Complete Restoration of Hearing Loss and Cochlear Synaptopathy via Minimally Invasive, Single-Dose, and Controllable Middle Ear Delivery of Brain-Derived Neurotrophic Factor-Poly(dl-lactic acid-co-glycolic acid)-Loaded Hydrogel.

Noise-induced hearing loss (NIHL) often accompanies cochlear synaptopathy, which can be potentially reversed to restore hearing. However, there has been little success in achieving complete recovery of sensorineural deafness using nearly noninvasive middle ear drug delivery before. Here, we present a study demonstrating the efficacy of a middle ear delivery system employing brain-derived neurotrophic factor (BDNF)-poly-(dl-lactic acid-co-glycolic acid) (PLGA)-loaded hydrogel in reversing synaptopathy and restoring hearing function in a mouse model with NIHL. The mouse model achieved using the single noise exposure (NE, 115 dBL, 4 h) exhibited an average 20 dBL elevation of hearing thresholds with intact cochlear hair cells but a loss of ribbon synapses as the primary cause of hearing impairment. We developed a BDNF-PLGA-loaded thermosensitive hydrogel, which was administered via a single controllable injection into the tympanic cavity of noise-exposed mice, allowing its presence in the middle ear for a duration of 2 weeks. This intervention resulted in complete restoration of NIHL at frequencies of click, 4, 8, 16, and 32 kHz. Moreover, the cochlear ribbon synapses exhibited significant recovery, whereas other cochlear components (hair cells and auditory nerves) remained unchanged. Additionally, the cochlea of NE treated mice revealed activation of tropomyosin receptor kinase B (TRKB) signaling upon exposure to BDNF. These findings demonstrate a controllable and minimally invasive therapeutic approach that utilizes a BDNF-PLGA-loaded hydrogel to restore NIHL by specifically repairing cochlear synaptopathy. This tailored middle ear delivery system holds great promise for achieving ideal clinical outcomes in the treatment of NIHL and cochlear synaptopathy.

Blast-Induced Central Auditory Neurodegeneration Affects Tinnitus Development Regardless of Peripheral Cochlear Damage.

Blast exposure causes serious complications, the most common of which are ear-related symptoms such as hearing loss and tinnitus. The blast shock waves can cause neurodegeneration of the auditory pathway in the brainstem, as well as the cochlea, which is the primary receptor for hearing, leading to blast-induced tinnitus. However, it is still unclear which lesion is more dominant in triggering tinnitus, the peripheral cochlea or the brainstem lesion owing to the complex pathophysiology and the difficulty in objectively measuring tinnitus. Recently, gap detection tests have been developed and are potentially well-suited for determining the presence of tinnitus. In this study, we investigated whether the peripheral cochlea or the central nervous system has a dominant effect on the generation of tinnitus using a blast-exposed mouse model with or without earplugs, which prevent cochlear damage from a blast transmitted via the external auditory canal. The results showed that the earplug (+) group, in which the cochlea was neither physiologically nor histologically damaged, showed a similar extent of tinnitus behavior in a gap prepulse inhibition of acoustic startle reflex test as the earplug (-) group, in which the explosion caused a cochlear synaptic loss in the inner hair cells and demyelination of auditory neurons. In contrast, both excitatory synapses labeled with VGLUT-1 and inhibitory synapses labeled with GAD65 were reduced in the ventral cochlear nucleus, and demyelination in the medial nucleus of the trapezoid body was observed in both groups. These disruptions significantly correlated with the presence of tinnitus behavior regardless of cochlear damage. These results indicate that the lesion in the brainstem could be dominant to the cochlear lesion in the development of tinnitus following blast exposure.

The middle ear muscle reflex: Current and future role in assessing noise-induced cochlear damage.

