Publications using TDT

Repressor element 1-silencing transcription factor (REST) is a transcriptional repressor that recognizes neuron-restrictive silencer elements in the mammalian genomes in a tissue- and cell-specific manner. The identity of REST target genes and molecular details of how REST regulates them are emerging. We performed conditional null deletion of Rest (cKO), mainly restricted to murine hair cells (HCs) and auditory neurons (aka spiral ganglion neurons [SGNs]). Null inactivation of full-length REST did not affect the development of normal HCs and SGNs but manifested as progressive hearing loss in adult mice. We found that the inactivation of REST resulted in an increased abundance of K v 7.4 channels at the transcript, protein, and functional levels. Specifically, we found that SGNs and HCs from Rest cKO mice displayed increased K v 7.4 expression and augmented K v 7 currents; SGN’s excitability was also significantly reduced. Administration of a compound with K v 7.4 channel activator activity, fasudil, recapitulated progressive hearing loss in mice. In contrast, inhibition of the K v 7 channels by XE991 rescued the auditory phenotype of Rest cKO mice. Previous studies identified some loss-of-function mutations within the K v 7.4-coding gene, Kcnq4 , as a causative factor for progressive hearing loss in mice and humans. Thus, the findings reveal that a critical homeostatic K v 7.4 channel level is required for proper auditory functions.

Peripheral sensory organ damage leads to compensatory cortical plasticity that supports a remarkable recovery of perceptual capabilities. A major knowledge gap is the lack of precise mechanisms that explain how this plasticity is implemented and distributed over a diverse collection of excitatory and inhibitory cortical neurons. Here, we explored these mechanisms in mouse A1. After peripheral damage, we found recovered sound-evoked activity of excitatory principal neurons (PNs) and parvalbumin (PVs) interneurons (INs), reduced activity in somatostatin-INs (SOMs), and recovered activity in vasoactive intestinal peptide-INs (VIPs). Given the sequentially organized cortical network where VIPs inhibit INs, SOMs inhibit PVs and PNs, and PVs inhibit PNs, our results suggest that PVs contribute to PN stability, SOMs allow for increased PN and PV activity, and VIPs enable the PN and PV recovery by inhibiting SOMs. These results highlight a strategic, cooperative, and cell-type-specific plasticity program that restores cortical sound processing after peripheral damage.

Among the different autism spectrum disorders, Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Sensory and especially auditory hypersensitivity is a key symptom in patients, which is well mimicked in the Fmr1 -/- mouse model. However, the physiological mechanisms underlying FXS’s acoustic hypersensitivity in particular remain poorly understood. Here, we categorized spike response patterns to pure tones of different frequencies and intensities from neurons in the inferior colliculus (IC), a central integrator in the ascending auditory pathway. Based on this categorization we analyzed differences in response patterns between IC neurons of wild-type (WT) and Fmr1 -/- mice. Our results report broadening of frequency tuning, an increased firing in response to monaural as well as binaural stimuli, an altered balance of excitation-inhibition, and reduced response latencies, all expected features of acoustic hypersensitivity. Furthermore, we noticed that all neuronal response types in Fmr1 -/- mice displayed enhanced offset-rebound activity outside their excitatory frequency response area. These results provide evidence that the loss of Fmr1 not only increases spike responses in IC neurons similar to auditory brainstem neurons, but also changes response patterns such as offset spiking. One can speculate this to be an underlying aspect of the receptive language problems associated with Fragile X syndrome.

While most anuran species are highly vocal, few of them seem to be endowed with a complex call repertoire. Odorrana tormota , combines a remarkable vocalization complexity with auditory sensitivity over an extended spectral range spanning from audible to ultrasonic frequencies. This species is also exceptional for its ability to modify its middle ear tuning by closing the Eustachian tubes (ET). Using scanning laser Doppler vibrometry, the tympanal vibrations were measured to investigate if the tuning shift caused by the ET closure contributes to intraspecific acoustic communication. To gain insight into the inner ear frequency selectivity and sensitivity of this species, distortion product otoacoustic emissions were recorded at multiple frequency-level combinations. Our measurements of inner ear responses indicated that in O. tormota each sex is more sensitive to the frequencies of the other sex's vocalizations, female ears are more sensitive to 2–7 kHz, while male ears are more sensitive to 3–15 kHz. We also found that in both sexes the ET closure impacts the sensitivity of the middle and inner ear at frequencies used for communication with conspecifics. This study broadens our understanding of peripheral auditory mechanisms contributing to intraspecific acoustic communication in anurans.

