Resveratrol noncompetitively inhibits glycine receptor-mediated currents in neurons of rat central auditory neurons.

Resveratrol, a naturally occurring stilbene found in red wine, is known to modulate the activity of several types of ion channels and membrane receptors, including Ca2+, K+, and Na+ ion channels. However, little is known about the effects of resveratrol on some important receptors, such as glycine receptors and GABAA receptors, in the central nervous system (CNS). In the present study, the effects of resveratrol on glycine receptor or GABAA receptor-mediated currents in cultured rat inferior colliculus (IC) and auditory cortex (AC) neurons were studied using whole-cell voltage-clamp recordings. Resveratrol itself did not evoke any currents in IC neurons but it reversibly decreased the amplitude of glycine-induced current (IGly) in a concentration-dependent manner. Resveratrol did not change the reversal potential of IGly but it shifted the concentration-response relationship to the right without changing the Hill coefficient and with decreasing the maximum response of IGly. Interestingly, resveratrol inhibited the amplitude of IGly but not that of GABA-induced current (IGABA) in AC neurons. More importantly, resveratrol inhibited GlyR-mediated but not GABAAR-mediated inhibitory postsynaptic currents in IC neurons using brain slice recordings. Together, these results demonstrate that resveratrol noncompetitively inhibits IGly in auditory neurons by decreasing the affinity of glycine to its receptor. These findings suggest that the native glycine receptors but not GABAA receptors in central neurons are targets of resveratrol during clinical administrations.

MPTP toxicity causes vocal, auditory, orientation and movement defects in the echolocation bat.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can damage dopaminergic neurons in the substantia nigra in many mammals with biochemical and cellular changes that are relatively similar to those observed in Parkinson's disease. Our study examined whether MPTP-treated echolocation bats can cause changes in bat echolocation system. By considering ultrasound spectrums, auditory brainstem-evoked potentials and flight trajectories of normal bats, we observed that the vocal, auditory, orientation and movement functions of MPTP-treated bats were significantly impaired, and they exhibited various symptoms resembling those in patients with Parkinson's disease. Our immunohistochemistry and western blot analyses further indicated that expression of vocal-related FOXP2 in the superior colliculus, auditory-related otoferlin in the inferior colliculus, dopamine synthesis-related aromatic l-amino acid decarboxylase in the substantia nigra and dopamine receptor in the striatum was significantly decreased. Furthermore, protein expression related to inflammation, oxidative stress and apoptosis in the substantia nigra was significantly increased in MPTP-treated bats. These results indicate that inflammation, oxidative stress and apoptosis may be instrumental in dopaminergic neurodegeneration in the substantia nigra. The vocal, auditory and orientation and movement dysfunctions of MPTP-treated bats are relatively consistent with symptoms of Parkinson's disease.

Amygdala inhibition impairs fear conditioning but increases the stimulus-driven activity in the inferior colliculus.

It has been shown that fear conditioning improves the steady-state evoked potentials driven by a long lasting amplitude modulated tone in the inferior colliculus. In this work we tested the hypothesis that the amygdala modulates this effect, since it plays a crucial role in assessing the biological relevance of environmental stimuli. We inhibited the basolateral nucleus of the amygdala of rats by injecting a GABAa receptor agonist (muscimol) before the recall test session of an auditory fear conditioning paradigm and recorded the evoked activity in the central nucleus of the inferior colliculus. According to our results, the treatment with muscimol decreased the expression of freezing behavior during the recall test session, but did not impair the entrainment of the evoked activity in the inferior colliculus induced by fear conditioning. We repeated the injection protocol with another group of rats but without pairing the tone to an aversive stimulus and observed that the inhibition of the basolateral amygdala enhances the stimulus-driven activity in the inferior colliculus regardless of the conditioning task. Our findings suggest that the basolateral amygdala exerts a tonic modulation over the encoding of sensory information at the early stages of the sensory pathway.

