ABSTRACT
Hydrogen sulfide (H2S) is a gaseous molecule found naturally in the environment, and as an industrial byproduct, and is known to cause acute death and induces long-term neurological disorders following acute high dose exposures. Currently, there is no drug approved for treatment of acute H2S-induced neurotoxicity and/or neurological sequelae. Lack of a deep understanding of pathogenesis of H2S-induced neurotoxicity has delayed the development of appropriate therapeutic drugs that target H2S-induced neuropathology. RNA sequencing analysis was performed to elucidate the cellular and molecular mechanisms of H2S-induced neurodegeneration, and to identify key molecular elements and pathways that contribute to H2S-induced neurotoxicity. C57BL/6J mice were exposed by whole body inhalation to 700 ppm of H2S for either one day, two consecutive days or 4 consecutive days. Magnetic resonance imaging (MRI) scan analyses showed H2S exposure induced lesions in the inferior colliculus (IC) and thalamus (TH). This mechanistic study focused on the IC. RNA Sequencing analysis revealed that mice exposed once, twice, or 4 times had 283, 193 and 296 differentially expressed genes (DEG), respectively (q-value < 0.05, fold-change> 1.5). Hydrogen sulfide exposure modulated multiple biological pathways including unfolded protein response, neurotransmitters, oxidative stress, hypoxia, calcium signaling, and inflammatory response in the IC. Hydrogen sulfide exposure activated PI3K/Akt and MAPK signaling pathways. Pro-inflammatory cytokines were shown to be potential initiators of the modulated signaling pathways following H2S exposure. Furthermore, microglia were shown to release IL-18 and astrocytes released both IL-1ß and IL-18 in response to H2S. This transcriptomic analysis data revealed complex signaling pathways involved in H2S-induced neurotoxicity and may provide important associated mechanistic insights.
Subject(s)
Hydrogen Sulfide/toxicity , Inferior Colliculi/drug effects , Neurotoxicity Syndromes/etiology , Signal Transduction/drug effects , Animals , Cytokines/metabolism , Gene Expression Profiling , Hydrogen Sulfide/administration & dosage , Magnetic Resonance Imaging , Male , Mice , Mice, Inbred C57BL , Oxidative Stress/drug effects , TranscriptomeABSTRACT
The central gain model of hyperacusis proposes that loss of auditory input can result in maladaptive neuronal gain increases in the central auditory system, leading to the over-amplification of sound-evoked activity and excessive loudness perception. Despite the attractiveness of this model, and supporting evidence for it, a critical test of the central gain theory requires that changes in sound-evoked activity be explicitly linked to perceptual alterations of loudness. Here we combined an operant conditioning task that uses a subject's reaction time to auditory stimuli to produce reliable measures of loudness growth with chronic electrophysiological recordings from the auditory cortex and inferior colliculus of awake, behaviorally-phenotyped animals. In this manner, we could directly correlate daily assessments of loudness perception with neurophysiological measures of sound encoding within the same animal. We validated this novel psychophysical-electrophysiological paradigm with a salicylate-induced model of hearing loss and hyperacusis, as high doses of sodium salicylate reliably induce temporary hearing loss, neural hyperactivity, and auditory perceptual disruptions like tinnitus and hyperacusis. Salicylate induced parallel changes to loudness growth and evoked response-intensity functions consistent with temporary hearing loss and hyperacusis. Most importantly, we found that salicylate-mediated changes in loudness growth and sound-evoked activity were correlated within individual animals. These results provide strong support for the central gain model of hyperacusis and demonstrate the utility of using an experimental design that allows for within-subject comparison of behavioral and electrophysiological measures, thereby making inter-subject variability a strength rather than a limitation.
Subject(s)
Hearing Loss/physiopathology , Hyperacusis/physiopathology , Loudness Perception/physiology , Sodium Salicylate/pharmacology , Acoustic Stimulation/methods , Animals , Auditory Cortex/drug effects , Auditory Cortex/physiopathology , Evoked Potentials, Auditory/drug effects , Female , Hearing/drug effects , Hearing/physiology , Hearing Loss/drug therapy , Inferior Colliculi/drug effects , Inferior Colliculi/physiopathology , Loudness Perception/drug effects , Male , Rats, Sprague-Dawley , RodentiaABSTRACT
Cannabinoid receptors (CBRs) are widely distributed in the brain, including the inferior colliculus (IC). Here, we aim to study whether endocannabinoids influence a specific type of neuronal adaptation, namely, stimulus-specific adaptation (SSA) found in some IC neurons. SSA is important because it has been found as early as the level of the midbrain and therefore it may be a neuronal correlate of early indices of deviance detection. Furthermore, recent studies have demonstrated a direct link between SSA and MMN, that is widely used as an outcome measure in a variety of human neurodegenerative disorders. SSA is considered a form of short-term plasticity, and CBRs have been shown to play a role in short-term neural plasticity. Therefore, it is reasonable to hypothesize that endocannabinoids may play a role in the generation or modulation of SSA. We recorded single units in the IC under an oddball paradigm stimulation. The results demonstrate that cannabinoid agonists lead to a reduction in the neuronal adaptation. This change is due to a differential increase of the neuronal firing rate to the standard tone alone. Furthermore, we show that the effect is mediated by the cannabinoid receptor 1 (CBR1). Thus, cannabinoid agonists down-modulate SSA in IC neurons.