Vertigo is a debilitating disease affecting 15–20% of adults worldwide. Vestibular peripheral vertigo is the most common cause of vertigo, often due to Meniere's disease and benign paroxysmal positional vertigo. Although some vertigo symptoms can be controlled by conservative treatment and/or vestibular rehabilitation therapy, these treatments do not work for some patients. Semicircular canal occlusion surgery has proven to be very effective for these patients with intractable vertigo. However, its application is limited due to concern that the procedure will disrupt normal hearing. In this study, we investigated if occlusion of two semicircular canals would jeopardize auditory function by comparing auditory function and hair cell morphology between the surgical and contralateral ears before and after the surgery in a mouse model. By measuring the auditory brainstem response and distortion product otoacoustic emission 4 weeks post-surgery, we show that auditory function does not significantly change between the surgical and contralateral ears. In addition, confocal imaging has shown no hair cell loss in the cochlear and vestibular sensory epithelia, and scanning electron microscopy also indicates normal stereocilia morphology in the surgical ear. More importantly, the endocochlear potential measured from the surgical ear is not significantly different than that seen in the contralateral ear. Our study suggests that occlusion of two semicircular canals does not disrupt normal hearing in the mouse model, providing a basis to extend the procedure to patients, even those with normal hearing, benefitting more patients with intractable vertigo attacks.

Anthropogenic noise of variable temporal patterns is increasing in aquatic environments, causing physiological stress and sensory impairment. However, scarce information exists on exposure effects to continuous versus intermittent disturbances, which is critical for noise sustainable management. We tested the effects of different noise regimes on the auditory system and behaviour in the zebrafish ( Danio rerio ). Adult zebrafish were exposed for 24 h to either white noise (150 ± 10 dB re 1 μPa) or silent control. Acoustic playbacks varied in temporal patterns—continuous, fast and slow regular intermittent, and irregular intermittent. Auditory sensitivity was assessed with Auditory Evoked Potential recordings, revealing hearing loss and increased response latency in all noise-treated groups. The highest mean threshold shifts (c. 13 dB) were registered in continuous and fast intermittent treatments, and no differences were found between regular and irregular regimes. Inner ear saccule did not reveal significant hair cell loss but showed a decrease in presynaptic Ribeye b protein especially after continuous exposure. Behavioural assessment using the standardized Novel Tank Diving assay showed that all noise-treated fish spent > 98% time in the bottom within the first minute compared to 82% in control, indicating noise-induced anxiety/stress. We provide first data on how different noise time regimes impact a reference fish model, suggesting that overall acoustic energy is more important than regularity when predicting noise effects.

The contribution of different brain regions to movement abnormalities in children with dystonia is unknown. Three awake subjects undergoing depth electrode implantation for assessments of potential deep brain recording targets performed a rhythmic figure-8 drawing task. Two subjects had dystonia, one was undergoing testing for treatment of Tourette Syndrome and had neither dystonia nor abnormal movements during testing. Movement-related signals were evaluated by determining the magnitude of task-related frequency components. Brain signals were recorded in globus pallidus internus (GPi), the ventral oralis anterior/posterior (VoaVop) and the ventral intermediate (Vim) nuclei of the thalamus. In comparison to the subject without dystonia, both children with dystonia showed increased task-related activity in GPi and Vim. This finding is consistent with a role of both basal ganglia and cerebellar outputs in the pathogenesis of dystonia. Our results further suggest that frequency analysis of brain recordings during cyclic movements may be a useful tool for analysis of the presence of movement-related signals in various brain regions.

The purpose of this study is to take preliminary steps to unify psychoacoustic techniques with reaction-time methodologies to address the perceptual mechanisms responsible for the detection of one vs. multiple sounds. We measured auditory redundancy gains for auditory detection of pure tones widely spaced in frequency using the tools of Systems Factorial Technology to evince the system architecture and workload capacity in two different scenarios (SOFT and LOUD). We adopted an experimental design in which the presence or absence of a target at each of two frequencies was combined factorially with two stimulus levels. Replicating previous work, results did not allow an assessment of system architecture due to a failure to observe factor influence at the level of distribution ordering for dual-target stimuli for both SOFT and LOUD scenarios. All subjects demonstrated very modest redundancy gains for the dual-target compared to the single-target stimuli, and results were similar for both LOUD and SOFT. We propose that these results can be predicted by a mental architecture that falls into the class of integrated subadditive parallel systems, using a well-supported assumption that reaction time is driven by loudness. We demonstrate that modeled loudness of the experimental sounds (which ranged between about 0.2 and 14 sones) is highly correlated with mean reaction time ( r = −0.87), and we provide a proof-of-concept model based on Steven’s Power law that predicts both a failure of distributional ordering for dual-target stimuli and very modest redundancy gains.

