrer noopener">10.1007/s10162-011-0276-1</a>
Inputs to combination-sensitive neurons of the inferior colliculus.
*Brain Mapping; Acoustic Stimulation; Animals; Auditory; Brain Stem/*physiology; Chiroptera/*physiology; Evoked Potentials; Inferior Colliculi/*physiology; Neurons/*physiology
In the mustached bat, combination-sensitive neurons display integrative responses to combinations of acoustic elements in biosonar or social vocalizations. One type of combination-sensitive neuron responds to multiple harmonics of the frequency-modulated (FM) components in the sonar pulse and echo of the bat. These neurons, termed FM-FM neurons, are sensitive to the pulse-echo delay and may encode the distance of sonar targets. FM-FM neurons are common in high-frequency regions of the central nucleus of the inferior colliculus (ICC) and may be created there. If so, they must receive low-frequency inputs in addition to the expected high-frequency inputs. We placed single deposits of a tracer at FM-FM recording sites in the ICC and then analyzed retrograde labeling in the brainstem and midbrain. We were particularly interested in labeling patterns suggestive of low-frequency input to these FM-FM neurons. In most nuclei containing labeled cells, there was a single focus of labeling in regions thought to be responsive to high-frequency sounds. More complex labeling patterns were observed in three nuclei. In the anteroventral cochlear nucleus, labeling in the anterior and marginal cell divisions occurred in regions thought to respond to low-frequency sounds. This labeling comprised 6% of total brainstem labeled cells. Labeling in the intermediate nucleus of the lateral lemniscus and the magnocellular part of the ventral nucleus of the lateral lemniscus together comprised nearly 40% of all labeled cells. In both nuclei, multiple foci of labeling occurred. These different foci may represent groups of cells tuned to different frequency bands. Thus, one or more of these three nuclei may provide low-frequency input to high-frequency-sensitive cells in the ICC, creating FM-FM responses. We also examined whether ICC neurons responsive to lower frequencies project to high-frequency-sensitive ICC regions; only 0.15% of labeling originated from these lower frequency representations. If the spectral integration of FM-FM neurons is created at the level of the ICC, these results suggest that neurons of the anteroventral cochlear nucleus or monaural nuclei of the lateral lemniscus may provide the essential low-frequency input. In contrast, there is little evidence that the low-frequency representation of the ICC contributes to these integrative responses.
Wenstrup J J; Mittmann D H; Grose C D
The Journal of comparative neurology
1999
1999-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/(sici)1096-9861(19990712)409:4%3C509::aid-cne1%3E3.0.co;2-s" target="_blank" rel="noreferrer noopener">10.1002/(sici)1096-9861(19990712)409:4%3C509::aid-cne1%3E3.0.co;2-s</a>