Subject(s)
Adaptation, Physiological , Endocannabinoids/metabolism , Inferior Colliculi/drug effects , Inferior Colliculi/physiology , Neurons/drug effects , Neurons/physiology , Acoustic Stimulation , Animals , Electroencephalography , Neuronal Plasticity , Rats , Receptor, Cannabinoid, CB1/metabolismABSTRACT
Abstract Introduction: Salicylate at high doses induces tinnitus in humans and experimental animals. However, the mechanisms and loci of action of salicylate in inducing tinnitus are still not well known. The expression of Immediate Early Genes (IEG) is traditionally associated with long-term neuronal modifications but it is still not clear how and where IEGs are activated in animal models of tinnitus. Objectives: Here we investigated the expression of c-fos and Egr-1, two IEGs, in the Dorsal Cochlear Nucleus (DCN), the Inferior Colliculus (IC), and the Posterior Ventral Cochlear Nucleus (pVCN) of rats. Methods: Rats were treated with doses known to induce tinnitus in rats (300 mg/kg i.p. daily, for 3 days), and c-fos and Egr-1 protein expressions were analyzed using western blot and immunocytochemistry. Results: After administration of salicylate, c-fos protein expression increased significantly in the DCN, pVCN and IC when assayed by western blot. Immunohistochemistry staining showed a more intense labeling of c-fos in the DCN, pVCN and IC and a significant increase in c-fos positive nuclei in the pVCN and IC. We did not detect increased Egr-1 expression in any of these areas. Conclusion: Our data show that a high dose of salicylate activates neurons in the DCN, pVCN and IC. The expression of these genes by high doses of salicylate strongly suggests that plastic changes in these areas are involved in the genesis of tinnitus.
Resumo Introdução: Salicilato em doses elevadas induz zumbido nos seres humanos e em animais experimentais. No entanto, os mecanismos e loci de ação do salicilato na indução de zumbido ainda não são bem conhecidos. A expressão dos genes precoces imediatos (GPIs) está tradicionalmente associada a alterações neuronais em longo prazo, mas ainda não está claro como e onde os GPIs são ativados em modelos animais de zumbido. Objetivos: No presente estudo investigamos a expressão de c-fos e Egr-1, dois GPIs, no núcleo coclear dorsal (NCD), colículo inferior (CI) e núcleo coclear ventral posterior (NCVp) de ratos. Métodos: Os ratos foram tratados com doses que, conhecidamente, induzem zumbido em ratos (300 mg/kg IP/dia, por três dias) e as expressões das proteínas c-fos e Egr-1 foram analisadas por meio de Western blot e imunoistoquímica. Resultados: Após a administração de salicilato, a expressão da proteína c-fos aumentou significativamente no NCD, NCVp e CI, quando analisados por Western blot. A coloração imunoistoquímica mostrou uma marcação mais intensa de c-fos no NCD, NCVp e CI e um aumento significativo de núcleos positivos de c-fos no NCVp e CI. Não detectamos aumento da expressão de Egr-1 em qualquer dessas áreas. Conclusão: Nossos dados mostram que uma dose alta de salicilato ativa neurônios no NCD, NCVp e CI. A expressão desses genes por doses altas de salicilato sugere que as alterações plásticas nessas áreas estão envolvidas na gênese do zumbido.