The middle ear muscle reflex (MEMR) in humans is a bilateral contraction of the middle ear stapedial muscle in response to moderate-to-high intensity acoustic stimuli. Clinically, MEMR thresholds have been used for differential diagnosis of otopathologies for decades. More recently, changes in MEMR amplitude or threshold have been proposed as an assessment for noise-induced synaptopathy, a subclinical form of cochlear damage characterized by suprathreshold hearing problems that occur as a function of inner hair cell (IHC) synaptic loss, including hearing-in-noise deficits, tinnitus, and hyperacusis. In animal models, changes in wideband MEMR immittance have been correlated with noise-induced synaptopathy; however, studies in humans have shown more varied results. The discrepancies observed across studies could reflect the heterogeneity of synaptopathy in humans more than the effects of parametric differences or relative sensitivity of the measurement. Whereas the etiology and degree of synaptopathy can be carefully controlled in animal models, synaptopathy in humans likely stems from multiple etiologies and thus can vary greatly across the population. Here, we explore the evolving research evidence of the MEMR response in relation to subclinical noise-induced cochlear damage and the MEMR as an early correlate of suprathreshold deficits.

Preventive Effects of Ginkgo-Extract EGb 761® on Noise Trauma-Induced Cochlear Synaptopathy.

Noise trauma-induced loss of ribbon synapses at the inner hair cells (IHC) of the cochlea may lead to hearing loss (HL), resulting in tinnitus. We are convinced that a successful and sustainable therapy of tinnitus has to treat both symptom and cause. One of these causes may be the mentioned loss of ribbon synapses at the IHC of the cochlea. In this study, we investigated the possible preventive and curative effects of the Ginkgo biloba extract EGb 761® on noise-induced synaptopathy, HL, and tinnitus development in Mongolian gerbils (Meriones unguiculatus). To this end, 37 male animals received EGb 761® or placebo orally 3 weeks before (16 animals) or after (21 animals) a monaural acoustic noise trauma (2 kHz, 115 dB SPL, 75 min). Animals' hearing thresholds were determined by auditory brainstem response (ABR) audiometry. A possible tinnitus percept was assessed by the gap prepulse inhibition acoustic startle reflex (GPIAS) response paradigm. Synaptopathy was quantified by cochlear immunofluorescence histology, counting the ribbon synapses of 15 IHCs at 11 different cochlear frequency locations per ear. We found a clear preventive effect of EGb 761® on ribbon synapse numbers with the surprising result of a significant increase in synaptic innervation on the trauma side relative to placebo-treated animals. Consequently, animals treated with EGb 761® before noise trauma did not develop a significant HL and were also less affected by tinnitus compared to placebo-treated animals. On the other hand, we did not see a curative effect (EGb 761® treatment after noise trauma) of the extract on ribbon synapse numbers and, consequently, a significant HL and no difference in tinnitus development compared to the placebo-treated animals. Taken together, EGb 761® prevented noise-induced HL and tinnitus by protecting from noise trauma-induced cochlear ribbon synapse loss; however, in our model, it did not restore lost ribbon synapses.

Simulated transient hearing loss improves auditory sensitivity.

Recently, it was proposed that a processing principle called adaptive stochastic resonance plays a major role in the auditory system, and serves to maintain optimal sensitivity even to highly variable sound pressure levels. As a side effect, in case of reduced auditory input, such as permanent hearing loss or frequency specific deprivation, this mechanism may eventually lead to the perception of phantom sounds like tinnitus or the Zwicker tone illusion. Using computational modeling, the biological plausibility of this processing principle was already demonstrated. Here, we provide experimental results that further support the stochastic resonance model of auditory perception. In particular, Mongolian gerbils were exposed to moderate intensity, non-damaging long-term notched noise, which mimics hearing loss for frequencies within the notch. Remarkably, the animals developed significantly increased sensitivity, i.e. improved hearing thresholds, for the frequency centered within the notch, but not for frequencies outside the notch. In addition, most animals treated with the new paradigm showed identical behavioral signs of phantom sound perception (tinnitus) as animals with acoustic trauma induced tinnitus. In contrast, animals treated with broadband noise as a control condition did not show any significant threshold change, nor behavioral signs of phantom sound perception.

