Cortical dysmorphology and reduced cortico-collicular projections in an animal model of autism spectrum disorder.

Autism spectrum disorder is a neurodevelopmental disability that includes sensory disturbances. Hearing is frequently affected and ranges from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid is associated with increased risk of autism spectrum disorder in humans and timed valproic acid exposure is a biologically relevant and validated animal model of autism spectrum disorder. Valproic acid-exposed rats have fewer neurons in their auditory brainstem and thalamus, fewer calbindin-positive neurons, reduced ascending projections to the midbrain and thalamus, elevated thresholds, and delayed auditory brainstem responses. Additionally, in the auditory cortex, valproic acid exposure results in abnormal responses, decreased phase-locking, elevated thresholds, and abnormal tonotopic maps. We therefore hypothesized that in utero, valproic acid exposure would result in fewer neurons in auditory cortex, neuronal dysmorphology, fewer calbindin-positive neurons, and reduced connectivity. We approached this hypothesis using morphometric analyses, immunohistochemistry, and retrograde tract tracing. We found thinner cortical layers but no changes in the density of neurons, smaller pyramidal and non-pyramidal neurons in several regions, fewer neurons immunoreactive for calbindin-positive, and fewer cortical neurons projecting to the inferior colliculus. These results support the widespread impact of the auditory system in autism spectrum disorder and valproic acid-exposed animals and emphasize the utility of simple, noninvasive auditory screening for autism spectrum disorder.

Auditory DUM neurons in a bush-cricket: inhibited inhibitors.

Thoracic ganglia of many hearing insects house the first level of auditory processing. In bush-crickets, the largest population of local auditory neurons in the prothoracic processing centre are dorsal unpaired median (DUM) neurons. It has been suggested that DUM neurons are inhibitory using γ-aminobutyric acid (GABA) as transmitter. Immunohistochemistry reveals a population of about 35-50 GABA-positive somata in the posterior medial cluster of the prothoracic ganglion. Only very few small somata in this cluster remain unstained. At least 10 neurites from 10 neurons can be identified. Intracellularly stained auditory DUM neurons have their soma in the cluster of median GABA positive cells and most of them exhibit GABA-immunoreactivity. Responses of certain DUM neurons show obvious signs of inhibition. Application of picrotoxin (PTX), a chloride-channel blocker in insects, changes the responses of many DUM neurons. They become broader in frequency tuning and broader or narrower in temporal pattern tuning. Furthermore, inhibitory postsynaptic potentials (IPSPs) may be replaced by excitatory postsynaptic potentials. Loss of an IPSP in the rising graded potential after PTX-application leads to a significant reduction of first-spike latency. Therefore, auditory DUM neurons receive effective inhibition and are the best candidates for inhibition in DUM neurons and other auditory interneurons.

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.

Age-Related Changes in Ang II Receptor Localization and Expression in the Developing Auditory Pathway.

We studied Ang II receptor localization in different nuclei of the auditory system, by means of binding autoradiography, during brain development. The inferior colliculus (IC), a large midbrain structure which serves as an obligatory synaptic station in both the ascending and descending auditory pathways, exhibited high Ang II AT2 binding at all ages (P0, P8, P15, P30), being maximal at P15. These observations were confirmed by in situ hybridization and immunofluorescence at P15, demonstrating that AT2 receptor mRNA localized at the same area recognized by AT2 antibodies and anti ß III-tubulin suggesting the neuronal nature of the reactive cells. Ang II AT1 receptors were absent at early developmental ages (P0) in all nuclei of the auditory system and a low level was observed in the IC at the age P8. AT2 receptors were present at ventral cochlear nucleus and superior olivary complex, being higher at P15 and P8, respectively. We also explored the effect of prenatal administration of Ang II or PD123319 (AT2 antagonist) on binding of Ang II receptors at P0, P8, P15. Both treatments increased significantly the level of AT2 receptors at P0 and P8 in the IC. Although total binding in the whole IC from P15 animals showed no difference between treatments, the central nucleus of the IC exhibited higher binding. Our results supports a correlation between the timing of the higher expression of Ang II AT2 receptors in different nuclei, the onset of audition and the establishment of neuronal circuits of the auditory pathway.

A complex mTOR response in habituation paradigms for a social signal in adult songbirds.