Subject(s)
Animals , Male , Rats , Inferior Colliculi/drug effects , Salicylates/pharmacology , Gene Expression Regulation/drug effects , Genes, Immediate-Early/drug effects , Cochlear Nucleus/drug effects , Salicylates/administration & dosage , Blotting, Western , Genes, fos/drug effects , Rats, Wistar , Dose-Response Relationship, Drug , Early Growth Response Protein 1/drug effectsABSTRACT
INTRODUCTION: Salicylate at high doses induces tinnitus in humans and experimental animals. However, the mechanisms and loci of action of salicylate in inducing tinnitus are still not well known. The expression of Immediate Early Genes (IEG) is traditionally associated with long-term neuronal modifications but it is still not clear how and where IEGs are activated in animal models of tinnitus. OBJECTIVES: Here we investigated the expression of c-fos and Egr-1, two IEGs, in the Dorsal Cochlear Nucleus (DCN), the Inferior Colliculus (IC), and the Posterior Ventral Cochlear Nucleus (pVCN) of rats. METHODS: Rats were treated with doses known to induce tinnitus in rats (300mg/kg i.p. daily, for 3 days), and c-fos and Egr-1 protein expressions were analyzed using western blot and immunocytochemistry. RESULTS: After administration of salicylate, c-fos protein expression increased significantly in the DCN, pVCN and IC when assayed by western blot. Immunohistochemistry staining showed a more intense labeling of c-fos in the DCN, pVCN and IC and a significant increase in c-fos positive nuclei in the pVCN and IC. We did not detect increased Egr-1 expression in any of these areas. CONCLUSION: Our data show that a high dose of salicylate activates neurons in the DCN, pVCN and IC. The expression of these genes by high doses of salicylate strongly suggests that plastic changes in these areas are involved in the genesis of tinnitus.
Subject(s)
Cochlear Nucleus/drug effects , Gene Expression Regulation/drug effects , Genes, Immediate-Early/drug effects , Inferior Colliculi/drug effects , Salicylates/pharmacology , Animals , Blotting, Western , Dose-Response Relationship, Drug , Early Growth Response Protein 1/drug effects , Genes, fos/drug effects , Male , Rats , Rats, Wistar , Salicylates/administration & dosageABSTRACT
Thiamine deficiency (TD) leads to Wernicke's encephalopathy (WE), in which focal histological lesions occur in periventricular areas of the brain. Recently, impaired neurogenesis has been reported in the hippocampus during the dietary form of TD, and in pyrithiamine-induced TD (PTD), a well-characterized model of WE. To further characterize the consequences of PTD on neural stem/progenitor cell (NSPC) activity, we have examined the effect of this treatment in the rat on both the subventricular zone (SVZ) of the rostral lateral ventricle and subgranular layer (SGL) of the hippocampus, and in the thalamus and inferior colliculus, two vulnerable brain regions in this disorder. In both the SVZ and SGL, PTD led to a decrease in the numbers of bromodeoxyuridine-stained cells, indicating that proliferation of NSPCs destined for neurogenesis in these areas was reduced. Doublecortin (DCX) immunostaining in the SGL was decreased, indicating a reduction in neuroblast formation, consistent with impaired NSPC activity. DCX labeling was not apparent in focal areas of vulnerability. In the thalamus, proliferation of cells was absent while in the inferior colliculus, numerous actively dividing cells were apparent, indicative of a differential response between these two brain regions. Exposure of cultured neurospheres to PTD resulted in decreased proliferation of NSPCs, consistent with our in vivo findings. Together, these results indicate that PTD considerably affects cell proliferation and neurogenesis activity in both neurogenic areas and parts of the brain known to display structural and functional vulnerability, confirming and extending recent findings on the effects of TD on neurogenesis. Future use of NSPCs in vitro may allow a closer and more detailed examination of the mechanism(s) underlying inhibition of these cells during TD.
Subject(s)
Brain/drug effects , Neurogenesis/drug effects , Pyrithiamine/toxicity , Wernicke Encephalopathy/pathology , Animals , Brain/pathology , Cell Division/drug effects , Cells, Cultured , DNA Replication/drug effects , Disease Models, Animal , Doublecortin Domain Proteins , Doublecortin Protein , Hippocampus/drug effects , Hippocampus/pathology , Inferior Colliculi/drug effects , Inferior Colliculi/pathology , Lateral Ventricles/drug effects , Lateral Ventricles/pathology , Male , Microtubule-Associated Proteins/analysis , Neural Stem Cells/drug effects , Neural Stem Cells/pathology , Neuropeptides/analysis , Rats , Rats, Sprague-Dawley , Thalamus/drug effects , Thalamus/pathology , Wernicke Encephalopathy/chemically inducedABSTRACT
Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviors which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. Thus, the purpose of the present study was to elucidate the role of glutamatergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether NMDA receptor stimulation or blockade would affect this response. Unilateral microinjections of NMDA (30 nmol/0.5 µL) into the IC did not alter PPI while microinjections of MK-801 (30 nmol/0.5 µL) into this structure disrupted PPI. We also examined the ability of the atypical antipsychotic olanzapine (5.0mg/kg; i.p.) to reverse the disruption of pre-pulse inhibition produced by unilateral microinjections of MK-801 into the IC of rats. Pretreatment with olanzapine blocked MK-801-induced disruption of PPI. Altogether, these results suggest that glutamate-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic olanzapine.