Evidence of Tinnitus Development Due to Stress: An Experimental Study in Rats.

OBJECTIVES/HYPOTHESIS: Tinnitus can develop due to, or be aggravated by, stress in a rat model. To investigate stress as a possible causal factor in the development of tinnitus, we designed an animal study that included tinnitus behavior and excitatory/inhibitory neurotransmitter expression after noise exposure as well as restraint stress. STUDY DESIGN: An experimental animal study. METHODS: Wistar rats were grouped according to single or double exposure to noise and restraint stress. The noise exposure (NE) group was subjected to 110 dB sound pressure level (SPL) of 16 kHz narrow-band noise (NBN) for 1 hour, and the restraint stress (RS) group was restrained for 1 hour with or without noise exposure. Gap prepulse inhibition of the acoustic startle (GPIAS) reflex was measured at an NBN of 16 kHz to investigate tinnitus development. Various immunohistopathologic and molecular biologic studies were undertaken to evaluate possible mechanisms of tinnitus development after noise and/or restraint stress. RESULTS: The RS-only group showed a reduced GPIAS response, which is a reliable sign of tinnitus development. In the double-stimulus groups, more tinnitus-development signs of reduced GPIAS responses were observed. The expression of γ-aminobutyric acid A receptor α1 (GABAAR α1) in the hippocampus decreased in the NE│RS group. Increased N-methyl-d-aspartate receptor1 intensities in the NE│RS group and decreased GABAAR α1 intensities in the RS and NE│RS groups were observed in the CA3 region of the hippocampus. CONCLUSIONS: Tinnitus appeared to develop after stress alone in this animal study. An imbalance in excitatory and inhibitory neurotransmitters in the hippocampus may be related to the development of tinnitus after acute NE and/or stress. LEVEL OF EVIDENCE: NA Laryngoscope, 131:2332-2340, 2021.

The PDE10A Inhibitor TAK-063 Reverses Sound-Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is a genetic neurodevelopmental syndrome characterized by increased anxiety, repetitive behaviors, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we have identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. In this study, we test a specific candidate mechanism for engagement of multielectrode array (MEA) EEG biomarkers in the FXS mouse model. We administered TAK-063, a potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor, to Fmr1 KO mice, and examined its effects on MEA EEG biomarkers. We demonstrate significant dose-related amelioration of inter-trial phase coherence (ITPC) to temporally modulated auditory stimuli by TAK-063 in Fmr1 KO mice. Our data suggest that TAK-063 improves cortical auditory stimulus processing in Fmr1 KO mice, without significantly depressing baseline EEG power or causing any noticeable sedation or behavioral side effects. Thus, the PDE10A inhibitor TAK-063 has salutary effects on normalizing EEG biomarkers in a mouse model of FXS and should be pursued in further translational treatment development.

Effects of Permethrin or Deltamethrin Exposure in Adult Sprague Dawley Rats on Acoustic and Light Prepulse Inhibition of Acoustic or Tactile Startle.

The effects of permethrin (PRM) and deltamethrin (DLM) on acoustic or light prepulse inhibition of the acoustic startle response (ASR) and tactile startle response (TSR) were studied in adult male Sprague Dawley rats. Preliminary studies were conducted to optimize the parameters of light and acoustic prepulse inhibition of ASR and TSR. Once these parameters were set, a new group of rats was administered PRM (0 or 90 mg/kg) or DLM (0 or 25 mg/kg) by gavage in 5 mL/kg corn oil. ASR and TSR were assessed using acoustic or light prepulses 6, 8, and 12 h after PRM and 2, 4, and 6 h after DLM exposure. PRM increased ASR 6 h post-treatment with no interaction with acoustic prepulse levels and with no effect on TSR. When light was used as the prepulse, PRM increased ASR and TSR at 6 h with no interaction with prepulse levels. DLM decreased ASR and TSR on trials without prepulses but not on trials with acoustic prepulses. DLM also decreased ASR when light prepulses were present 4 h post-treatment. A final experiment assessed whether the house light in the test cabinet affected ASR and TSR after PRM or DLM exposure. Rats had increased ASR and TSR when house lights were on compared with when they were off, but lighting did not differentially interact with PRM or DLM. Light and acoustic prepulses of ASR and TSR have different effects depending on the test agent and the test parameters.