Nonassociative learning is considered simple because it depends on presentation of a single stimulus, but it likely reflects complex molecular signaling. To advance understanding of the molecular mechanisms of one form of nonassociative learning, habituation, for ethologically relevant signals we examined song recognition learning in adult zebra finches. These colonial songbirds learn the unique song of individuals, which helps establish and maintain mate and other social bonds, and informs appropriate behavioral interactions with specific birds. We leveraged prior work demonstrating behavioral habituation for individual songs, and extended the molecular framework correlated with this behavior by investigating the mechanistic Target of Rapamycin (mTOR) signaling cascade. We hypothesized that mTOR may contribute to habituation because it integrates a variety of upstream signals and enhances associative learning, and it crosstalks with another cascade previously associated with habituation, ERK/ZENK. To begin probing for a possible role for mTOR in song recognition learning, we used a combination of song playback paradigms and bidirectional dysregulation of mTORC1 activation. We found that mTOR demonstrates the molecular signatures of a habituation mechanism, and that its manipulation reveals the complexity of processes that may be invoked during nonassociative learning. These results thus expand the molecular targets for habituation studies and raise new questions about neural processing of complex natural signals.

Wild-Type Monomeric α-Synuclein Can Impair Vesicle Endocytosis and Synaptic Fidelity via Tubulin Polymerization at the Calyx of Held.

α-Synuclein is a presynaptic protein the function of which has yet to be identified, but its neuronal content increases in patients of synucleinopathies including Parkinson's disease. Chronic overexpression of α-synuclein reportedly expresses various phenotypes of synaptic dysfunction, but the primary target of its toxicity has not been determined. To investigate this, we acutely loaded human recombinant α-synuclein or its pathological mutants in their monomeric forms into the calyces of Held presynaptic terminals in slices from auditorily mature and immature rats of either sex. Membrane capacitance measurements revealed significant and specific inhibitory effects of WT monomeric α-synuclein on vesicle endocytosis throughout development. However, the α-synuclein A53T mutant affected vesicle endocytosis only at immature calyces, whereas the A30P mutant had no effect throughout. The endocytic impairment by WT α-synuclein was rescued by intraterminal coloading of the microtubule (MT) polymerization blocker nocodazole. Furthermore, it was reversibly rescued by presynaptically loaded photostatin-1, a photoswitcheable inhibitor of MT polymerization, in a light-wavelength-dependent manner. In contrast, endocytic inhibition by the A53T mutant at immature calyces was not rescued by nocodazole. Functionally, presynaptically loaded WT α-synuclein had no effect on basal synaptic transmission evoked at a low frequency, but significantly attenuated exocytosis and impaired the fidelity of neurotransmission during prolonged high-frequency stimulation. We conclude that monomeric WT α-synuclein primarily inhibits vesicle endocytosis via MT overassembly, thereby impairing high-frequency neurotransmission.SIGNIFICANCE STATEMENT Abnormal α-synuclein abundance is associated with synucleinopathies including Parkinson's disease, but neither the primary target of α-synuclein toxicity nor its mechanism is identified. Here, we loaded monomeric α-synuclein directly into mammalian glutamatergic nerve terminals and found that it primarily inhibits vesicle endocytosis and subsequently impairs exocytosis and neurotransmission fidelity during prolonged high-frequency stimulation. Such α-synuclein toxicity could be rescued by blocking microtubule polymerization, suggesting that microtubule overassembly underlies the toxicity of acutely elevated α-synuclein in the nerve terminal.

ERG Channels Regulate Excitability in Stellate and Bushy Cells of Mice Ventral Cochlear Nucleus.

ERG (ether-a-go-go-related gene) channels are the members of the voltage-dependent potassium channel family, which have three subtypes, as ERG1 (Kv 11.1), ERG2 (Kv 11.2), and ERG3 (Kv11.3). There is no information on ERG channels in the cochlear nucleus (CN) neurons, which is the first relay station of the auditory pathway. As occur in some of congenital long QT Syndromes (LQTS), mutation of the KCNQ11 genes for ERG channel has been reported to be accompanied by hearing loss. For that reason, we aimed to study biophysical properties and physiological importance, and contribution of ERG K+ currents to the formation of action potentials in the stellate and bushy neurons of the ventral cochlear nucleus (VCN). A total of 70 mice at 14-17 days old were used for this study. Electrophysiological characterization of ERG channels was performed using patch-clamp technique in the CN slices. In current clamp, ERG channel blockers, terfenadine (10 µM) and E-4031 (10 µM), were applied in both cell types. The activation, inactivation, and deactivation kinetics of the ERG channels were determined by voltage clamp. In conclusion, the findings obtained in the present study suggest that stellate and bushy neurons express ERG channels and ERG channels appear to contribute to setting action potential (AP) frequency, threshold for AP induction, and, possibly, resting membrane potentials in this cells.