Subject(s)
Antipsychotic Agents/pharmacology , Benzodiazepines/pharmacology , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Inferior Colliculi/drug effects , Sensory Gating/drug effects , Acoustic Stimulation/methods , Analysis of Variance , Animals , Excitatory Amino Acid Agonists/pharmacology , Male , Microinjections , N-Methylaspartate/pharmacology , Olanzapine , Psychoacoustics , Rats , Rats, Wistar , Reflex, Startle/drug effectsABSTRACT
Stress leads to secretion of the adrenal steroid hormone corticosterone (CORT). The aim of this study was to determine the effects of chronic CORT administration on auditory and visual fear conditioning. Male Sprague-Dawley rats received CORT (400 mg/ml) in their drinking water for 10 consecutive days; this treatment induces stress levels of serum CORT. CORT impaired fear conditioning (F((1,28)) = 11.52, p < 0.01) and extinction (F((1,28)) = 4.86, p < 0.05) of auditory fear learning, but did not affect visual fear conditioning. In addition, we analyzed the CORT effects on the neuronal morphology of the inferior colliculus (flat neurons, auditory mesencephalon, a key brain area for auditory processing) and superior colliculus (wide-field neurons, related to visual processing) by Golgi stain. CORT decreased dendritic arborization of inferior colliculus neurons by approximately 50%, but did not affect superior colliculus neurons. Thus, CORT had more deleterious effects on the auditory fear processing than the visual system in the brain.
Subject(s)
Corticosterone/pharmacology , Inferior Colliculi/drug effects , Inferior Colliculi/physiology , Acoustic Stimulation , Animals , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Corticosterone/blood , Dendrites/drug effects , Dendrites/physiology , Fear/drug effects , Fear/physiology , Inferior Colliculi/anatomy & histology , Male , Maze Learning/drug effects , Maze Learning/physiology , Models, Neurological , Photic Stimulation , Rats , Rats, Sprague-Dawley , Stress, PhysiologicalABSTRACT
Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.
Subject(s)
Geniculate Bodies/drug effects , Neurons/drug effects , Sodium Salicylate/toxicity , Synaptic Transmission/drug effects , Tinnitus/physiopathology , Acoustic Stimulation , Action Potentials/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Excitatory Postsynaptic Potentials/drug effects , Female , Geniculate Bodies/physiopathology , Inferior Colliculi/drug effects , Inferior Colliculi/physiopathology , Inhibitory Postsynaptic Potentials/drug effects , Male , Membrane Potentials/drug effects , Neural Inhibition/drug effects , Neurons/physiology , Patch-Clamp Techniques , Rats , Rats, Wistar , Receptors, GABA-A/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Reflex, Startle/drug effects , Tinnitus/chemically inducedABSTRACT
Both human speech and animal vocal signals contain frequency-modulated (FM) sounds. Although central auditory neurons that selectively respond to the direction of frequency modulation are known, the synaptic mechanisms underlying the generation of direction selectivity (DS) remain elusive. Here we show the emergence of DS neurons in the inferior colliculus by mapping the three major subcortical auditory nuclei. Cell-attached recordings reveal a highly reliable and precise firing of DS neurons to FM sweeps in a preferred direction. By using in vivo whole-cell current-clamp and voltage-clamp recordings, we found that the synaptic inputs to DS neurons are not direction selective, but temporally reversed excitatory and inhibitory synaptic inputs are evoked in response to opposing directions of FM sweeps. The construction of such temporal asymmetry, resulting DS, and its topography can be attributed to the spectral disparity of the excitatory and the inhibitory synaptic tonal receptive fields.
Subject(s)
Auditory Pathways/physiology , Sound Localization/physiology , Space Perception/physiology , Action Potentials/physiology , Anesthetics, Local/pharmacology , Animals , Auditory Pathways/anatomy & histology , Auditory Pathways/drug effects , Biotin/analogs & derivatives , Biotin/metabolism , Cesium/pharmacology , Cochlear Nucleus/cytology , Cochlear Nucleus/drug effects , Cochlear Nucleus/physiology , Electric Stimulation/methods , Female , Inferior Colliculi/cytology , Inferior Colliculi/drug effects , Inferior Colliculi/physiology , Lidocaine/analogs & derivatives , Lidocaine/pharmacology , Patch-Clamp Techniques , Photic Stimulation , Potassium Channel Blockers/pharmacology , Rats , Rats, Sprague-Dawley , Sensory Receptor Cells/physiology , Synaptic Transmission/physiology , Tetraethylammonium/pharmacology , Thalamus/cytology , Thalamus/drug effects , Thalamus/physiologyABSTRACT
Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in schizophrenia patients and in rats with central dopamine (DA) activation. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The aim of this study was to elucidate the role of DA transmission of the IC on the development of acoustic PPI. Bilateral microinjections of apomorphine (9.0 µg/0.5 µL), an agonist of D(2) receptors, into the IC disrupted PPI while microinjections of haloperidol (0.5 µg/0.5 µL), an antagonist of D(2) receptors, into this structure did not alter PPI. These results suggest that dopamine-mediated mechanisms of the IC are involved in the expression of PPI in rodents.
