Electrophysiology publications

Auditory nerve single-unit recordings were obtained from two groups of young barn owls (age, between posthatching days 11 and 86) in terminal experiments under two different anesthetic regimes: ketamine (6-11 mg/kg) plus xylazine (∼2 mg/kg); or isoflurane (1-1.5%) in oxygen, delivered via artificial respiration. In a second series of minimally invasive experiments, auditory brainstem responses (ABRs) were recorded in the same four adult barn owls (Tyto alba; age, between 5 and 32 months) under three different anesthetic protocols: ketamine (10 mg/kg) plus xylazine (3 mg/kg), isoflurane (1-1.5%), and sevoflurane (2-3%) in carbogen. Finally, the ABR measurements on adult owls were repeated in terminal experiments including more invasive procedures such as artificial respiration and higher isoflurane dosage. The main finding was a significant deterioration of auditory sensitivity in barn owls under gas anesthesia, at the level of the auditory nerve (i.e., a very peripheral level of the auditory system). The effect was drastic in the young animals that experienced threshold elevations in auditory nerve single-unit responses of ≥20 dB. ABR thresholds assessed repeatedly in experiments on adult owls were also significantly higher under isoflurane and sevoflurane, on average by 7 and 15 dB, compared with ketamine/xylazine. This difference already occurred with minimal dosages and was reversibly enlarged with increased isoflurane concentration. Finally, there was evidence for confounding detrimental effects associated with artificial respiration over many hours, which suggested oxygen toxicity.

Pairing vagus nerve stimulation (VNS) with movements or sounds can direct robust plasticity in motor or auditory cortex, respectively. The degree of map plasticity is influenced by the intensity and pulse width of VNS, number of VNS-event pairings, and the interval between each pairing. It is likely that these parameters interact, influencing optimal implementation of VNS pairing protocols. We varied VNS intensity, number of stimulations, and inter-stimulation interval (ISI) to test for interactions among these parameters. Rats were implanted with a vagus nerve stimulating cuff and randomly assigned to one of three treatment groups to receive 20 days of VNS paired with a 9-kHz tone: (1) Fast VNS: 50 daily pairings of 400-µA VNS with a 30-s ISI; (2) Dispersed VNS: 50 daily pairings of 400-µA VNS with a 180-s ISI; and (3) Standard VNS: 300 daily pairings of 800-µA VNS with a 30-s ISI. Following 20 days of VNS-tone pairing, multi-unit recordings were conducted in primary auditory cortex (A1) and receptive field properties were analyzed. Increasing ISI (Dispersed VNS) did not lead to an enhancement of cortical plasticity. Reducing the current intensity and number of stimulations (Fast VNS) resulted in robust cortical plasticity, using 6 times fewer VNS pairings than the Standard protocol. These findings reveal an interaction between current intensity, stimulation number, and ISI and identify a novel VNS paradigm that is substantially more efficient than the previous standard paradigm.

Current neuroprosthetics rely on stable, high quality recordings from chronically implanted microelectrode arrays (MEAs) in neural tissue. While chronic electrophysiological recordings and electrode failure modes have been reported from rodent and larger non-human primate (NHP) models, chronic recordings from the marmoset model have not been previously described. The common marmoset is a New World primate that is easier to breed and handle compared to larger NHPs and has a similarly organized brain, making it a potentially useful smaller NHP model for neuroscience studies. This study reports recording stability and signal quality of MEAs chronically implanted in behaving marmosets. Six adult male marmosets, trained for reaching tasks, were implanted with either a 16-channel tungsten microwire array (five animals) or a Pt-Ir floating MEA (one animal) in the hand-arm region of the primary motor cortex (M1) and another MEA in the striatum targeting the nucleus accumbens (NAcc). Signal stability and quality was quantified as a function of array yield (active electrodes that recorded action potentials), neuronal yield (isolated single units during a recording session), and signal-to-noise ratio (SNR). Out of 11 implanted MEAs, nine provided functional recordings for at least three months, with two arrays functional for 10 months. In general, implants had high yield, which remained stable for up to several months. However, mechanical failure attributed to MEA connector was the most common failure mode. In the longest implants, signal degradation occurred, which was characterized by gradual decline in array yield, reduced number of isolated single units, and changes in waveform shape of action potentials. This work demonstrates the feasibility of long-term recordings from MEAs implanted in cortical and deep brain structures in the marmoset model. The ability to chronically record cortical signals for neural prosthetics applications in the common marmoset extends the potential of this model in neural interface research.