In utero exposure to valproic acid disrupts ascending projections to the central nucleus of the inferior colliculus from the auditory brainstem.

Prenatal exposure to the antiepileptic valproic acid (VPA) is associated with an increased risk of autism spectrum disorder (ASD) in humans. Accordingly, in utero exposure to VPA is a validated and biologically relevant animal model of ASD. The majority of individuals with ASD exhibit some degree of auditory dysfunction, ranging from deafness to hypersensitivity. Animals exposed to VPA in utero have abnormal tonotopic maps and responses in the cerebral cortex and hyperactivation, hypoplasia, abnormal neuronal morphology and reduced calcium binding protein expression throughout the auditory brainstem nuclei. Further, our previous work suggests that GABAergic neuronal populations may be more severely impacted by in utero VPA exposure. However, the axonal projection patterns of brainstem nuclei to the inferior colliculus (IC) have not been investigated in VPA-exposed animals. Herein, we use stereotaxic injections of the retrograde tracer Fast Blue into the central nucleus of the IC (CNIC) and examine the proportions of retrogradely labeled neurons in the nuclei of the lateral lemniscus, superior olivary complex and cochlear nuclei. Our results indicate that not only are there fewer neurons in the auditory brainstem after VPA exposure, but also that fewer neurons are retrogradely labeled from the CNIC. Together, our results indicate that in utero VPA exposure may result in altered patterns of input to the auditory midbrain.

GABAA receptors contribute more to rate than temporal coding in the IC of awake mice.

Speech is our most important form of communication, yet we have a poor understanding of how communication sounds are processed by the brain. Mice make great model organisms to study neural processing of communication sounds because of their rich repertoire of social vocalizations and because they have brain structures analogous to humans, such as the auditory midbrain nucleus inferior colliculus (IC). Although the combined roles of GABAergic and glycinergic inhibition on vocalization selectivity in the IC have been studied to a limited degree, the discrete contributions of GABAergic inhibition have only rarely been examined. In this study, we examined how GABAergic inhibition contributes to shaping responses to pure tones as well as selectivity to complex sounds in the IC of awake mice. In our set of long-latency neurons, we found that GABAergic inhibition extends the evoked firing rate range of IC neurons by lowering the baseline firing rate but maintaining the highest probability of firing rate. GABAergic inhibition also prevented IC neurons from bursting in a spontaneous state. Finally, we found that although GABAergic inhibition shaped the spectrotemporal response to vocalizations in a nonlinear fashion, it did not affect the neural code needed to discriminate vocalizations, based either on spiking patterns or on firing rate. Overall, our results emphasize that even if GABAergic inhibition generally decreases the firing rate, it does so while maintaining or extending the abilities of neurons in the IC to code the wide variety of sounds that mammals are exposed to in their daily lives.NEW & NOTEWORTHY GABAergic inhibition adds nonlinearity to neuronal response curves. This increases the neuronal range of evoked firing rate by reducing baseline firing. GABAergic inhibition prevents bursting responses from neurons in a spontaneous state, reducing noise in the temporal coding of the neuron. This could result in improved signal transmission to the cortex.

Exposure to sodium salicylate disrupts VGLUT3 expression in cochlear inner hair cells and contributes to tinnitus.

To examine whether exposure to sodium salicylate disrupts expression of vesicular glutamate transporter 3 (VGLUT3) and whether the alteration in expression corresponds to increased risk for tinnitus. Rats were treated with saline (control) or sodium salicylate (treated) Rats were examined for tinnitus by monitoring gap-pre-pulse inhibition of the acoustic startle reflex (GPIAS). Auditory brainstem response (ABR) was applied to evaluate hearing function after treatment. Rats were sacrificed after injection to obtain the cochlea, cochlear nucleus (CN), and inferior colliculus (IC) for examination of VGLUT3 expression. No significant differences in hearing thresholds between groups were identified (p>0.05). Tinnitus in sodium salicylate-treated rats was confirmed by GPIAS. VGLUT3 encoded by solute carrier family 17 members 8 (SLC17a8) expression was significantly increased in inner hair cells (IHCs) of the cochlea in treated animals, compared with controls (p<0.01). No significant differences in VGLUT3 expression between groups were found for the cochlear nucleus (CN) or IC (p>0.05). Exposure to sodium salicylate may disrupt SLC17a8 expression in IHCs, leading to alterations that correspond to tinnitus in rats. However, the CN and IC are unaffected by exposure to sodium salicylate, suggesting that enhancement of VGLUT3 expression in IHCs may contribute to the pathogenesis of tinnitus.