Subject(s)
Apomorphine/administration & dosage , Apomorphine/pharmacology , Haloperidol/administration & dosage , Haloperidol/pharmacology , Inferior Colliculi/drug effects , Reflex, Startle/drug effects , Reflex, Startle/physiology , Acoustic Stimulation , Animals , Dopamine/metabolism , Dopamine Agonists/administration & dosage , Dopamine Agonists/pharmacology , Dopamine Antagonists/administration & dosage , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Inferior Colliculi/physiology , Male , Microinjections , Rats , Rats, Wistar , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/metabolism , SchizophreniaABSTRACT
The inferior colliculus (IC) is primarily involved in the processing of acoustic stimuli, being in a position to send auditory information to motor centers that participate in behaviors such as prey catching and predators' avoidance. The role of the central nucleus of the IC (CIC) on fear and anxiety has been suggested on the basis that rats are able to engage in tasks to decrease the aversiveness of CIC stimulation, increased Fos immunolabeling during diverse aversive states and increased CIC auditory evoked potentials (AEP) induced by conditioned fear stimuli. Additionally, it was shown that brainstem AEP, represented by wave V, for which the main generator is the IC, is increased during experimentally-induced anxiety. Rats segregated according to their low or high emotional reactivity have been used as an important tool in the study of fear and anxiety. The IC contains a high density of GABA receptors. Since the efficacy of an anxiolytic compound is a function of the animal's anxiety level, it is possible that GABA-benzodiazepine (Bzp) agents affect LA and HA animals differently. In this study we investigated the GABA-Bzp influence on the modulation of AEP in rats with low- (LA) or high-anxiety (HA) levels, as assessed by the elevated plus-maze test (EPM). GABA-Bzp modulation on the unconditioned AEP response was analyzed by using intra-CIC injections (0.2 µl) of the GABA-Bzp agonists muscimol (121 ng) and diazepam (30 µg), or the GABA inhibitors bicuculline (10 ng) and semicarbazide (7 µg). In a second experiment, we evaluate the effects of contextual aversive conditioning on AEP using foot-shocks as unconditioned stimuli. On the unconditioned fear paradigm GABA inhibition increased AEP in LA rats and decreases this measure in HA counterparts. Muscimol was effective in reducing AEP in both LA and HA rats. Contextual fear stimuli increased the magnitude of AEP. In spite of no effect obtained with diazepam in LA rats the drug inhibited AEP in HA animals. The specificity of the regulatory mechanisms mediated by GABA-Bzp for the ascending neurocircuits responsible for the acquisition of aversive information in LA and HA animals shed light on the processing of sensory information underlying the generation of defensive reactions.
Subject(s)
Anxiety/complications , Conditioning, Classical/physiology , Fear , Sensory Gating/physiology , gamma-Aminobutyric Acid/metabolism , Acoustic Stimulation/methods , Animals , Behavior, Animal , Benzodiazepines/pharmacology , Bicuculline/pharmacology , Clonixin/analogs & derivatives , Clonixin/pharmacology , Conditioning, Classical/drug effects , Diazepam/pharmacology , Disease Models, Animal , Electroencephalography/methods , Evoked Potentials, Auditory/drug effects , Evoked Potentials, Auditory/physiology , GABA-A Receptor Agonists/pharmacology , GABA-A Receptor Antagonists/pharmacology , Inferior Colliculi/cytology , Inferior Colliculi/drug effects , Male , Maze Learning/drug effects , Maze Learning/physiology , Microinjections , Muscimol/pharmacology , Neurons/drug effects , Prostaglandin Antagonists/pharmacology , Rats , Rats, Wistar , Sensory Gating/drug effects , Statistics as TopicABSTRACT
Speech recognition and language learning can be affected by both peripheral and central auditory system impairment. However, whether sensorineural hearing loss would affect central auditory processing is not clear. Recent studies found that salicylate not only affects outer hair cell motility in the cochlea, but also blocks GABAergic neuron activities in central nervous systems. This provides a good animal model to evaluate the role of sensorineural hearing loss and central inhibition in auditory temporal processing. In this study, gap prepulse inhibition (gap-PPI) of the acoustic startle reflex was used to measure effects of salicylate on gap detection acuity. Salicylate administration (250 mg/kg) resulted in a significant reduction in gap-PPI amplitude and an increased gap detection threshold at 50 dB SPL, but not at 60 or 80 dB SPL. To identify the physiological effects of salicylate on central auditory system function, the inferior colliculus (IC) and auditory cortex (AC) responses were measured from conscious rats with chronically implanted electrodes. Salicylate induced a significant increase of the gap-detection threshold in AC-evoked potentials, but not in the IC-evoked potentials. The AC gap-detection threshold shift was diminished measured at an equal sensational level. These results suggest that salicylate-induced temporal processing deficits may be due to peripheral hearing loss, not central disinhibition.