Hearing and balance depend upon the precise morphogenesis and mechanosensory function of stereocilia, the specialized structures on the apical surface of sensory hair cells in the inner ear. Previous studies of Grxcr1 mutant mice indicated a critical role for this gene in control of stereocilia dimensions during development. In this study, we analyzed expression of the paralog Grxcr2 in the mouse and evaluated auditory and vestibular function of strains carrying targeted mutations of the gene. Peak expression of Grxcr2 occurs during early postnatal development of the inner ear and GRXCR2 is localized to stereocilia in both the cochlea and in vestibular organs. Homozygous Grxcr2 deletion mutants exhibit significant hearing loss by 3 weeks of age that is associated with developmental defects in stereocilia bundle orientation and organization. Despite these bundle defects, the mechanotransduction apparatus assembles in relatively normal fashion as determined by whole cell electrophysiological evaluation and FM1-43 uptake. Although Grxcr2 mutants do not exhibit overt vestibular dysfunction, evaluation of vestibular evoked potentials revealed subtle defects of the mutants in response to linear accelerations. In addition, reduced Grxcr2 expression in a hypomorphic mutant strain is associated with progressive hearing loss and bundle defects. The stereocilia localization of GRXCR2, together with the bundle pathologies observed in the mutants, indicate that GRXCR2 plays an intrinsic role in bundle orientation, organization, and sensory function in the inner ear during development and at maturity.

Patients with chronic spinal cord injury (SCI) cannot urinate at will and must empty the bladder by self-catheterization. We tested the hypothesis that non-invasive, transcutaneous magnetic spinal cord stimulation (TMSCS) would improve bladder function in individuals with SCI. Five individuals with American Spinal Injury Association Impairment Scale A/B, chronic SCI and detrusor sphincter dyssynergia enrolled in this prospective, interventional study. After a two-week assessment to determine effective stimulation characteristics, each patient received sixteen weekly TMSCS treatments and then received “sham” weekly stimulation for six weeks while bladder function was monitored. Bladder function improved in all five subjects, but only during and after repeated weekly sessions of 1 Hz TMSCS. All subjects achieved volitional urination. The volume of urine produced voluntarily increased from 0 cc/day to 1120 cc/day (p = 0.03); self-catheterization frequency decreased from 6.6/day to 2.4/day (p = 0.04); the capacity of the bladder increased from 244 ml to 404 ml (p = 0.02); and the average quality of life ranking increased significantly (p = 0.007). Volitional bladder function was re-enabled in five individuals with SCI following intermittent, non-invasive TMSCS. We conclude that neuromodulation of spinal micturition circuitry by TMSCS may be used to ameliorate bladder function.

Background Primate distal forelimb behaviors are commonly assessed using reach-to-grasp tasks. While these tasks are widely recognized as sensitive assays for forelimb function, they often require experimenter input, lack precise temporal cues for physiological monitoring, and can be expensive. New Method Using components developed by open-source electronics platforms, we have designed and tested a low-cost system to measure distal forelimb function in non-human primates. Our system is inexpensive; it is made primarily of acrylic and 3D printed plastic parts. Our control software, developed in MATLAB, was also used to control two cameras in order to capture and process video during behavior. The system was equipped with sensors, motors and microcontrollers to control the timing of the task and facilitate synchronization between behavior and neurophysiology with high temporal precision. Results We demonstrate that this system can be used to monitor motor recovery after stroke and investigate neurophysiological correlates of motor control. Comparison with Existing Methods Compared to a previous version of this task, our setup reduces experimenter input while providing unbiased delivery of behavioral cues and behavioral measurements with the temporal precision necessary for electrophysiological studies. Conclusions In summary, our system will allow unbiased monitoring of forelimb function in both healthy and injured animals that is compatible with electrophysiological studies.

