Search

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

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

Purpose: A variety of options for behavioral assessment of tinnitus in laboratory animals are available to researchers today. These options are briefly reviewed, followed by data suggesting that gap detection procedures might be used to efficiently measure acute, salicylate-induced tinnitus and possibly hyperacusis in rats. Method: Fischer Brown Norway rats (n = 10) were given intraperitoneal injections of 350 mg/kg sodium salicylate on 2 consecutive days, and the effects on gap detection were observed across 9 different frequency bands. Pretest, posttest, and washout data were collected. An additional 4 rats were each given 4 different doses of sodium salicylate (0, 150, 250, and 300 mg/kg), and gap detection and prepulse inhibition were measured. Results: Significant gap detection deficits were observed from pre- to posttest that were consistent with tinnitus. Consistent gap detection deficits were found using broadband noise backgrounds, while significant improvements in responding to frequency-specific test bands were found. Similar effects were repeated in the dose response portion of the study. Conclusions: Gap detection procedures efficiently measured salicylate-induced changes in behavior that were consistent with the presence of tinnitus. In addition, the reliable, stronger responses at many frequencies after salicylate injections suggest the possibility of measuring a hyperacusis-like phenomenon using these methods. [ABSTRACT FROM AUTHOR]

Cisplatin, a chemotherapeutic agent of choice for the treatment of solid tumors, produces hearing loss in approximately half a millionnew cancer patients annually in the United States. The hearing loss is due, in part, to increased generation of reactive oxygen species (ROS) in the cochlea, leading to lipid peroxidation and damage or death of outer hair cells in the organ of Corti. The cochlea expresses the transient receptor potential vanilloid 1 (TRPV1), which are normally expressed on small diameter neurons in the peripheral nervous system and mediate thermal sensitivity, but whose role in the cochlea is unclear. In this study, we show that TRPV1 is coregulated along with the NADPHoxidase isoform, NOX3, by cisplatin. Induction of these proteins by cisplatin is dependent on ROS generation, since it is reversed by systemic lipoic acid administration. In organ of Corti hair cell cultures (UB/OC-1 cells), cisplatin activates and induces TRPV1 and NOX3, leading to apoptosis of these cells. Inhibition of TRPV1 by capsazepine or ruthenium red reduced the apoptosis, implicating TRPV1 in this process. Treatment of UB/OC-1 cultures with short interfering RNA (siRNA) against either TRPV1 or NOX3 reduced cisplatin-induced apoptosis, while round window application of TRPV1 siRNA to rats reduced TRPV1 expression, decreased damage to outer hair cells and reduced cisplatin-induced hearing loss. These data provide a link between NOX3 and TRPV1 in cisplatin-induced hearing loss and suggest that targeting these proteins for knockdown by siRNA could serve as a novel approach in treating cisplatin ototoxicity. [ABSTRACT FROM AUTHOR]

Aging and acoustic trauma may result in partial peripheral deafferentation in the central auditory pathway of the mammalian brain. In accord with homeostatic plasticity, loss of sensory input results in a change in pre- and postsynaptic GABAergic and glycinergic inhibitory neurotransmission. As seen in development, age-related changes may be activity dependent. Age-related presynaptic changes in the cochlear nucleus include reduced glycine levels, while in the auditory midbrain and cortex, GABA synthesis and release are altered. Presumably, in response to age-related decreases in presynaptic release of inhibitory neurotransmitters, there are age-related postsynaptic subunit changes in the composition of the glycine (GlyR) and GABAA (GABAAR) receptors. Age-related changes in the subunit makeup of inhibitory pentameric receptor constructs result in altered pharmacological and physiological responses consistent with a net down-regulation of functional inhibition. Age-related functional changes associated with glycine neurotransmission in dorsal cochlear nucleus (DCN) include altered intensity and temporal coding by DCN projection neurons. Loss of synaptic inhibition in the superior olivary complex (SOC) and the inferior colliculus (IC) likely affect the ability of aged animals to localize sounds in their natural environment. Age-related postsynaptic GABAAR changes in IC and primary auditory cortex (Al) involve changes in the subunit makeup of GABAARs. In turn, these changes cause age-related changes in the pharmacology and response properties of neurons in IC and Al circuits, which collectively may affect temporal processing and response reliability. Findings of age-related inhibitory changes within mammalian auditory circuits are similar to age and deafferentation plasticity changes observed in other sensory systems. Although few studies have examined sensory aging in the wild, these age-related changes would likely compromise an animal's ability to avoid predation or to be a successful predator in their natural environment. [ABSTRACT FROM AUTHOR]

An abstract of the article "Behavioral measures of tinnitus in laboratory animals," by Jeremy G. Turner is presented.