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Auditory Cortex/drug effects , Evoked Potentials, Auditory, Brain Stem/drug effects , Inferior Colliculi/drug effects , Salicylates/pharmacology , Acoustic Stimulation/methods , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Male , Neural Inhibition/drug effects , Psychoacoustics , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effectsABSTRACT
Rats segregated according to low (LA) or high (HA) anxiety levels have been used as an important tool in the study of fear and anxiety. Since the efficacy of an anxiolytic compound is a function of the animal's basal anxiety level, it is possible that chronic treatment with a benzodiazepine (Bzp) affects LA and HA animals differently. Based on these assumptions, this study aimed to provide some additional information on the influence of acute, chronic (18 days) and withdrawal effects (48 h) from diazepam (10 mg/kg), in rats with LA or HA levels, on startle response amplitude. For this purpose, the elevated plus-maze (EPM) test was used. In addition, the role of glutamate receptors of the central nucleus of the inferior colliculus (cIC), the most important mesencephalic tectum integrative structure of the auditory pathways and a brain region that is linked to the processing of auditory information of aversive nature, was also evaluated. Our results showed that, contrary to the results obtained in LA rats, long-term treatment with diazepam promoted anxiolytic and aversive effects in HA animals that were tested under chronic effects or withdrawal from this drug, respectively. In addition, since Bzp withdrawal may function as an unconditioned stressor, the negative affective states observed in HA rats could be a by-product of GABA-glutamate imbalance in brain systems that modulate unconditioned fear and anxiety behaviors, since the blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors in the cIC clearly reduced the aversion promoted by diazepam withdrawal.
Subject(s)
Anti-Anxiety Agents/administration & dosage , Diazepam/administration & dosage , Inferior Colliculi/drug effects , Receptors, Glutamate/metabolism , Reflex, Startle/drug effects , Acoustic Stimulation , Animals , Anti-Anxiety Agents/adverse effects , Anxiety/psychology , Diazepam/adverse effects , Evoked Potentials, Auditory/drug effects , Excitatory Amino Acid Antagonists/administration & dosage , Inferior Colliculi/physiology , Male , Maze Learning/drug effects , Maze Learning/physiology , Rats , Rats, Wistar , Receptors, AMPA/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Reflex, Startle/physiology , Species Specificity , Substance Withdrawal Syndrome , Ultrasonics , Vocalization, Animal/drug effects , Vocalization, Animal/physiologyABSTRACT
The effects of sodium salicylate (NaSA) on the expressions of gamma-aminobutyricacid (GABA) and glutamate (Glu), and auditory response properties of the inferior colliculus neurons in mice were studied. Thirty-six Kunming mice were divided into three groups: control group (saline injection); NaSA group (NaSA 450 mg/kg, i.p., each day for 15 d); NaSA + lidocaine group (NaSA 450 mg/kg + lidocaine 10 mg/kg, i.p., each day for 15 d). The expressions of GABA and Glu were examined with immunohistochemical method. The intensity-rate function, intensity-latency function and frequency-tuning curve were determined with extracellular electrophysiological recording. Results are as follows: (1) The expression of GABA in the NaSA and NaSA + lidocaine groups decreased remarkably compared with that in the control group; there was no noticeable difference between the NaSA and NaSA + lidocaine groups. The expression of Glu in the NaSA group increased significantly compared with that in the control and NaSA + lidocaine groups. No difference in the expression of Glu was found between the control and NaSA + lidocaine groups. (2) In NaSA group, the intensity-rate function displayed a non-monotonic pattern, rising at low intensity and descending at high intensity; the tip of frequency-tuning curves became broad after administration of NaSA. (3) The changes in intensity-rate function and intensity-latency function were not evident and the tips of the frequency-tuning curves sharpened in the NaSA + lidocaine group. These results suggest that administration of NaSA increases the expression of Glu-positive neurons and reduces that of GABA-positive neurons in the inferior colliculus. NaSA changes the auditory response properties of the inferior colliculus and lidocaine can reverse these changes.