Transcriptomic profile analysis of brain inferior colliculus following acute hydrogen sulfide exposure.

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.

Auditory Brainstem Changes in Timing may Underlie Hyperacusis in a Salicylate-induced Acute Rat Model.

Hyperacusis, an exaggerated, sometimes painful perception of loudness even for soft sounds, is a poorly understood distressing condition. While the involvement of modified gain of central auditory neurons and the influence of nonauditory brain regions are well-documented, the issue of where in the auditory system these abnormalities arise remains open, particularly when hyperacusis comes without sensorineural hearing loss. Here we used acute intraperitoneal administration of sodium salicylate (150 mg/kg) in rats, enough to produce > 10-dB decrease in acoustic startle threshold with mild hearing loss at low frequencies (<10 kHz). Anesthesia, necessary for middle-ear-reflex (MEMR) threshold measurements, abolished the olivocochlear efferent reflex but not the MEMR acting on frequencies < 10 kHz, and its mean threshold increased from 55 dB SPL in controls to 80 dB SPL in salicylate-treated animals 60-90 minutes after injection, with an about 3-dB increase in acoustic energy reaching the cochlea. The mean latencies of auditory brainstem-evoked responses (ABR) conspicuously decreased after salicylate, by 0.25 millisecond at 6 kHz at every level, a frequency-dependent effect absent above 12 kHz. A generic model of loudness based upon cross-frequency coincidence detection predicts that with such timing changes, a transient sound may seem as loud at <40 dB SPL as it does in controls at >60 dB SPL. Candidate circuits able to act at the same time on the startle reflex, the MEMR and ABRs may be serotoninergic, as salicylate is known to increase brain serotonin and 5-HT neurons participate in MEMR and ABR circuits.

Differential cell-type dependent brain state modulations of sensory representations in the non-lemniscal mouse inferior colliculus.

Sensory responses of the neocortex are strongly influenced by brain state changes. However, it remains unclear whether and how the sensory responses of the midbrain are affected. Here we addressed this issue by using in vivo two-photon calcium imaging to monitor the spontaneous and sound-evoked activities in the mouse inferior colliculus (IC). We developed a method enabling us to image the first layer of non-lemniscal IC (IC shell L1) in awake behaving mice. Compared with the awake state, spectral tuning selectivity of excitatory neurons was decreased during isoflurane anesthesia. Calcium imaging in behaving animals revealed that activities of inhibitory neurons were highly correlated with locomotion. Compared with stationary periods, spectral tuning selectivity of excitatory neurons was increased during locomotion. Taken together, our studies reveal that neuronal activities in the IC shell L1 are brain state dependent, whereas the brain state modulates the excitatory and inhibitory neurons differentially.

Neuroprotective activation of astrocytes by methylmercury exposure in the inferior colliculus.