Effects of psychological or physical prenatal stress on attention and locomotion in juvenile rats.

Background: Prenatal stress has been shown to affect the cognition of offspring, including memory and learning abilities.Methods: In the current study, the long-term effects of chronic prenatal exposure to the physical or psychological stress on locomotion and attention were evaluated by using open field test (OFT) and prepulse inhibition (PPI) of the acoustic startle reflex (ASR). In addition, the level of corticosterone was measured after the ASR trial.Results: Male and female rodents that underwent prenatal physical and psychological stress had an augmented velocity in OFT, and only male animals showed an increased ASR. Neither male nor female offsprings had an alteration in the level of corticosterone and PPI values regardless of the stress type.Conclusion: Our results revealed that exposure to stress during the development of fetus increases ASR in a sex-dependent manner. This finding might implicate the effect of prenatal stress on attention in male offspring regardless of the stress type.

Noninvasive Measures of Distorted Tonotopic Speech Coding Following Noise-Induced Hearing Loss.

Animal models of noise-induced hearing loss (NIHL) show a dramatic mismatch between cochlear characteristic frequency (CF, based on place of innervation) and the dominant response frequency in single auditory-nerve-fiber responses to broadband sounds (i.e., distorted tonotopy, DT). This noise trauma effect is associated with decreased frequency-tuning-curve (FTC) tip-to-tail ratio, which results from decreased tip sensitivity and enhanced tail sensitivity. Notably, DT is more severe for noise trauma than for metabolic (e.g., age-related) losses of comparable degree, suggesting that individual differences in DT may contribute to speech intelligibility differences in patients with similar audiograms. Although DT has implications for many neural-coding theories for real-world sounds, it has primarily been explored in single-neuron studies that are not viable with humans. Thus, there are no noninvasive measures to detect DT. Here, frequency following responses (FFRs) to a conversational speech sentence were recorded in anesthetized male chinchillas with either normal hearing or NIHL. Tonotopic sources of FFR envelope and temporal fine structure (TFS) were evaluated in normal-hearing chinchillas. Results suggest that FFR envelope primarily reflects activity from high-frequency neurons, whereas FFR-TFS receives broad tonotopic contributions. Representation of low- and high-frequency speech power in FFRs was also assessed. FFRs in hearing-impaired animals were dominated by low-frequency stimulus power, consistent with oversensitivity of high-frequency neurons to low-frequency power. These results suggest that DT can be diagnosed noninvasively. A normalized DT metric computed from speech FFRs provides a potential diagnostic tool to test for DT in humans. A sensitive noninvasive DT metric could be used to evaluate perceptual consequences of DT and to optimize hearing-aid amplification strategies to improve tonotopic coding for hearing-impaired listeners.

Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat.

Kir5.1 is an inwardly rectifying potassium (Kir) channel subunit abundantly expressed in the kidney and brain. We previously established the physiologic consequences of a Kcnj16 (gene encoding Kir5.1) knockout in the Dahl salt-sensitive rat (SSKcnj16-/-), which caused electrolyte/pH dysregulation and high-salt diet-induced mortality. Since Kir channel gene mutations may alter neuronal excitability and are linked to human seizure disorders, we hypothesized that SSKcnj16-/- rats would exhibit neurological phenotypes, including increased susceptibility to seizures. SSKcnj16-/- rats exhibited increased light sensitivity (fMRI) and reproducible sound-induced tonic-clonic audiogenic seizures confirmed by electroencephalography. Repeated seizure induction altered behavior, exacerbated hypokalemia, and led to approximately 38% mortality in male SSKcnj16-/- rats. Dietary potassium supplementation did not prevent audiogenic seizures but mitigated hypokalemia and prevented mortality induced by repeated seizures. These results reveal a distinct, nonredundant role for Kir5.1 channels in the brain, introduce a rat model of audiogenic seizures, and suggest that yet-to-be identified mutations in Kcnj16 may cause or contribute to seizure disorders.