Subject(s)
Glutamates/analysis , Inferior Colliculi/drug effects , Sodium Salicylate/pharmacology , gamma-Aminobutyric Acid/analysis , Acoustic Stimulation , Animals , Female , Glutamic Acid/analysis , Immunohistochemistry , Inferior Colliculi/chemistry , Inferior Colliculi/physiology , Male , Mice , Reaction Time/drug effectsABSTRACT
In midbrain tectum (MT) structures, such as the dorsal periaqueductal gray (dPAG), the superior colliculus (SC) and the inferior colliculus (IC) GABAergic neurons exert a tonic control on the neural substrates involved in the expression of defensive reactions. In this review, we summarize behavioral, immunohistochemical (brain Fos distribution) and electrophysiological (auditory evoked potentials) data obtained with the reduction of GABA transmission by local injections of a GABA receptor blocker (bicuculline, BIC) or a glutamic acid decarboxylase inhibitor (semicarbazide, SMC) into the MT. Distinct patterns of Fos distribution were obtained following the freezing and escape reactions induced by MT injections of SMC and BIC, respectively. While only the laterodorsal nucleus of the thalamus was labeled after SMC-induced freezing, a widespread increase in Fos expression in the brain occurred after BIC-induced escape. Also, injections of SMC into the IC increased the auditory evoked potentials recorded from this structure. It is suggested that GABAergic mechanisms of MT are also called into play when sensory gating of the MT is activated during different emotional states.
Subject(s)
Fear/physiology , Freezing Reaction, Cataleptic/physiology , Inferior Colliculi/physiology , Periaqueductal Gray/physiology , gamma-Aminobutyric Acid/physiology , Animals , Bicuculline/pharmacology , Brain Mapping , Escape Reaction/drug effects , Escape Reaction/physiology , Freezing Reaction, Cataleptic/drug effects , GABA Antagonists/pharmacology , Inferior Colliculi/drug effects , Models, Neurological , Oncogene Proteins v-fos/metabolism , Periaqueductal Gray/drug effects , Semicarbazides/pharmacology , Thalamus/metabolism , Time FactorsABSTRACT
The magnitude of an acoustic startle response can be reduced by a weak stimulus presented immediately before the startle-eliciting noise. This phenomenon has been termed prepulse inhibition of the startle reaction (PPI). Previous studies indicated that the primary neural pathways mediating PPI belong to the brain stem and that the inferior colliculus (IC) was crucial. Its destruction reduced PPI. Stimulations applied to brain areas may be as deleterious as lesions. Therefore, we looked for the possibility of a brain stimulation applied to the IC during a PPI test to reduce also PPI. Rats were implanted with chronic electrodes, their tips being aimed at the IC. They were located within or close to the inter-colliculus nucleus. A train of stimulations was applied and PPI was tested alternately during and between periods of stimulation. As the most common method used to attenuate PPI consists in administrating drugs, for example ketamine, we also tested the effect of this drug. Another drug was also tested, diazepam, since it alters the functioning of the IC without any known effect on PPI. This allowed a comparative analysis of the neurobiological and the pharmacological effects. It appeared that the stimulation decreased PPI quantitatively as much as ketamine (6 mg/kg) without an effect of the basic startle reaction. These effects did not interfere with each other. Diazepam (1 mg/kg) did not modify PPI, neither under stimulation nor per se. Only for a very high dose (4 mg/kg), a sedative and myo-relaxant one the basic startle and PPI were altered.
Subject(s)
Diazepam/pharmacology , Electric Stimulation , Inferior Colliculi/radiation effects , Ketamine/pharmacology , Reflex, Startle/radiation effects , Acoustic Stimulation , Animals , Behavior, Animal , Brain Mapping , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacology , Functional Laterality , GABA Modulators/pharmacology , Inferior Colliculi/drug effects , Inferior Colliculi/physiology , Inhibition, Psychological , Male , Rats , Rats, Long-Evans , Reflex, Startle/drug effects , Reflex, Startle/physiologyABSTRACT
A major cue for the localization of sound in space is the interaural time difference (ITD). We examined the role of inhibition in the shaping of ITD responses in the inferior colliculus (IC) by iontophoretically ejecting gamma-aminobutyric acid (GABA) antagonists and GABA itself using a multibarrel pipette. The GABA antagonists block inhibition, whereas the applied GABA provides a constant level of inhibition. The effects on ITD responses were evaluated before, during and after the application of the drugs. If GABA-mediated inhibition is involved in shaping ITD tuning in IC neurons, then applying additional amounts of this inhibitory transmitter should alter ITD tuning. Indeed, for almost all neurons tested, applying GABA reduced the firing rate and consequently sharpened ITD tuning. Conversely, blocking GABA-mediated inhibition increased the activity of IC neurons, often reduced the signal-to-noise ratio and often broadened ITD tuning. Blocking GABA could also alter the shape of the ITD function and shift its peak suggesting that the role of inhibition is multifaceted. These effects indicate that GABAergic inhibition at the level of the IC is important for ITD coding.