Sensory processing, and auditory processing in particular, is altered in individuals with neurodevelopmental disorders such as autism spectrum disorders (ASDs). The typical maturation of the auditory system is perturbed in these individuals during early development, which may underlie altered auditory reactivity that persists in later life. Of the many genes that regulate the auditory system development, loss-of-function mutations in the CNTNAP2 gene are strongly associated with language processing deficits and ASD. Therefore, using a novel Cntnap2 knock-out rat model, we tested the impact of Cntnap2 loss on auditory processing, filtering, and reactivity throughout development and young adulthood in male and female animals. Although hearing thresholds were not altered in Cntnap2 knock-out animals, we found a reduction in response amplitudes and a delay in response latency of the auditory brainstem response (ABR) in juvenile Cntnap2 knock-out rats compared with age-matched controls. Amplitudes and latency of the ABR largely normalized by adulthood, indicating a delayed maturation of auditory processing pathways in Cntnap2 knock-out rats. Despite the reduced ABR amplitudes, adolescent Cntnap2 knock-out animals displayed increased startle reactivity accompanied by disruptions in sensory filtering and sensorimotor gating across various conditions, most of which persisted in adulthood. All of these observations show striking parallels to disruptions reported in ASD. Our results also imply that developmental disruptions of sensory signal processing are associated with persistent changes in neural circuitries responsible for implicit auditory evoked behavior, emphasizing the need for interventions that target sensory processing disruptions early during development in ASD. SIGNIFICANCE STATEMENT This is the first study of brainstem auditory processing in a novel knock-out rat model with very high construct and face validity for autism spectrum disorders. Electrophysiological and behavioral measures of implicit auditory-evoked responses were systematically taken across developmental stages. Auditory processing, filtering, and reactivity disruptions show striking similarities to observations in autism. We also show for the first time that, whereas auditory brainstem responses normalize by adulthood, disruptions in brainstem-mediated auditory-evoked behavior persist. This indicates that early developmental perturbations in sensory processing can cause permanent maladaptive changes in circuitries responsible for auditory reactivity, underlining the importance for interventions early during development aiming at normalizing sensory processing.

The systems-level mechanisms underlying loss of consciousness (LOC) under anesthesia remain unclear. General anesthetics suppress sensory responses within higher-order cortex and feedback connections, both critical elements of predictive coding hypotheses of conscious perception. Responses to auditory novelty may offer promise as biomarkers for consciousness. This study examined anesthesia-induced changes in auditory novelty responses over short (local deviant [LD]) and long (global deviant [GD]) time scales, envisioned to engage preattentive and conscious levels of processing, respectively. Electrocorticographic recordings were obtained in human neurosurgical patients (3 male, 3 female) from four hierarchical processing levels: core auditory cortex, non-core auditory cortex, auditory-related, and PFC. Stimuli were vowel patterns incorporating deviants within and across stimuli (LD and GD). Subjects were presented with stimuli while awake, and during sedation (responsive) and following LOC (unresponsive) under propofol anesthesia. LD and GD effects were assayed as the averaged evoked potential and high gamma (70–150 Hz) activity. In the awake state, LD and GD effects were present in all recorded regions, with averaged evoked potential effects more broadly distributed than high gamma activity. Under sedation, LD effects were preserved in all regions, except PFC. LOC was accompanied by loss of LD effects outside of auditory cortex. By contrast, GD effects were markedly suppressed under sedation in all regions and were absent following LOC. Thus, although the presence of GD effects is indicative of being awake, its absence is not indicative of LOC. Loss of LD effects in higher-order cortical areas may constitute an alternative biomarker of LOC. SIGNIFICANCE STATEMENT Development of a biomarker that indexes changes in the brain upon loss of consciousness (LOC) under general anesthesia has broad implications for elucidating the neural basis of awareness and clinical relevance to mechanisms of sleep, coma, and disorders of consciousness. Using intracranial recordings from neurosurgery patients, we investigated changes in the activation of cortical networks involved in auditory novelty detection over short (local deviance) and long (global deviance) time scales associated with sedation and LOC under propofol anesthesia. Our results indicate that, whereas the presence of global deviance effects can index awareness, their loss cannot serve as a biomarker for LOC. The dramatic reduction of local deviance effects in areas beyond auditory cortex may constitute an alternative biomarker of LOC.

