Functional architecture of the inferior colliculus revealed with voltage-sensitive dyes.
Animals; Mice; Acoustic Stimulation/methods; Rats; local circuits; Auditory Pathways/chemistry/cytology/physiology; Fluorescent Dyes/*analysis; Inferior Colliculi/*chemistry/*cytology/physiology; laminar organization; microcircuits; Nerve Net/*chemistry/*cytology/physiology; population coding; post-inhibitory rebound; Voltage-Sensitive Dye Imaging/*methods; Long-Evans; Inbred CBA
We used optical imaging with voltage-sensitive dyes to investigate the spatio-temporal dynamics of synaptically evoked activity in brain slices of the inferior colliculus (IC). Responses in transverse slices which preserve cross-frequency connections and in modified sagittal slices that preserve connections within frequency laminae were evoked by activating the lateral lemniscal tract. Comparing activity between small and large populations of cells revealed response areas in the central nucleus of the IC that were similar in magnitude but graded temporally. In transverse sections, these response areas are summed to generate a topographic response profile. Activity through the commissure to the contralateral IC required an excitation threshold that was reached when GABAergic inhibition was blocked. Within laminae, module interaction created temporal homeostasis. Diffuse activity evoked by a single lemniscal shock re-organized into distinct spatial and temporal compartments when stimulus trains were used, and generated a directional activity profile within the lamina. Using different stimulus patterns to activate subsets of microcircuits in the central nucleus of the IC, we found that localized responses evoked by low-frequency stimulus trains spread extensively when train frequency was increased, suggesting recruitment of silent microcircuits. Long stimulus trains activated a circuit specific to post-inhibitory rebound neurons. Rebound microcircuits were defined by a focal point of initiation that spread to an annular ring that oscillated between inhibition and excitation. We propose that much of the computing power of the IC is derived from local circuits, some of which are cell-type specific. These circuits organize activity within and across frequency laminae, and are critical in determining the stimulus-selectivity of auditory coding.
Chandrasekaran Lakshmi; Xiao Ying; Sivaramakrishnan Shobhana
Frontiers in neural circuits
2013
1905-7
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/fncir.2013.00041" target="_blank" rel="noreferrer noopener">10.3389/fncir.2013.00041</a>
Coding the meaning of sounds: contextual modulation of auditory responses in the basolateral amygdala.
Female; Male; Animals; Mice; Acoustic Stimulation/*methods; Auditory Perception/*physiology; Action Potentials/*physiology; Amygdala/*physiology; Cats; Animal/*physiology; Inbred CBA; Vocalization
Female mice emit a low-frequency harmonic (LFH) call in association with distinct behavioral contexts: mating and physical threat or pain. Here we report the results of acoustic, behavioral, and neurophysiological studies of the contextual analysis of these calls in CBA/CaJ mice. We first show that the acoustical features of the LFH call do not differ between contexts. We then show that male mice avoid the LFH call in the presence of a predator cue (cat fur) but are more attracted to the same exemplar of the call in the presence of a mating cue (female urine). The males thus use nonauditory cues to determine the meaning of the LFH call, but these cues do not generalize to noncommunication sounds, such as noise bursts. We then characterized neural correlates of contextual meaning of the LFH call in responses of basolateral amygdala (BLA) neurons from awake, freely moving mice. There were two major findings. First, BLA neurons typically displayed early excitation to all tested behaviorally aversive stimuli. Second, the nonauditory context modulates the BLA population response to the LFH call but not to the noncommunication sound. These results suggest that the meaning of communication calls is reflected in the spike discharge patterns of BLA neurons.
Grimsley Jasmine M S; Hazlett Emily G; Wenstrup Jeffrey J
The Journal of neuroscience : the official journal of the Society for Neuroscience
2013
2013-10
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/10.1523/JNEUROSCI.2205-13.2013" target="_blank" rel="noreferrer noopener">10.1523/JNEUROSCI.2205-13.2013</a>
L-type calcium channels refine the neural population code of sound level.