Responses to Predictable versus Random Temporally Complex Stimuli from Single Units in Auditory Thalamus: Impact of Aging and Anesthesia.

Human aging studies suggest that an increased use of top-down knowledge-based resources would compensate for degraded upstream acoustic information to accurately identify important temporally rich signals. Sinusoidal amplitude-modulated (SAM) stimuli have been used to mimic the fast-changing temporal features in speech and species-specific vocalizations. Single units were recorded from auditory thalamus [medial geniculate body (MGB)] of young awake, aged awake, young anesthetized, and aged anesthetized rats. SAM stimuli were modulated between 2 and 1024 Hz with the modulation frequency (fm) changed randomly (RAN) across trials or sequentially (SEQ) after several repeated trials. Units were found to be RAN-preferring, SEQ-preferring, or nonselective based on total firing rate. Significant anesthesia and age effects were found. The majority (86%) of young anesthetized units preferred RAN SAM stimuli; significantly fewer young awake units (51%, p < 0.0001) preferred RAN SAM signals with 16% preferring SEQ SAM. Compared with young awake units, there was a significant increase of aged awake units preferring SEQ SAM (30%, p < 0.05). We examined RAN versus SEQ differences across fms by measuring selective fm areas under the rate modulation transfer function curve. The largest age-related differences from awake animals were found for mid-to-high fms in MGB units, with young units preferring RAN SAM while aged units showed a greater preference for SEQ-presented SAM. Together, these findings suggest that aged MGB units/animals employ increased top-down mediated stimulus context to enhance processing of "expected" temporally rich stimuli, especially at more challenging higher fms. SIGNIFICANCE STATEMENT: Older individuals compensate for impaired ascending acoustic information by increasing use of cortical cognitive and attentional resources. The interplay between ascending and descending influences in the thalamus may serve to enhance the salience of speech signals that are degraded as they ascend to the cortex. The present findings demonstrate that medial geniculate body units from awake rats show an age-related preference for predictable modulated signals relative to randomly presented signals, especially at higher, more challenging modulation frequencies. Conversely, units from anesthetized animals, with little top-down influences, strongly preferred randomly presented modulated sequences. These results suggest a neuronal substrate for an age-related increase in experience/attentional-based influences in processing temporally complex auditory information in the auditory thalamus.

Sr2+ has low efficiency in regulating spontaneous release at the Calyx of Held synapses.

It has been known that Ca2+ plays an essential role in mediating different modes of neurotransmitter release via different sensing mechanisms. Synaptotagmin 1, 2, and 9 were found to act as the Ca2+ sensors for synchronous release and synaptotagmin 7 and Doc-2 were proposed as the Ca2+ sensors for asynchronous release. Comparatively, the Ca2+ sensor for spontaneous release remains a mystery. At the Calyx of Held synapse, the Ca2+ sensor for spontaneous release was found not identical to the sensor for synchronous release, synaptotagmin 2. As Ca2+ sensors have different sensitivity to Sr2+ and Ca2+ and induce significantly different rate of vesicle release, Sr2+ is traditionally used as a tool to examine the intrinsic properties of different Ca2+ sensors. Here, we employed cell-attached patch recording and presynaptic/postsynaptic whole-cell recording at the Calyx of Held synapses of synaptotagmin 2 knock-out mice to assay the Sr2+ and Ca2+ influx into the nerve terminal at resting potential and observed the effects of Ca2+ and Sr2+ on spontaneous neurotransmitter release. We found that the dwell time of single voltage gated Ca2+ channel opening increased around threefold for Sr2+ than Ca2+ with the channel conductance unchanged; the divalent cation sensing machinery in regulating spontaneous release has much lower sensitivity to Sr2+ than Ca2+ . Thus, our study reveals some of the intrinsic properties of Ca2+ sensor(s) of spontaneous transmitter release and provided an insight into the underlying mechanisms.

Auditory processing following infantile spasms: An event-related potential study.