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

Animal research facilities are noisy environments. The high air change rates required in animal housing spaces tend to create higher noise levels from the heating and cooling systems. Housing rooms are typically constructed of hard wall material that is easily cleaned but simultaneously highly reverberant, meaning that the sound cannot be controlled/attenuated so the sounds that are generated bounce around the room uncontrolled. (Soft, sound-absorbing surfaces generally cannot be used in animal facilities because they collect microbes; various wall surface features and sound control panel options are available, although rarely used.) In addition, many of our husbandry tasks such as cage changing, animal health checks, cleaning, and transporting animals produce high levels of noise. Finally, much of the equipment we have increasingly employed in animal housing spaces, such as ventilated caging motors, biosafety, or procedure cabinets, can generate high levels of background noise, including ultrasound. These and many additional factors conspire to create an acoustic environment that is neither naturalistic nor conducive to a stress-free environment. The acoustic variability both within and between institutions can serve as an enormous confounder for research studies and a threat to our ability to reproduce studies over time and between research laboratories. By gaining a better appreciation for the acoustic variables, paired with transparency in reporting the levels, we might be able to gain a better understanding of their impacts and thereby gain some level of control over such acoustic variables in the animal housing space. The result of this could improve both animal welfare and study reproducibility, helping to address our 3Rs goals of Replacement, Reduction, and Refinement in the animal biomedical research enterprise.

Noise and vibration are present in every room of laboratory animal vivaria, with great variability from room-to-room and facility-to-facility. Such stimuli are rarely measured. As a result, the many stakeholders involved in biomedical research, (for example, funding agencies, construction personnel, equipment manufacturers, animal facility administrators, veterinarians, technicians, and scientists) have little awareness of the effects such stimuli may have on their research animals. Noise and vibration present a potential source of unrecognized animal distress, and a significant, uncontrolled and confounding variable in scientific studies. Unmeasured and unrecognized noise and vibration can therefore undermine the fundamental goals of the 3R's to refine animal models and reduce the number of animals used in biomedical and behavioral research. This overview serves to highlight the scope of this problem and proposes a series of recommended practices to limit its negative effects on research animals and the scientific data derived from them. These practices consist of developing a written plan for managing noise and vibration concerns, assessment of noise and vibration both annually and whenever unexpected changes in the facility or animals are observed, and for maintaining levels of chronic noise below thresholds that might cause animal welfare concerns or disruptions in ongoing studies.

Accumulating evidence suggests a role for inhibitory neurotransmitter dysfunction in the pathology of tinnitus. Opposing hypotheses proposed either a pathologic decrease or increase of GABAergic inhibition in medial geniculate body (MGB). In thalamus, GABA mediates fast synaptic inhibition via synaptic GABAA receptors (GABAARs) and persistent tonic inhibition via high-affinity extrasynaptic GABAARs. Given that extrasynaptic GABAARs control the firing mode of thalamocortical neurons, we examined tonic GABAAR currents in MGB neurons in vitro, using the following three groups of adult rats: unexposed control (Ctrl); sound exposed with behavioral evidence of tinnitus (Tin); and sound exposed with no behavioral evidence of tinnitus (Non-T). Tonic GABAAR currents were evoked using the selective agonist gaboxadol. Months after a tinnitus-inducing sound exposure, gaboxadol-evoked tonic GABAAR currents showed significant tinnitus-related increases contralateral to the sound exposure. In situ hybridization studies found increased mRNA levels for GABAAR δ-subunits contralateral to the sound exposure. Tin rats showed significant increases in the number of spikes per burst evoked using suprathreshold-injected current steps. In summary, we found little evidence of tinnitus-related decreases in GABAergic neurotransmission. Tinnitus and chronic pain may reflect thalamocortical dysrhythmia, which results from abnormal theta-range resonant interactions between thalamus and cortex, due to neuronal hyperpolarization and the initiation of low-threshold calcium spike bursts (Walton and Llinás, 2010). In agreement with this hypothesis, we found tinnitus-related increases in tonic extrasynaptic GABAAR currents, in action potentials/evoked bursts, and in GABAAR δ-subunit gene expression. These tinnitus-related changes in GABAergic function may be markers for tinnitus pathology in the MGB., (Copyright © 2015 the authors 0270-6474/15/359369-12$15.00/0.)