*auditory midbrain; *dynamic range; *inferior colliculus; *level tuning; *local circuits; *rate-level functions; *Sound; 4-Aminopyridine/analogs & derivatives/pharmacology; Acoustic Stimulation; Action Potentials/drug effects/*physiology; Amifampridine; Animals; Biophysical Phenomena/drug effects; Calcium Channel Blockers/pharmacology; Calcium Channels; Calcium/metabolism; Excitatory Amino Acid Antagonists/pharmacology; In Vitro Techniques; Inbred CBA; Inferior Colliculi/*cytology; L-Type/*metabolism; Mice; Neurons/*physiology; Nimodipine/pharmacology; omega-Conotoxin GVIA/pharmacology; Potassium Channel Blockers/pharmacology; Quinoxalines/pharmacology; Wakefulness
The coding of sound level by ensembles of neurons improves the accuracy with which listeners identify how loud a sound is. In the auditory system, the rate at which neurons fire in response to changes in sound level is shaped by local networks. Voltage-gated conductances alter local output by regulating neuronal firing, but their role in modulating responses to sound level is unclear. We tested the effects of L-type calcium channels (CaL: CaV1.1-1.4) on sound-level coding in the central nucleus of the inferior colliculus (ICC) in the auditory midbrain. We characterized the contribution of CaL to the total calcium current in brain slices and then examined its effects on rate-level functions (RLFs) in vivo using single-unit recordings in awake mice. CaL is a high-threshold current and comprises approximately 50% of the total calcium current in ICC neurons. In vivo, CaL activates at sound levels that evoke high firing rates. In RLFs that increase monotonically with sound level, CaL boosts spike rates at high sound levels and increases the maximum firing rate achieved. In different populations of RLFs that change nonmonotonically with sound level, CaL either suppresses or enhances firing at sound levels that evoke maximum firing. CaL multiplies the gain of monotonic RLFs with dynamic range and divides the gain of nonmonotonic RLFs with the width of the RLF. These results suggest that a single broad class of calcium channels activates enhancing and suppressing local circuits to regulate the sensitivity of neuronal populations to sound level.
Grimsley Calum Alex; Green David Brian; Sivaramakrishnan Shobhana
Journal of neurophysiology
2016
2016-12
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/10.1152/jn.00657.2016" target="_blank" rel="noreferrer noopener">10.1152/jn.00657.2016</a>
Postnatal developmental changes in the medial nucleus of the trapezoid body in a mouse model of auditory pathology.
*Disease Models; AHL; Animal; Animals; Auditory brainstem responses; Auditory Pathways/*growth & development/*pathology; Auditory system; DBA/2; Hearing Loss/*pathology; Inbred CBA; Inbred DBA; Mice; MNTB; Newborn; Olivary Nucleus/*growth & development/*pathology; Organ Culture Techniques
Age-related hearing loss (AHL) is a multifactorial disorder characterized by a decline in peripheral and central auditory function. Here, we examined synaptic transmission in DBA/2 mice, which carry the AHL8 gene, at the identifiable glutamatergic synapse in the medial nucleus of the trapezoid body (MNTB), a nucleus in the superior olivary complex critical for acoustic timing. Mice exhibited raised auditory brainstem thresholds by P14, soon after hearing onset. Excitatory postsynaptic currents were prolonged; however, postsynaptic excitability was normal. By P18, high-frequency hearing loss was evident. Coincident with the onset of hearing loss, MNTB principal neurons displayed changes in intrinsic firing properties. These results suggest that changes in transmission in the superior olivary complex are associated with early onset hearing loss.
Grimsley Calum A; Sivaramakrishnan Shobhana
Neuroscience letters
2014
2014-01
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/10.1016/j.neulet.2013.11.051" target="_blank" rel="noreferrer noopener">10.1016/j.neulet.2013.11.051</a>
mGluRs modulate neuronal firing in the auditory midbrain.
Acoustic Stimulation/methods; Action Potentials/drug effects/*physiology; Animals; Auditory Perception/drug effects/physiology; Excitatory Amino Acid Agonists/pharmacology; Excitatory Amino Acid Antagonists/pharmacology; Glutamic Acid/physiology; Inbred CBA; Inferior Colliculi/drug effects/metabolism/*physiology; Metabotropic Glutamate/agonists/antagonists & inhibitors/*physiology; Mice; Neural Inhibition/drug effects/physiology; Neurons/drug effects/*physiology; Perceptual Masking/physiology; Receptors; Synaptic Transmission/drug effects/physiology
The mechanisms underlying sound-evoked suppression of neuronal firing in the auditory system are poorly understood. To explore these mechanisms in the inferior colliculus (IC), agonists and antagonists targeting different groups of metabotropic glutamate receptors (mGluRs) were applied iontophoretically to IC neurons in awake mice. We found that a group I-specific mGluR agonist predominantly increased neuronal firing in 52% of neurons, whereas group I antagonist had the opposite effect in 51% of neurons. A group II specific agonist showed no effect on neuronal firing but an antagonist increased firing rate in 48% of neurons. Neither a group III-specific mGluR agonist nor an antagonist had an effect on neuronal firing in the IC. We also found that sound stimuli triggered suppression of spontaneous firing in 70% of IC neurons. This suppression was reversibly blocked by group I mGluR antagonists. There is a possible link between this suppression and two perceptual phenomena: forward masking and "residual inhibition," the brief reduction/elimination of tinnitus following an appropriate masking sound.