OBJECTIVES: To investigate acoustic auditory processing in patients with recent infantile spasms (IS). METHODS: Patients (n = 22; 12 female; median age 8 months; range 5-11 months) had normal preceding development, brain magnetic resonance imaging (MRI), and neurometabolic testing (West syndrome of unknown cause, uWS). Controls were healthy babies (n = 22; 11 female; median age 6 months; range 3-12 months). Event-related potentials (ERPs) and psychometry (Bayley Scales of Infant Development, Second Edition, BSID-II) took place at a month following IS remission. RESULTS: Following a repeated pure tone, uWS patients showed less suppression of the N100 at the mid-temporal electrodes (p = 0.006), and a prolonged response latency (p = 0.019). Their novelty P300 amplitude over the mid-temporal electrodes was halved (p = 0.001). The peak of the novelty P300 to environmental broadband sounds emerged later over the left temporal lobe in patients (p = 0.015), the lag correlating with duration of spasms (r = 0.547, p = 0.015). BSID-II scores were lower in patients (p < 0.001), with no correlation to ERP. SIGNIFICANCE: Complex acoustic information is processed poorly following IS. This would impair language. Treatment did not reverse this phenomenon, but may have limited its severity. The data are most consistent with altered connectivity of the cortical acoustic processing areas induced by IS.

Adverse effects of pesticides on central auditory functions in tobacco growers.

OBJECTIVE: To investigate the effects of exposure to pesticides on the central auditory functions (CAF) of Brazilian tobacco growers. DESIGN: This was a cross-sectional study carried out between 2010 and 2012. Participants were evaluated with two behavioural procedures to investigate CAF, the random gap detection test (RGDT) and the dichotic digit test in Portuguese (DDT). STUDY SAMPLE: A total of 22 growers exposed to pesticides (study group) and 21 subjects who were not exposed to pesticides (control group) were selected. RESULTS: No significant differences between groups were observed for pure-tone thresholds. A significant association between pesticide exposure and the results for RGDT and DDT was found. Significant differences between pesticide-exposed and nonexposed subjects were found for RGDT frequency average and DDT binaural average, when including age and hearing level as covariates. Age was significantly associated with RGDT frequency average, DDT left ear score, DDT binaural average and DDT right ear advantage. Hearing levels were not significantly associated with any of the test scores. The relative risk of failing the DDT and RGDT for the study group was 1.88 (95% CI: 1.10-3.20) and 1.74 (95% CI: 1.06-2.86), respectively, as compared with the control group. CONCLUSIONS: The results showed that tobacco growers exposed to pesticides exhibited signs of central auditory dysfunction characterised by decrements in temporal processing and binaural integration processes/abilities.

Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X2 in the Auditory System.

The P2X purinergic receptors are cation-selective channels gated by extracellular adenosine 5'-triphosphate (ATP). These purinergic receptors are found in virtually all mammalian cell types and facilitate a number of important physiological processes. Within the past few years, the characterization of crystal structures of the zebrafish P2X4 receptor in its closed and open states has provided critical insights into the mechanisms of ligand binding and channel activation. Understanding of this gating mechanism has facilitated to design and interpret new modeling and structure-function experiments to better elucidate how different agonists and antagonists can affect the receptor with differing levels of potency. This review summarizes the current knowledge on the structure, activation, allosteric modulators, function, and location of the different P2X receptors. Moreover, an emphasis on the P2X2 receptors has been placed in respect to its role in the auditory system. In particular, the discovery of three missense mutations in P2X2 receptors could become important areas of study in the field of gene therapy to treat progressive and noise-induced hearing loss. J. Cell. Physiol. 231: 1656-1670, 2016. © 2015 Wiley Periodicals, Inc.

Thalamocortical-auditory network alterations following cuprizone-induced demyelination.

BACKGROUND: Demyelination and remyelination are common pathological processes in many neurological disorders, including multiple sclerosis (MS). Clinical evidence suggests extensive involvement of the thalamocortical (TC) system in patients suffering from MS. METHODS: Using murine brain slices of the primary auditory cortex, we investigated the functional consequences of cuprizone-induced de- and remyelination on neuronal activity and auditory TC synaptic transmission in vitro. RESULTS: Our results revealed an impact of myelin loss and restoration on intrinsic cellular firing patterns, synaptic transmission, and neuronal plasticity in layer 3 and 4 neurons of the auditory TC network. While there was a complex hyper- and depolarizing shift of the resting membrane potential, spontaneous and induced action potential firing was reduced during demyelination and early remyelination. In addition, excitatory postsynaptic potential amplitudes were decreased and induction of LTP was reduced during demyelination. CONCLUSIONS: These data indicate that demyelination-induced impairment of neurons and network activity within the TC system may underlie clinical symptoms observed in demyelinating diseases, corroborating human findings that disease progression is significantly correlated with microstructural tissue damage of the TC system. Further investigation into focal inflammation-induced demyelination models ex vivo and in vivo are needed to understand the functional implication of local and remote lesion formation on TC network activity in MS.