The integration of Gaussian noise by long-range amygdala inputs in frontal circuit promotes fear learning in mice.

Survival depends on the ability of animals to select the appropriate behavior in response to threat and safety sensory cues. However, the synaptic and circuit mechanisms by which the brain learns to encode accurate predictors of threat and safety remain largely unexplored. Here, we show that frontal association cortex (FrA) pyramidal neurons of mice integrate auditory cues and basolateral amygdala (BLA) inputs non-linearly in a NMDAR-dependent manner. We found that the response of FrA pyramidal neurons was more pronounced to Gaussian noise than to pure frequency tones, and that the activation of BLA-to-FrA axons was the strongest in between conditioning pairings. Blocking BLA-to-FrA signaling specifically at the time of presentation of Gaussian noise (but not 8 kHz tone) between conditioning trials impaired the formation of auditory fear memories. Taken together, our data reveal a circuit mechanism that facilitates the formation of fear traces in the FrA, thus providing a new framework for probing discriminative learning and related disorders.

Integrated stress response inhibition provides sex-dependent protection against noise-induced cochlear synaptopathy.

Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator Integrated Stress Response InhiBitor (ISRIB) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.

Selective suppression of rapid eye movement sleep increases next-day negative affect and amygdala responses to social exclusion.

Healthy sleep, positive general affect, and the ability to regulate emotional experiences are fundamental for well-being. In contrast, various mental disorders are associated with altered rapid eye movement (REM) sleep, negative affect, and diminished emotion regulation abilities. However, the neural processes mediating the relationship between these different phenomena are still not fully understood. In the present study of 42 healthy volunteers, we investigated the effects of selective REM sleep suppression (REMS) on general affect, as well as on feelings of social exclusion, cognitive reappraisal (CRA) of emotions, and their neural underpinnings. Using functional magnetic resonance imaging we show that, on the morning following sleep suppression, REMS increases general negative affect, enhances amygdala responses and alters its functional connectivity with anterior cingulate cortex during passively experienced experimental social exclusion. However, we did not find effects of REMS on subjective emotional ratings in response to social exclusion, their regulation using CRA, nor on functional amygdala connectivity while participants employed CRA. Our study supports the notion that REM sleep is important for affective processes, but emphasizes the need for future research to systematically investigate how REMS impacts different domains of affective experience and their neural correlates, in both healthy and (sub-)clinical populations.

Fluoxetine attenuates prepulse inhibition deficit induced by neonatal administration of MK-801 in mice.

Increasing evidence supports schizophrenia may be a neurodevelopmental and neurodegenerative disorder. Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to have neuroprotective effects and be effective in treating neurodegenerative disorders including schizophrenia. The objective of the present study was to evaluate the effect and underlying neuroprotective mechanism of fluoxetine on the sensorimotor gating deficit, a schizophrenia-like behavior in a neurodevelopmental schizophrenic mouse model induced by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist. On postnatal day 7, mouse pups were treated with a total seven subcutaneous daily injections of MK-801 (1 mg/kg/day), followed by intraperitoneal injection of fluoxetine (5 or 10 mg/kg/day) starting on postnatal day 14 in the MK-801-injected mice for 4 weeks. The sensorimotor gating deficit in mice was measured by prepulse inhibition (PPI) behavioral test on postnatal day 43. After the behavioral test, the protein expression of brain-derived neurotrophic factor (BDNF) was measured by western blot or ELISA in the frontal cortex of mice. Our results showed fluoxetine attenuated PPI deficit and the decrease of cerebral BDNF expression in the MK-801-injected mice. These results suggest that fluoxetine can be used to treat sensorimotor gating deficit in a neurodevelopmental mouse model of schizophrenia, and the attenuating effect of fluoxetine on sensorimotor gating deficit may be related to fluoxetine's neuroprotective effect targeting on the modulation of cerebral BDNF.