Methylmercury (MeHg) is well known to induce auditory disorders such as dysarthria. When we performed a global analysis on the brains of mice exposed to MeHg by magnetic resonance imaging, an increase in the T1 signal in the inferior colliculus (IC), which is localized in the auditory pathway, was observed. Therefore, the purpose of this study is to examine the pathophysiology and auditory dysfunction induced by MeHg, focusing on the IC. Measurement of the auditory brainstem response revealed increases in latency and decreases in threshold in the IC of mice exposed to MeHg for 4 weeks compared with vehicle mice. Incoordination in MeHg-exposed mice was noted after 6 weeks of exposure, indicating that IC dysfunction occurs earlier than incoordination. There was no change in the number of neurons or microglial activity, while the expression of glial fibrillary acidic protein, a marker for astrocytic activity, was elevated in the IC of MeHg-exposed mice after 4 weeks of exposure, indicating that astrogliosis occurs in the IC. Suppression of astrogliosis by treatment with fluorocitrate exacerbated the latency and threshold in the IC evaluated by the auditory brainstem response. Therefore, astrocytes in the IC are considered to play a protective role in the auditory pathway. Astrocytes exposed to MeHg increased the expression of brain-derived neurotrophic factor in the IC, suggesting that astrocytic brain-derived neurotrophic factor is a potent protectant in the IC. This study showed that astrogliosis in the IC could be an adaptive response to MeHg toxicity. The overall toxicity of MeHg might be determined on the basis of the balance between MeHg-mediated injury to neurons and protective responses from astrocytes.

The Blockade of µ1- and κ-Opioid Receptors in the Inferior Colliculus Decreases the Expression of Panic Attack-Like Behaviours Induced by Chemical Stimulation of the Dorsal Midbrain.

BACKGROUND: Gamma-aminobutyric acid (GABA)ergic and opioid systems play a crucial role in the neural modulation of innate fear organised by the inferior colliculus (IC). In addition, the IC is rich in GABAergic fibres and opioid neurons, which are also connected to other mesencephalic structures, such as the superior colliculus and the substantia nigra. However, the contribution of distinct opioid receptors (ORs) in the IC during the elaboration and expression of innate fear and panic-like responses is unclear. The purpose of the present work was to investigate a possible integrated action exerted by ORs and the GABAA receptor-mediated system in the IC on panic-like responses. METHODS: The effect of the blockade of either µ1- or κ-ORs in the IC was evaluated in the unconditioned fear-induced responses elicited by GABAA antagonism with bicuculline. Microinjections of naloxonazine, a µ1-OR antagonist, or nor-binaltorphimine (nor-BNI), a κ-OR antagonist, were made into the IC, followed by intramesencephalic administration of the GABAA-receptor antagonist bicuculline. The defensive behaviours elicited by the treatments in the IC were quantitatively analysed, recording the number of escapes expressed as running (crossing), jumps, and rotations, over a 30-min period in a circular arena. The exploratory behaviour of rearing was also recorded. RESULTS: GABAA-receptor blockade with bicuculline in the IC increased defensive behaviours. However, pretreatment of the IC with higher doses (5 µg) of naloxonazine or nor-BNI followed by bicuculline resulted in a significant decrease in unconditioned fear-induced responses. CONCLUSIONS: These findings suggest a role played by µ1- and κ-OR-containing connexions and GABAA receptor-mediated neurotransmission on the organisation of panic attack-related responses elaborated by the IC neurons.

General anesthetic induced differential changes in latency of auditory evoked potential in the central nucleus of inferior colliculus of mouse.

Confirming the effect of general anesthetic on brainstem auditory evoked potential (BAEP) is important to interpret BAEP data, elucidate the neuroanatomical sites of action of general anesthetic and monitor the effect of general anesthetic. However, the effect of general anesthetic on BAEP is not thoroughly understood, which may be due to unreasonable acoustic stimulation scheme. This study aimed to redesign acoustic stimulation scheme and attempted to test our hypothesis that general anesthetic induces differential changes in BAEP latency in mouse. Auditory evoked potential in the central nucleus of inferior colliculus (AEP-ICC) was used to represent BAEP. Every 10 min after pentobarbital anesthesia, AEP-ICC was recorded by delivering tones with a rate of 1/s, and pentobarbital blood concentration (PBC) was measured, until the mice awoke. AEP-ICC latency to 80-dB SPL sounds (L80) and latency change in nerve fibers (ΔL) did not present regular changes, and AEP-ICC latency to 50-dB SPL sounds (L50) and latency change in synapses (ΔI) gradually decreased as pentobarbital was metabolized. L50 and ΔI changes were exponentially associated with decreased PBC, and L50 showed a linear relationship with ΔI. We conclude that, general anesthetic acts on auditory brainstem; general anesthetic does not alter L80 and ΔL but increases L50 and ΔI; L80 and ΔL can evaluate the function of auditory brainstem and its inferior structures under general anesthesia; L50 and ΔI exponentially reflect the blood concentration of a general anesthetic.