Subject(s)
Auditory Pathways/physiology , Inferior Colliculi/physiology , Neural Inhibition/physiology , Sound Localization/physiology , Time Perception/physiology , gamma-Aminobutyric Acid/metabolism , Acoustic Stimulation/methods , Action Potentials/drug effects , Action Potentials/radiation effects , Animals , Auditory Pathways/drug effects , Auditory Pathways/radiation effects , Auditory Threshold/physiology , Bicuculline/pharmacology , Brain Mapping , Dose-Response Relationship, Radiation , Female , Functional Laterality , GABA Antagonists/pharmacology , Glutamic Acid/pharmacology , Inferior Colliculi/drug effects , Inferior Colliculi/radiation effects , Iontophoresis/methods , Neural Inhibition/drug effects , Neural Inhibition/radiation effects , Rabbits , Sound , Sound Localization/drug effects , Sound Localization/radiation effects , Time Perception/drug effects , Time Perception/radiation effectsABSTRACT
Distributions of arg3.1 and c-fos immunoreactive neurons (IRN) in gerbil auditory cortex (AC) and amygdala showed characteristic differences when comparing systemic application of the tinnitus-eliciting drug salicylate with acoustic stimulation or saline injections. In AC, arg3.1 IRN induced by stimulation focused in regions corresponding to the frequency content of the stimulus. Injections of salicylate (350 mg/kg body weight) led to accumulation of arg3.1 IRN in the high frequency domain, while saline injections produced a diffuse distribution. After all treatments, c-fos IRN outnumbered arg3.1 IRN in AC and showed a broad distribution. In subcortical auditory structures arg3.1 IRN were absent in all but one brain. In ventral cochlear nucleus, c-fos IRN were always found after stimulation and often also after saline injections, whereas none were present when injecting salicylate. Similarly, in inferior colliculus, numbers of c-fos IRN were lowest after salicylate injections. In the amygdala, c-fos and arg3.1 IRN were increased substantially after salicylate injections compared to auditory stimulation or saline injections. In particular in its central nucleus, c-fos and arg3.1 IRN were found exclusively after the tinnitus-inducing treatment, suggesting that coactivation of the AC and the amygdala may by an essential feature of tinnitus-related activation.
Subject(s)
Amygdala/physiopathology , Auditory Cortex/physiopathology , Cytoskeletal Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neuronal Plasticity , Proto-Oncogene Proteins c-fos/metabolism , Tinnitus/physiopathology , Acoustic Stimulation , Amygdala/drug effects , Animals , Auditory Cortex/drug effects , Auditory Pathways/drug effects , Auditory Pathways/metabolism , Cell Count , Cochlear Nucleus/drug effects , Cochlear Nucleus/metabolism , Female , Gerbillinae , Immunohistochemistry , Inferior Colliculi/drug effects , Inferior Colliculi/metabolism , Injections , Male , Neurons/metabolism , Neurons/pathology , Salicylates/administration & dosage , Salicylates/pharmacology , Sodium Chloride/administration & dosage , Sodium Chloride/pharmacology , Tinnitus/chemically induced , Tinnitus/metabolism , Tinnitus/pathologyABSTRACT
Carboplatin is currently being used as an anticancer drug against human cancers. However, high dose of carboplatin chemotherapy resulted in ototoxicity in cancer patients. Carboplatin-induced ototoxicity was related to oxidative stress to the cochlea and inner hair cell loss in animals. It is likely that initial oxidative injury spreads throughout the neuroaxis of the auditory system later. The study aim was to evaluate carboplatin-induced hearing loss and oxidative injury to the central auditory system (inferior colliculus) of the rat. Male Wistar rats were divided into two groups of seven animals each and treated as follows: (1) control (normal saline, intraperitoneal [i.p.]) and (2) carboplatin (256 mg/kg, i.p.). Auditory brain-evoked responses (ABRs) were recorded before and 4 days after treatments. The animals were sacrificed on the 4th day and inferior colliculus from brain stem and cerebellum were isolated and analyzed. Carboplatin significantly elevated the hearing threshold shifts at clicks, 2-, 4-, 8-, 16-, and 32-kHz tone burst stimuli. Carboplatin significantly increased nitric oxide and lipid peroxidation, xanthine oxidase, and manganese superoxide dismutase activities in the inferior colliculus, but not in the cerebellum, indicating an enhanced flux of free radicals in the central auditory system. Carboplatin significantly depressed the reduced to oxidized glutathione ratio, antioxidant enzyme activities, such as copper-zinc superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, and enzyme protein expressions in the inferior colliculus, but not in the cerebellum, 4 days after treatment. The data suggest that carboplatin induced oxidative injury specifically in the inferior colliculus of the rat leading to hearing loss.