Multimodal Sensory Input in the Utricle and Lateral Line of the Toadfish, Opsanus tau.

The utricular otolith and the mechanosensory lateral line of the toadfish, Opsanus tau, were investigated for sensitivity to multimodal sensory input by recording neural activity from free swimming fish. The utricle was sensitive to horizontal body movement, and displayed broad sensitivity to low frequency (80-200 Hz) sound. The lateral line was sensitive to water currents, swimming, prey movements, and sound with maximal sensitivity at 100 Hz. Both systems showed directional sensitivity to pure tones and toadfish vocalizations, indicating potential for sound localization. Thus, toadfish possess two hair cell based sensory systems that integrate information from disparate sources. However, swimming movements or predation strikes can saturate each system and it is unclear the effect that self-generated movement has on sensitivity. It is hypothesized that the toadfish's strategy of short distance swim movements allows it to sample the acoustical environment while static. Further study is needed to determine the integration of the two systems and if they are able to segregate and/or integrate multimodal sensory input.

Medial auditory thalamus is necessary for acquisition and retention of eyeblink conditioning to cochlear nucleus stimulation.

Associative learning tasks commonly involve an auditory stimulus, which must be projected through the auditory system to the sites of memory induction for learning to occur. The cochlear nucleus (CN) projection to the pontine nuclei has been posited as the necessary auditory pathway for cerebellar learning, including eyeblink conditioning. However, the medial auditory thalamic nuclei (MATN), consisting of the medial division of the medial geniculate, suprageniculate, and posterior interlaminar nucleus have also been implicated as a critical auditory relay to the pontine nuclei for cerebellum-dependent motor learning. The MATN also conveys auditory information to the amygdala necessary for avoidance and fear conditioning. The current study used CN stimulation to increase activity in the pontine nuclei, relative to a tone stimulus, and possibly provide sufficient input to the cerebellum for acquisition or retention of eyeblink conditioning during MATN inactivation. Primary and secondary effects of CN stimulation and MATN inactivation were examined using 2-deoxy-glucose autoradiography. Stimulation of CN increased activity in the pontine nuclei, however, this increase was not sufficient for cerebellar learning during MATN inactivation. Results of the current experiment provide additional evidence indicating the MATN may be the critical auditory relay for many associative learning tasks.

Dopaminergic Modulation of Lateral Amygdala Neuronal Activity: Differential D1 and D2 Receptor Effects on Thalamic and Cortical Afferent Inputs.

BACKGROUND: In auditory fear conditioning, the lateral nucleus of the amygdala (LA) integrates a conditioned stimulus (CS) from the auditory thalamus (MGN) and the auditory association cortex (Te3) with an aversive unconditioned stimulus. The thalamic input provides a basic version of the CS, while the cortical input provides a processed representation of the stimulus. Dopamine (DA) is released in the LA under heightened arousal during the presentation of the CS. METHODS: In this study we examined how D1 or D2 receptor activation affects LA afferent-driven neuronal firing using in vivo extracellular single-unit recordings with local micro-iontophoretic drug application in anesthetized rats. LA neurons that were responsive (~50%) to electrical stimulation in either the MGN or the Te3 were tested by iontophoresis of either the D1 agonist, SKF38393, or the D2 agonist, quinpirole. RESULTS: We found that most of the LA projection neurons exhibited either facilitatory or attenuating effects (changes in evoked probability >15% relative to baseline) on afferent input by activation of D1 or D2 receptors. In general, it required significantly higher stimulation current to evoke ~50% baseline responses to the cortical input. Activation of the D1 receptor showed no difference in modulation between the thalamic or cortical pathways. On the other hand, activation of the D2 receptor had a stronger inhibitory modulation of the cortical pathway, but a stronger excitatory modulation of the thalamic pathway. CONCLUSIONS: Our results suggest that there is a shift in balance favoring the thalamic pathway in response to DA acting via the D2 receptor.

Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: cochlear and cortical responses after an increase in antioxidant defense.

This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II-III and V-VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway.

Chronic fluoxetine treatment suppresses plasticity (long-term potentiation) in the mature rodent primary auditory cortex in vivo.

Several recent studies have provided evidence that chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine can facilitate synaptic plasticity (e.g., ocular dominance shifts) in the adult central nervous system. Here, we assessed whether fluoxetine enhances long-term potentiation (LTP) in the thalamocortical auditory system of mature rats, a developmentally regulated form of plasticity that shows a characteristic decline during postnatal life. Adult rats were chronically treated with fluoxetine (administered in the drinking water, 0.2 mg/mL, four weeks of treatment). Electrophysiological assessments were conducted using an anesthetized (urethane) in vivo preparation, with LTP of field potentials in the primary auditory cortex (A1) induced by theta-burst stimulation of the medial geniculate nucleus. We find that, compared to water-treated control animals, fluoxetine-treated rats did not express higher levels of LTP and, in fact, exhibited reduced levels of potentiation at presumed intracortical A1 synapses. Bioactivity of fluoxetine was confirmed by a reduction of weight gain and fluid intake during the four-week treatment period. We conclude that chronic fluoxetine treatment fails to enhance LTP in the mature rodent thalamocortical auditory system, results that bring into question the notion that SSRIs act as general facilitators of synaptic plasticity in the mammalian forebrain.

Ototoxicity effects of low exposure to solvent mixture among paint manufacturing workers.

OBJECTIVE: To evaluate auditory function in a group of workers exposed to organic solvent mixture at a paint factory. DESIGN: Cross-sectional study. STUDY SAMPLE: One hundred and sixty-one workers were studied, 77 exposed to solvents and 84 unexposed. Fourteen solvents were measured, including toluene, xylene, and n-hexane. Pure-tone audiometry and brainstem auditory-evoked potentials (BAEP) were performed. Industrial noise was < 85 dBA and exposure levels to organic solvents were low. RESULTS: The exposed group showed a hearing impairment in both ears compared with the unexposed workers. Multiple linear regression models adjusted by age, chronic pathologies, and environmental noise for frequency means between 125 and 8000 Hz produced the following results: for the left ear, R(2) = 33.3%, exposed vs. unexposed ß = 4.1 (p < 0.001); and for the right ear, R(2) = 38%, exposed vs. unexposed ß = 4.8 (p < 0.001). Adjusted for age and chronic pathologies, waves III and V, and interpeak interval latencies were increased (p < 0.05) in both ears in the exposed group. CONCLUSIONS: Although solvent mixture concentrations and noise levels were low, our results demonstrate that there may be a concurrent ototoxicity and neurotoxicity condition and emphasize the importance of including BAEP analysis for comprehensive assessments. Future studies that include otoacoustic emissions assessments to monitor cochlear function and central auditory processing tests are imperative.

[Carbamazepine produces changes in the auditory pathway of Wistar rats]. / Cambios que produce la carbamazepina en la vía auditiva de ratas Wistar.

BACKGROUND: Different results have been reported by various authors in studies regarding the impact of the (carbamazepine) CBZ on the auditory evoked responses. OBJECTIVE: To evaluate the changes in auditory pathway at different sound intensities with CBZ at doses 30 mg/kg, in latencies and interpeak-interval brainstem auditory evoked potentials (BAEPs) in Wistar rats. MATERIAL AND METHODS: Twenty adult male Wistar rats (body weight mean, 280-300 g) were used as subjects in this study. BAEPs elicited by stimulus of (30, 50 and 70 dB nHL) intensity and BAEP were obtained with and without CBZ treatment. RESULTS: Peak latencies of BAEPs, between groups were different, in the group with CBZ peak latencies were delaying, but we compared interpeak-intervals between groups and we found significative differences in III-V and I-V at 70 dB nHL intensity. CONCLUSIONS: Our results suggest that CBZ modifies BAEPs interpeak-intervals at 70 dB, and latencies since they were delayed. Alterations in the generators of the later waves of BAEPs underlie, AED produced changes in hearing sensitivity with a single no toxic doses. Probably CBZ causes changes in endolymphatic ion composition in the rat inner ear, provoking that latency of BAEPs were delaying, but this requires further studies.