Panicolytic-like effect of µ1-opioid receptor blockade in the inferior colliculus of prey threatened by Crotalus durissus terrificus pit vipers.

BACKGROUND: The endogenous opioid peptide system has been implicated in the neural modulation of fear and anxiety organised by the dorsal midbrain. Furthermore, previous results indicate a fundamental role played by inferior colliculus (IC) opioid mechanisms during the expression of defensive behaviours, but the involvement of the IC µ1-opioid receptor in the modulation of anxiety- and panic attack-related behaviours remains unclear. Using a prey-versus-snake confrontation paradigm, we sought to investigate the effects of µ1-opioid receptor blockade in the IC on the defensive behaviour displayed by rats in a dangerous situation. METHODS: Specific pathogen-free Wistar rats were treated with microinjection of the selective µ1-opioid receptor antagonist naloxonazine into the IC at different concentrations (1.0, 3.0 and 5.0 µg/0.2 µL) and then confronted with rattlesnakes ( Crotalus durissus terrificus). The defensive behavioural repertoire, such as defensive attention, flat back approach (FBA), startle, defensive immobility, escape or active avoidance, displayed by rats either during the confrontations with wild snakes or during re-exposure to the experimental context without the predator was analysed. RESULTS: The blockade of µ1-opioid receptors in the IC decreased the expression of both anxiety-related behaviours (defensive attention, FBA) and panic attack-related responses (startle, defensive immobility and escape) during the confrontation with rattlesnakes. A significant decrease in defensive attention was also recorded during re-exposure of the prey to the experimental apparatus context without the predator. CONCLUSION: Taken together, these results suggest that a decrease in µ1-opioid receptor signalling activity within the IC modulates anxiety- and panic attack-related behaviours in dangerous environments.

Auditory Midbrain Hypoplasia and Dysmorphology after Prenatal Valproic Acid Exposure.

Prenatal exposure to the antiepileptic valproic acid (VPA) is associated with an increased risk of autism spectrum disorder (ASD) in humans and is used as an animal model of ASD. The majority of individuals with ASD exhibit adverse reactions to sensory stimuli and auditory dysfunction. Previous studies of animals exposed to VPA reveal abnormal neuronal responses to sound and mapping of sound frequency in the cerebral cortex and hyperactivation, hypoplasia and abnormal neuronal morphology in the cochlear nuclei (CN) and superior olivary complex (SOC). Herein, we examine the neuronal populations in the lateral lemniscus and inferior colliculus in animals exposed in utero to VPA. We used a combination of morphometric techniques, histochemistry and immunofluorescence to examine the nuclei of the lateral lemniscus (NLL) and the central nucleus of the inferior colliculus (CNIC). We found that the VPA exposure resulted in larger neurons in the CNIC and the dorsal nucleus of the lateral lemniscus (DNLL). However, we found that there were significantly fewer neurons throughout all nuclei examined in the auditory brainstem of VPA-exposed animals. Additionally, we found significantly fewer calbindin-immunopositive neurons in the DNLL. VPA exposure had no impact on the proportions of perineuronal nets in the NLL or CNIC. Finally, consistent with our observations in the CN and SOC, VPA exposure resulted in fewer dopaminergic terminals in the CNIC. Together, these results indicate that in utero VPA exposure significantly impacts structure and function of nearly the entire central auditory pathway.