Inhibition in the cerebral cortex is delivered by a variety of GABAergic interneurons. These cells have been categorized by their morphology, physiology, gene expression and connectivity. Many of these classes appear to be conserved across species, suggesting that the classes play specific functional roles in cortical processing. What these functions are, is still largely unknown. The largest group of interneurons in the upper layers of mouse primary visual cortex (V1) is formed by cells expressing the calcium-binding protein calretinin (CR). This heterogeneous class contains subsets of vasoactive intestinal polypeptide (VIP) interneurons and somatostatin (SOM) interneurons. Here we show, using in vivo two-photon calcium imaging in mice, that CR neurons can be sensitive to stimulus orientation, but that they are less selective on average than the overall neuronal population. Responses of CR neurons are suppressed by a surrounding stimulus, but less so than the overall population. In rats and primates, CR interneurons have been suggested to provide disinhibition, but we found that in mice their in vivo activation by optogenetics causes a net inhibition of cortical activity. Our results show that the average functional properties of CR interneurons are distinct from the averages of the parvalbumin, SOM and VIP interneuron populations.

Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia.

Recent work has demonstrated that transmembrane channel-like 1 protein (TMC1) is an essential component of the sensory transduction complex in hair cells of the inner ear. A closely related homolog, TMC2, is expressed transiently in the neonatal mouse cochlea and can enable sensory transduction in Tmc1 -null mice during the first postnatal week. Both TMC1 and TMC2 are expressed at adult stages in mouse vestibular hair cells. The extent to which TMC1 and TMC2 can substitute for each other is unknown. Several biophysical differences between TMC1 and TMC2 suggest these proteins perform similar but not identical functions. To investigate these differences, and whether TMC2 can substitute for TMC1 in mature hair cells, we generated a knock-in mouse model allowing Cre -inducible expression of Tmc2 . We assayed for changes in hair cell sensory transduction and auditory and vestibular function in Tmc2 knockin mice ( Tm [ Tmc2 ]) in the presence or absence of endogenous Tmc1 , Tmc2 or both. Our results show that expression of Tm[TMC2] restores sensory transduction in vestibular hair cells and transiently in cochlear hair cells in the absence of TMC1. The cellular rescue leads to recovery of balance but not auditory function. We conclude that TMC1 provides some additional necessary function, not provided by TMC2.

Significance Early linguistic experience affects perception and cortical processing of speech, even in infants. The current study examined whether linguistic effects extend to brainstem speech encoding, where responses are rapid, automatic, and preattentive. We focused on transient consonants and measured perception behaviorally and the corresponding complex auditory brainstem response (cABR) onset using simultaneous electroencephalography/magnetoencephalography (EEG/MEG) in native Spanish and English speakers. We demonstrate that the latency of an EEG-cABR onset peak predicts consonant perception and that the perception differs according to language background. MEG-cABR analysis demonstrates deep sources for the onset, providing complimentary support for a brainstem origin. Effects of early linguistic experience on speech perception can be observed at the earlier stage of speech encoding at the brainstem.

Rats have the ability to learn and perform sophisticated behavioral tasks, making them very useful for investigating neural circuit functions. In contrast to the extensive mouse genetic toolkit, the paucity of recombinase-expressing rat models has limited the ability to monitor and manipulate molecularly-defined neural populations in this species. Here we report the generation and validation of two knock-in rat strains expressing either Cre or Flp recombinase under the control of Parvalbumin (Pvalb) , a gene expressed in the critical “fast-spiking” subset of inhibitory interneurons (FSIs). These strains were generated with CRISPR-Cas9 gene editing and show highly specific and penetrant labeling of Pvalb -expressing neurons, as demonstrated by in situ hybridization and immunohistochemistry. We validated these models in both prefrontal cortex and striatum using both ex vivo and in vivo approaches, including whole-cell recording, optogenetics, extracellular physiology and photometry. Our results demonstrate the utility of these new transgenic models for a wide range of neuroscience experiments.

Classic models of attention suggest that sustained neural firing constitutes a neural correlate of sustained attention. However, recent evidence indicates that behavioral performance fluctuates over time, exhibiting temporal dynamics that closely resemble the spectral features of ongoing, oscillatory brain activity. Therefore, it has been proposed that periodic neuronal excitability fluctuations might shape attentional allocation and overt behavior. However, empirical evidence to support this notion is sparse. Here, we address this issue by examining data from large-scale subdural recordings, using two different attention tasks that track perceptual ability at high temporal resolution. Our results reveal that perceptual outcome varies as a function of the theta phase even in states of sustained spatial attention. These effects were robust at the single-subject level, suggesting that rhythmic perceptual sampling is an inherent property of the frontoparietal attention network. Collectively, these findings support the notion that the functional architecture of top-down attention is intrinsically rhythmic.