Effect of gabapentin on sleep-deprivation-induced disruption of prepulse inhibition.

RATIONALE: There are controversial reports on the effects of gabapentin in respect to psychotic symptoms. Prepulse inhibition of the acoustic startle response is an operational measure of sensorimotor gating. In laboratory rodents, deficits in sensorimotor gating are used to model behavioral endophenotypes of schizophrenia. Sleep deprivation disrupts prepulse inhibition and can be used as a psychosis model to evaluate effects of gabapentin. OBJECTIVES: This study aimed to investigate behavioral effects of gabapentin in both naïve and sleep-deprived rats. METHODS: Sleep deprivation was induced in male Wistar rats by using the modified multiple platform technique in a water tank for 72 h. The effect of water tank itself was studied in a sham group. The effects of oral acute and subchronic (4.5 days) gabapentin doses (25, 100, or 200 mg/kg/day) on sensorimotor gating and locomotor activity was evaluated by prepulse inhibition test and locomotor activity test, respectively. Plasma gabapentin levels of some groups and body weights of all groups were also assessed. RESULTS: Sleep deprivation disrupted prepulse inhibition, increased locomotor activity, reduced gabapentin plasma levels, and body weights. Some gabapentin doses disrupted sensorimotor gating irrespective of sleep condition. Some gabapentin doses increased locomotor activity in non-sleep-deprived rats and decreased locomotor activity in sleep-deprived rats. On the contrary, gabapentin did not normalize sleep deprivation-induced disruption in sensorimotor gating. CONCLUSIONS: Sleep deprivation via modified multiple platform technique could be used as an animal model for psychosis. Gabapentin may have dose- and duration-dependent effects on sensorimotor gating and locomotor activity.

Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects.

Focal epileptic seizures can in some patients be managed by inhibiting γ-aminobutyric acid (GABA) uptake via the GABA transporter 1 (GAT1) using tiagabine (Gabitril®). Synergistic anti-seizure effects achieved by inhibition of both GAT1 and the betaine/GABA transporter (BGT1) by tiagabine and EF1502, compared to tiagabine alone, suggest BGT1 as a target in epilepsy. Yet, selective BGT1 inhibitors are needed for validation of this hypothesis. In that search, a series of BGT1 inhibitors typified by (1R,2S)-2-((4,4-bis(3-methylthiophen-2-yl)but-3-en-yl)(methyl)amino)cyclohexanecarboxylic acid (SBV2-114) was developed. A thorough pharmacological characterization of SBV2-114 using a cell-based [3H]GABA uptake assay at heterologously expressed BGT1, revealed an elusive biphasic inhibition profile with two IC50 values (4.7 and 556 µM). The biphasic profile was common for this structural class of compounds, including EF1502, and was confirmed in the MDCK II cell line endogenously expressing BGT1. The possibility of two binding sites for SBV2-114 at BGT1 was assessed by computational docking studies and examined by mutational studies. These investigations confirmed that the conserved residue Q299 in BGT1 is involved in, but not solely responsible for the biphasic inhibition profile of SBV2-114. Animal studies revealed anti-seizure effects of SBV2-114 in two mouse models, supporting a function of BGT1 in epilepsy. However, as SBV2-114 is apparent to be rather non-selective for BGT1, the translational relevance of this observation is unknown. Nevertheless, SBV2-114 constitutes a valuable tool compound to study the molecular mechanism of an emerging biphasic profile of BGT1-mediated GABA transport and the putative involvement of two binding sites for this class of compounds.