Testing the Central Gain Model: Loudness Growth Correlates with Central Auditory Gain Enhancement in a Rodent Model of Hyperacusis.

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.

Synergistic Transcriptional Changes in AMPA and GABAA Receptor Genes Support Compensatory Plasticity Following Unilateral Hearing Loss.

Debilitating perceptual disorders including tinnitus, hyperacusis, phantom limb pain and visual release hallucinations may reflect aberrant patterns of neural activity in central sensory pathways following a loss of peripheral sensory input. Here, we explore short- and long-term changes in gene expression that may contribute to hyperexcitability following a sudden, profound loss of auditory input from one ear. We used fluorescence in situ hybridization to quantify mRNA levels for genes encoding AMPA and GABAA receptor subunits (Gria2 and Gabra1, respectively) in single neurons from the inferior colliculus (IC) and auditory cortex (ACtx). Thirty days after unilateral hearing loss, Gria2 levels were significantly increased while Gabra1 levels were significantly decreased. Transcriptional rebalancing was more pronounced in ACtx than IC and bore no obvious relationship to the degree of hearing loss. By contrast to the opposing, synergistic shifts in Gria2 and Gabra1 observed 30 days after hearing loss, we found that transcription levels for both genes were equivalently reduced after 5 days of hearing loss, producing no net change in the excitatory/inhibitory transcriptional balance. Opposing transcriptional shifts in AMPA and GABA receptor genes that emerge several weeks after a peripheral insult could promote both sensitization and disinhibition to support a homeostatic recovery of neural activity following auditory deprivation. Imprecise transcriptional changes could also drive the system toward perceptual hypersensitivity, degraded temporal processing and the irrepressible perception of non-existent environmental stimuli, a trio of perceptual impairments that often accompany chronic sensory deprivation.

The endogenous opioid system modulates defensive behavior evoked by Crotalus durissus terrificus: Panicolytic-like effect of intracollicular non-selective opioid receptors blockade.

BACKGROUND: There is a controversy regarding the key role played by opioid peptide neurotransmission in the modulation of panic-attack-related responses. AIMS: Using a prey versus rattlesnakes paradigm, the present work investigated the involvement of the endogenous opioid peptide-mediated system of the inferior colliculus in the modulation of panic attack-related responses. METHODS: Wistar rats were pretreated with intracollicular administration of either physiological saline or naloxone at different concentrations and confronted with rattlesnakes ( Crotalus durissus terrificus). The prey versus rattlesnake confrontations were performed in a polygonal arena for snakes. The defensive behaviors displayed by prey (defensive attention, defensive immobility, escape response, flat back approach and startle) were recorded twice: firstly, over a period of 15 min the presence of the predator and a re-exposure was performed 24 h after the confrontation, when animals were exposed to the experimental enclosure without the rattlesnake. RESULTS: The intramesencephalic non-specific blockade of opioid receptors with microinjections of naloxone at higher doses decreased both anxiety- (defensive attention and flat back approach) and panic attack-like (defensive immobility and escape) behaviors, evoked in the presence of rattlesnakes and increased non-defensive responses. During the exposure to the experimental context, there was a decrease in duration of defensive attention. CONCLUSIONS: These findings suggest a panicolytic-like effect of endogenous opioid receptors antagonism in the inferior colliculus on innate (panic attack) and conditioned (anticipatory anxiety) fear in rats threatened by rattlesnakes.

Behavioral and Auditory Electrophysiological Rebound as a Compensatory Response to the Reinforcing Effects of Morphine.