The delivery of brain-controlled neuromodulation therapies during motor rehabilitation may augment recovery from neurological disorders. To test this hypothesis, we conceived a brain-controlled neuromodulation therapy that combines the technical and practical features necessary to be deployed daily during gait rehabilitation. Rats received a severe spinal cord contusion that led to leg paralysis. We engineered a proportional brain–spine interface whereby cortical ensemble activity constantly determines the amplitude of spinal cord stimulation protocols promoting leg flexion during swing. After minimal calibration time and without prior training, this neural bypass enables paralyzed rats to walk overground and adjust foot clearance in order to climb a staircase. Compared to continuous spinal cord stimulation, brain-controlled stimulation accelerates and enhances the long-term recovery of locomotion. These results demonstrate the relevance of brain-controlled neuromodulation therapies to augment recovery from motor disorders, establishing important proofs-of-concept that warrant clinical studies.

The human auditory cortex simultaneously processes speech and determines the location of a speaker in space. Neuroimaging studies in humans have implicated core auditory areas in processing the spectrotemporal and the spatial content of sound; however, how these features are represented together is unclear. We recorded directly from human subjects implanted bilaterally with depth electrodes in core auditory areas as they listened to speech from different directions. We found local and joint selectivity to spatial and spectrotemporal speech features, where the spatial and spectrotemporal features are organized independently of each other. This representation enables successful decoding of both spatial and phonetic information. Furthermore, we found that the location of the speaker does not change the spectrotemporal tuning of the electrodes but, rather, modulates their mean response level. Our findings contribute to defining the functional organization of responses in the human auditory cortex, with implications for more accurate neurophysiological models of speech processing.

Early visual experience is essential for the maturation of visual functions in which the primary visual cortex plays crucial roles. The extraction of visual features based on response selectivity of individual neurons, a fundamental process in the cortex, is basically established by eye opening in rodents, suggesting that visual experience is required for the development of neural functions other than feature extraction. Here, we show that synchronized firing, which is important for visual information processing, occurs selectively in adjacent neurons sharing similar orientation or spatial frequency preferences in layers 2-4 (upper layer) of rat visual cortex. This feature-selective spike synchrony was rudimentary when the eyes opened and became prominent during the first few weeks after eye opening only in the presence of pattern vision. In contrast, synchronization in layers 5-6 (lower layer) was almost independent of orientation similarity and more weakly dependent on spatial frequency similarity compared with upper layer synchrony. Lower layer synchronization was strengthened during development after eye opening independently of visual experience as a whole. However, the feature selectivity of synchronization was regulated by visual inputs, whereas the inputs without contours were sufficient for this regulation. Therefore, we speculate that feature-selective synchronization in the upper layer may convey detailed information on visual objects to the higher-order cortex, whereas weakly feature-selective synchronization in the lower layer may covey rather rough visual information to the subcortical areas or higher-order cortex. A major role of visual experience may be to establish the specific neural circuits underlying highly feature-selective synchronization.SIGNIFICANCE STATEMENT The neuronal mechanisms underlying experience-dependent improvement of visual functions still remain unresolved. In this study, we investigated whether early visual experience contributes to the development of synchronized neural firing in the primary visual cortex, which plays important roles in visual information processing. We found that synchronized firing depends more remarkably on the similarity of preferred visual stimuli in the upper than lower layer neurons. Pattern vision during development was required for the establishment of spike synchrony in the upper but not the lower layer. These findings provide a new view regarding the role of sensory experience in the functional development of the cortex and the differences in the modes of information processing in the upper and lower cortical layers.