Voytenko S V; Galazyuk A V
Neuroscience letters
2011
2011-04
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/10.1016/j.neulet.2011.01.075" target="_blank" rel="noreferrer noopener">10.1016/j.neulet.2011.01.075</a>
An improved approach to separating startle data from noise.
*Electronic Data Processing; *Noise; Acoustic startle reflex; Acoustic Stimulation/methods; Analysis of Variance; Animal locomotion; Animals; Auditory/*physiology; Automated classification; Evoked Potentials; Inbred CBA; Male; Mice; Reflex; Startle waveform analysis; Startle/*physiology; Time Factors; Video Recording
BACKGROUND: The acoustic startle reflex (ASR) is a rapid, involuntary movement to sound, found in many species. The ASR can be modulated by external stimuli and internal state, making it a useful tool in many disciplines. ASR data collection and interpretation varies greatly across laboratories making comparisons a challenge. NEW METHOD: Here we investigate the animal movement associated with a startle in mouse (CBA/CaJ). Movements were simultaneously captured with high-speed video and a piezoelectric startle plate. We also use simple mathematical extrapolations to convert startle data (force) into center of mass displacement ("height"), which incorporates the animal's mass. RESULTS: Startle plate force data revealed a stereotype waveform associated with a startle that contained three distinct peaks. This waveform allowed researchers to separate trials into 'startles' and 'no-startles' (termed 'manual classification). Fleiss' kappa and Krippendorff"s alpha (0.865 for both) indicate very good levels of agreement between researchers. Further work uses this waveform to develop an automated startle classifier. The automated classifier compares favorably with manual classification. A two-way ANOVA reveals no significant difference in the magnitude of the 3 peaks as classified by the manual and automated methods (P1: p=0.526, N1: p=0.488, P2: p=0.529). COMPARISON WITH EXISTING METHOD(S): The ability of the automated classifier was compared with three other commonly used classification methods; the automated classifier far outperformed these methods. CONCLUSIONS: The improvements made allow researchers to automatically separate startle data from noise, and normalize for an individual animal's mass. These steps ease inter-animal and inter-laboratory comparisons of startle data.
Grimsley Calum A; Longenecker Ryan J; Rosen Merri J; Young Jesse W; Grimsley Jasmine M S; Galazyuk Alexander V
Journal of neuroscience methods
2015
2015-09
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.jneumeth.2015.07.001" target="_blank" rel="noreferrer noopener">10.1016/j.jneumeth.2015.07.001</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>
Long-Lasting forward Suppression of Spontaneous Firing in Auditory Neurons: Implication to the Residual Inhibition of Tinnitus.
acoustic trauma; Animals; Brain Stem – Physiology; Clinical Assessment Tools; Cochlear Nerve – Physiology; Cochlear Nerve/*physiology; Inbred CBA; Inferior Colliculi/*physiology; inferior colliculus; Male; mice; Mice; residual inhibition; Sound; Tinnitus – Physiopathology; Tinnitus/*physiopathology
Tinnitus is the perception of a sound that has no external source. Sound stimuli can suppress spontaneous firing in auditory neurons long after stimulus offset. It is unknown how changes in sound stimulus parameters affect this forward suppression. Using in vivo extracellular recording in awake mice, we found that about 40 % of spontaneously active inferior colliculus (IC) neurons exhibited forward suppression of spontaneous activity after sound offset. The duration of this suppression increased with sound duration and lasted about 40 s following a
Galazyuk A V; Voytenko S V; Longenecker R J
Journal of the Association for Research in Otolaryngology : JARO
2017
2017-04
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/10.1007/s10162-016-0601-9" target="_blank" rel="noreferrer noopener">10.1007/s10162-016-0601-9</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>