A longstanding hypothesis is that tinnitus, the perception of sound without an external acoustic source, is triggered by a distinctive pattern of cochlear hair cell (HC) damage and that this subsequently leads to altered neural activity in the central auditory pathway. This hypothesis was tested by assessing behavioral evidence of tinnitus and spontaneous neural activity in the inferior colliculus (IC) after unilateral cochlear trauma. Chinchillas were assigned to four cochlear treatment groups. Each treatment produced a distinctive pattern of HC damage, as follows: acoustic exposure (AEx): sparse low-frequency inner hair cell (IHC) and outer hair cell (OHC) loss; round window cisplatin (CisEx): pronounced OHC loss mixed with some IHC loss; round window carboplatin (CarbEx): pronounced IHC loss without OHC loss; control: no loss. Compared with controls, all experimental groups displayed significant and similar psychophysical evidence of tinnitus with features resembling a 1-kHz tone. Contralateral IC spontaneous activity was elevated in the AEx and CisEx groups, which showed increased spiking and increased cross-fiber synchrony. A multidimensional analysis identified a subpopulation of neurons more prevalent in animals with tinnitus. These units were characterized by high bursting, low ISI variance, and within-burst peak spiking of approximately 1,000/sec. It was concluded that cochlear trauma in general, rather than its specific features, leads to multiple changes in central activity that underpin tinnitus. Particularly affected was a subpopulation ensemble of IC neurons with the described unique triad of features.

Environmental noise can alter endocrine, reproductive and cardiovascular function, disturb sleep/wake cycles, and can mask normal communication between animals. These outcomes indicate that noise in the animal facility might have wide-ranging affects on animals, making what laboratory animals hear of consequence for all those who use animals in research, not just the hearing researcher. Given the wide-ranging effects of noise on laboratory animals, routine monitoring of noise in animal facilities would provide important information on the nature and stability of the animal environment. This special issue will highlight the need for more thorough monitoring and will serve as an introduction to noise and its various effects on animals.

Advanced age is commonly associated with progressive cochlear pathology and central auditory deficits, collectively known as presbycusis. The present study examined central correlates of presbycusis by measuring response properties of primary auditory cortex (AI) layer V neurons in the Fischer Brown Norway rat model. Layer V neurons represent the major output of AI to other cortical and subcortical regions (primarily the inferior colliculus). In vivo single-unit extracellular recordings were obtained from 114 neurons in aged animals (29-33 mo) and compared with 105 layer V neurons in young-adult rats (4-6 mo). Three consecutive repetitions of a pure-tone receptive field map were run for each neuron. Age was associated with fewer neurons exhibiting classic V/U-shaped receptive fields and a greater percentage of neurons with more Complex receptive fields. Receptive fields from neurons in aged rats were also less reliable on successive repetitions of the same stimulus set. Aging was also associated with less firing during the stimulus in V/U-shaped receptive field neurons and more firing during the stimulus in Complex neurons, which were generally associated with inhibited firing in young controls. Finally, neurons in aged rats with Complex receptive fields were more easily driven by current pulses delivered to the soma. Collectively, these findings provide support for the notion that age is associated with diminished signal-to-noise coding by AI layer V neurons and are consistent with other research suggesting that GABAergic neurotransmission in AI may be compromised by aging.

Hearing in laboratory animals is a topic that traditionally has been the domain of the auditory researcher. However, hearing loss and exposure to various environmental sounds can lead to changes in multiple organ systems, making what laboratory animals hear of consequence for researchers beyond those solely interested in hearing. For example, several inbred mouse strains commonly used in biomedical research (e.g., C57BL/6, DBA/2, and BALB/c) experience a genetically determined, progressive hearing loss that can lead to secondary changes in systems ranging from brain neurochemistry to social behavior. Both researchers and laboratory animal facility personnel should be aware of both strain and species differences in hearing in order to minimize potentially confounding variables in their research and to aid in the interpretation of data. Independent of genetic differences, acoustic noise levels in laboratory animal facilities can have considerable effects on the inhabitants. A large body of literature describes the nonauditory impact of noise on the biology and behavior of various strains and species of laboratory animals. The broad systemic effects of noise exposure include changes in endocrine and cardiovascular function, sleep-wake cycle disturbances, seizure susceptibility, and an array of behavioral changes. These changes are determined partly by species and strain; partly by noise intensity level, duration, predictability, and other characteristics of the sound; and partly by animal history and exposure context. This article reviews some of the basic strain and species differences in hearing and outlines how the acoustic environment affects different mammals.