Auditory-evoked potentials (AEPs) can be modified by associative learning, where the appearance of learned compensatory responses (CCRs) may result in the emergence of drug withdrawal symptoms and relapse. Although CCRs' influence on later attentive and cognitive domains has been extensively examined, contextual conditioned tolerance occurring in preattentive mechanisms operating at earlier stages of information processing has remained largely unexplored. To extend our knowledge on this subject, compensatory changes on the motor and emotional aspects of behavior evoked by contextual cues were investigated with an electronic open field in morphine-pretreated rats challenged with two morphine overdoses (40 and 80 mg/kg). CCRs influence on the AEPs recorded in the central nucleus of the inferior colliculus (CIC) was analyzed with the help of a field potential recording device and a two-chamber shuttle box placed inside a Faraday cage system. The emergence of electrophysiological CCRs was analyzed by recording AEP latency and amplitude elicited in the central nucleus of the IC (CIC) with the aid of a field potential recording device and a two-chamber shuttle box placed inside a Faraday cage system. Behavioral analysis indicated that CCRs ensue in non-familiar contexts. Electrophysiological data revealed increases in the amplitude of AEPs evoked in a non-familiar context. Our results indicate that behavioral learning responses emerge following Pavlovian conditioning even with the use of low and regular doses of morphine over a short-term treatment. Changes in the CIC electrophysiology may indicate that the development of drug dependence occurs covertly in the early stages of sensory information processing.

Increased spontaneous firing rates in auditory midbrain following noise exposure are specifically abolished by a Kv3 channel modulator.

Noise exposure has been shown to produce long-lasting increases in spontaneous activity in central auditory structures in animal models, and similar pathologies are thought to contribute to clinical phenomena such as hyperacusis or tinnitus in humans. Here we demonstrate that multi-unit spontaneous neuronal activity in the inferior colliculus (IC) of mice is significantly elevated four weeks following noise exposure at recording sites with frequency tuning within or near the noise exposure band, and this selective central auditory pathology can be normalised through administration of a novel compound that modulates activity of Kv3 voltage-gated ion channels. The compound had no statistically significant effect on IC spontaneous activity without noise exposure, nor on thresholds or frequency tuning of tone-evoked responses either with or without noise exposure. Administration of the compound produced some reduction in the magnitude of evoked responses to a broadband noise, but unlike effects on spontaneous rates, these effects on evoked responses were not specific to recording sites with frequency tuning within the noise exposure band. Thus, the results suggest that modulators of Kv3 channels can selectively counteract increases in spontaneous activity in the auditory midbrain associated with noise exposure.

Paradoxical kinesia induced by appetitive 50-kHz ultrasonic vocalizations in rats depends on glutamatergic mechanisms in the inferior colliculus.

Paradoxical kinesia is a sudden transient ability of akinetic patients to perform motor tasks they are otherwise unable to perform. This phenomenon is known to depend on the patient's emotional state and external stimuli. Paradoxical kinesia can be induced by appetitive 50-kHz ultrasonic vocalizations (USV) in rats displaying catalepsy following systemic haloperidol. We investigated the role of the inferior colliculus (IC) in paradoxical kinesia induced by 50-kHz USV, since the IC modulates haloperidol-induced catalepsy. We focused on glutamatergic and GABAergic neurotransmission, with male rats receiving intracollicular NMDA or the GABA receptor agonist diazepam 10 min before systemic haloperidol. Catalepsy time was assessed by means of the bar test, during which rats were exposed to playback of 50-kHz USV, white noise, and background noise. Our results show that playback of 50-kHz USV induced paradoxical kinesia by reducing haloperidol-induced catalepsy in rats which had received saline intracollicular microinjection. This paradoxical kinesia effect of 50-kHz USV playback on haloperidol-induced catalepsy was prevented by intracollicular NMDA administration. Although intracollicular diazepam microinjection potentiated haloperidol-induced catalepsy, it did not affect the response to 50-kHz USV playback. Together, NMDA receptor agonist suppressed the effectiveness of 50-kHz USV playback, whereas diazepam did not. These findings suggest that the IC is a key structure involved in paradoxical kinesia, with relevant processes being glutamatergic rather than GABAergic. Our approach thus appears useful for uncovering neural mechanisms of paradoxical kinesia and it might help identifying novel therapeutic targets for Parkinson's disease.