By identifying endogenous molecules in brain extracellular fluid metabolomics can provide insight into the regulatory mechanisms and functions of sleep. Here we studied how the cortical metabolome changes during sleep, sleep deprivation and spontaneous wakefulness. Mice were implanted with electrodes for chronic sleep/wake recording and with microdialysis probes targeting prefrontal and primary motor cortex. Metabolites were measured using ultra performance liquid chromatography-high resolution mass spectrometry. Sleep/wake changes in metabolites were evaluated using partial least squares discriminant analysis, linear mixed effects model analysis of variance, and machine-learning algorithms. More than 30 known metabolites were reliably detected in most samples. When used by a logistic regression classifier, the profile of these metabolites across sleep, spontaneous wake, and enforced wake was sufficient to assign mice to their correct experimental group (pair-wise) in 80–100% of cases. Eleven of these metabolites showed significantly higher levels in awake than in sleeping mice. Some changes extend previous findings (glutamate, homovanillic acid, lactate, pyruvate, tryptophan, uridine), while others are novel (D-gluconate, N-acetyl-beta-alanine, N-acetylglutamine, orotate, succinate/methylmalonate). The upregulation of the de novo pyrimidine pathway, gluconate shunt and aerobic glycolysis may reflect a wake-dependent need to promote the synthesis of many essential components, from nucleic acids to synaptic membranes.

Aims 2‐(4‐methyl‐thiazol‐5‐yl) ethyl nitrate maleate (NMZM), a derivative of clomethiazole (CMZ), had been investigated for the treatment of Alzheimer's disease (AD). The beneficial effects of NMZM in AD included reversing cognitive deficit, improving learning and memory as well as neuroprotection. The pharmacological effects of NMZM on GABA A receptors were reported previously; however, the mechanisms were unclear and were explored therefore. Results In this study, we demonstrated that NMZM improved learning and memory by alleviating scopolamine‐induced long‐term potentiation (LTP) suppression in the dentate gyrus of rats, indicating that NMZM had protective effects against scopolamine‐induced depression of LTP. Next, we investigated the action of NMZM on GABA A receptors in hippocampal neurons and the binding site of NMZM on GABA A receptors. NMZM directly activated GABA A receptors in hippocampal neurons in a weak manner. However, NMZM could potentiate the response of GABA A receptors to GABA and NMZM positively modulated GABA A receptors with an EC 50 value of 465 μmol/L at 3 μmol/L GABA while this potentiation at low concentration of GABA (1, 3 μmol/L) was more significant than that at high concentration (10, 30 μmol/L). In addition, NMZM could enhance GABA currents after using diazepam and pentobarbital, the positive modulators of GABA A receptors. NMZM could not affect the etomidate‐potentiated GABA A current. It suggested that the binding site of NMZM on GABA A receptors is the same as etomidate. Conclusions These results provided support for the neuroprotective effect of NMZM, which was partly dependent on the potentiation of GABA A receptors. The etomidate binding site might be a new target for neuronal protection and for drug development.

Sensorineural hearing loss (SNHL) has been demonstrated in many clinical reports as a risk factor that promotes the development of cognitive impairment. However, the underlying neurological mechanisms are not clear. Noise exposure is one of the most common causes of SNHL. Although noise exposure causes relatively less damage to general health as compared with other methods for creating hearing loss (such as ototoxicity), it does impair cognitive function. Many studies have shown that the noise-induced cognitive impairment occur via the oxidative stress induced by the noise. In those studies, the effects of the noise-induced hearing loss induced (NIHL) were not addressed. Previously, we have demonstrated in the CBA/CaJ mouse model that oxidative stress was transient after a brief noise exposure, but the NIHL was permanent. In addition, NIHL was followed by a declined cognitive function and decreased hippocampal neurogenesis that were developed long after the oxidative stress disappeared. Therefore, NIHL can cause cognitive impairment independent of its stress effect and can serve as a model to investigate the relationship between hearing loss and the development of cognitive impairment. In the present study, we further demonstrated that the oxidative stress produced by the brief noise exposure did not damage the stem cell bank of hippocampus that was evaluated shortly after the noise exposure. In addition to the reduction in the rate of cell proliferation in hippocampus that was found previously, we found that the NIHL significantly reduced the promoting effect of learning activity on various stages of hippocampal neurogenesis, accompanied by the reduction in learning-induced expression of immediate early genes (IEGs) in hippocampus. Since the MWM-tested spatial function does not directly require auditory input, the results provide evidence for the maintenance role of auditory input on the cognitive function; the reduction of IEG expression that is required in memory-formation may be the initial step in blocking the effect of learning activity on neurogenesis in subjects with NIHL.