It takes two: Bilateral bed nuclei of the stria terminalis mediate the expression of contextual fear, but not of moderate cued fear.

A growing body of research supports a prominent role for the bed nucleus of the stria terminalis (BST) in the expression of adaptive and perhaps even pathological anxiety. The traditional premise that the BST is required for long-duration responses to threats, but not for fear responses to distinct, short-lived cues may, however, be oversimplified. A thorough evaluation of the involvement of the BST in cued and contextual fear is therefore warranted. In a series of preregistered experiments using male Wistar rats, we first addressed the involvement of the BST in cued fear. Following up on earlier work where we found that BST lesions disrupted auditory fear while the animals were in a rather high stress state, we here show that the BST is not required for the expression of more specific fear for the tone under less stressful conditions. In the second part, we corroborate that the same lesion method does attenuate contextual fear. Furthermore, despite prior indications for an asymmetric recruitment of the BST during the expression of anxiety, we found that bilateral lesioning of the BST is required for a significant attenuation of the expression of contextual fear. A functional BST in only one hemisphere resulted in increased variability in the behavioral outcome. We conclude that, in animals that acquired a fear memory with an intact brain, the bilateral BST mediates the expression of contextual fear, but not of unambiguous cued fear.

Nicotinamide riboside protects noise-induced hearing loss by recovering the hair cell ribbon synapses.

OBJECTIVE: Nicotinamide riboside (NR) has been proved to protect the hearing. To achieve animal models of temporary threshold shift (TTS) and permanent threshold shift (PTS) respectively, evaluate the dynamic change of ribbon synapse before and after NR administration. METHODS: Mice were divided into control group, noise exposure (NE) group and NR group. The noise was exposed to NE and NR group, and NR was injected before noise exposure. Auditory brainstem response (ABR), ribbon synapse count and cochlear morphology were tested, as well as the concentration of hydrogen peroxide (H2O2) and ATP. RESULTS: Ribbon synapse count decrease with the intensity of noise exposure, and the cochlear morphology remains stable during TTS and was damaged during PTS. NR promotes the oxidation resistance to protect the synapse and the inner ear morphology. CONCLUSION: Our findings suggest that TTS mice are more vulnerable to noise, and NR can promote the recovery of the synapse count to protect the animals' hearing.

Attenuation of noisy environment-induced neuroinflammation and dysfunction of learning and memory by minocycline during perioperative period in mice.

Noisy environment often occurs in hospitals. We set out to determine whether noisy environment induces neuroinflammation and impairment of learning and memory and whether the effects of noise contribute to the development of neuroinflammation and impairment of learning and memory during the perioperative period. Seven-week old CD-1 male mice were exposed to noisy environment in the presence or absence of surgery (right carotid artery exposure). Noisy environment was 75 db, 6 h/day, for 3 days or 5 days. Minocycline (40 mg/kg), an antibiotic with anti-inflammatory property, was administered intraperitoneally 1 h before surgery or each episode of noise. The learning and memory of mice were assessed by Barnes maze and fear conditioning tests. Brain was harvested for the determination of interleukin (IL)-1ß and IL-6 and for immunohistochemical staining. We found that noise induced learning and memory impairment. Noise also increased IL-1ß, IL-6 and ionized calcium binding adapter molecule 1 (Iba-1) in the hippocampus. The combination of noisy environment and surgery induced dysfunction of additional domains of learning and memory and a higher expression of Iba-1 in the hippocampus. The effects of noisy environment or the combination of noisy environment and surgery were attenuated by minocycline. These findings suggest that noisy environment induces neuroinflammation and impairment of learning and memory. These effects may contribute to the development of neuroinflammation and dysfunction of learning and memory during the perioperative period. Neuroinflammation may be an underlying pathophysiological process for cognitive dysfunction induced by noise or the combination of noise and surgery. Minocycline may be effective in attenuating these noise-induced effects.