Objective . Although neural-enabled prostheses have been used to restore some lost functionality in clinical trials, they have faced difficulty in achieving high degree of freedom, natural use compared to healthy limbs. This study investigated the in vivo functionality of a flexible and scalable regenerative peripheral-nerve interface suspended within a microchannel-embedded, tissue-engineered hydrogel (the magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI)) as a potential approach to improving current issues in peripheral nerve interfaces. Approach . Assembled MARTEENI devices were implanted in the gaps of severed sciatic nerves in Lewis rats. Both acute and chronic electrophysiology were recorded, and channel-isolated activity was examined. In terminal experiments, evoked activity during paw compression and stimulus response curves generated from proximal nerve stimulation were examined. Electrochemical impedance spectroscopy was performed to assess the complex impedance of recording sites during chronic data collection. Features of the foreign-body response (FBR) in non-functional implants were examined using immunohistological methods. Main results . Channel-isolated activity was observed in acute, chronic, and terminal experiments and showed a typically biphasic morphology with peak-to-peak amplitudes varying between 50 and 500 µ V. For chronic experiments, electrophysiology was observed for 77 days post-implant. Within the templated hydrogel, regenerating axons formed minifascicles that varied in both size and axon count and were also found to surround device threads. No axons were found to penetrate the FBR. Together these results suggest the MARTEENI is a promising approach for interfacing with peripheral nerves. Significance . Findings demonstrate a high likelihood that observed electrophysiological activity recorded from implanted MARTEENIs originated from neural tissue. The variation in minifascicle size seen histologically suggests that amplitude distributions observed in functional MARTEENIs may be due to a combination of individual axon and mini-compound action potentials. This study provided an assessment of a functional MARTEENI in an in vivo animal model for the first time.

Kanamycin and cisplatin are ototoxic drugs. The mechanisms are incompletely known. With subcutaneous kanamycin (400 mg/kg, 15 days), auditory threshold shifts were detected at days 12–13 at 16 and 32 kHz, extending to 8 and 4 kHz at days 14–15. The outer hair cell (OHC) loss was concentrated past day 12. The maximum cochlear length showing apoptotic cells, tested with TUNEL, was at day 13. At day 15, 1/5 of the apical cochlea contained preserved OHCs. 3-nitrotyrosine (3-NT) immunolabeling, showing oxidative stress, was found in surviving OHCs and in basal and middle portions of the stria vascularis (SV). The antioxidant Gpx1 gene expression was decreased. The immunocytochemistry showed diminished Gpx1 in OHCs. With intraperitoneal cisplatin (16 mg/kg, single injection), no evoked auditory activity was recorded at the end of treatment, at 72 h. The basal third of the cochlea lacked OHCs. Apoptosis occupied the adjacent 1/3, and the apical third contained preserved OHCs. 3-NT immunolabeling was extensive in OHCs and the SV. Gpx1 and Sod1 gene expression was downregulated. Gpx1 immunostaining diminished in middle and basal SV. More OHCs survived cisplatin than kanamycin towards the apex, despite undetectable evoked activity. Differential regulation of antioxidant enzyme levels suggests differences in the antioxidant response for both drugs.

All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance use disorders. Here, we demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by either optogenetic stimulation or by morphine administration specifically within the reward center ventral tegmental area (VTA), but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens (NAc). Genetic blockade of oligodendrogenesis dampens NAc dopamine release dynamics, which is critical for reward learning, and impairs behavioral conditioning to morphine. Our findings identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward. One-Sentence Summary Activity-dependent myelin plasticity in the ventral tegmental area modulates dopaminergic circuit function and opioid reward

Seasonal changes in day length (photoperiod) affect numerous physiological functions. The suprachiasmatic nucleus (SCN)–paraventricular nucleus (PVN) axis plays a key role in processing photoperiod-related information. Seasonal variations in SCN and PVN neurotransmitter expression have been observed in humans and animal models. However, the molecular mechanisms by which the SCN-PVN network responds to altered photoperiod is unknown. Here, we show in mice that neuromedin S (NMS) and vasoactive intestinal polypeptide (VIP) neurons in the SCN display photoperiod-induced neurotransmitter plasticity. In vivo recording of calcium dynamics revealed that NMS neurons alter PVN network activity in response to winter-like photoperiod. Chronic manipulation of NMS neurons is sufficient to induce neurotransmitter switching in PVN neurons and affects locomotor activity. Our findings reveal previously unidentified molecular adaptations of the SCN-PVN network in response to seasonality and the role for NMS neurons in adjusting hypothalamic function to day length via a coordinated multisynaptic neurotransmitter switching affecting behavior.

Voluntary stream segregation was investigated in cochlear implant (CI) users and normal-hearing (NH) listeners using a segregation-promoting objective approach which evaluated the role of spectral and amplitude-modulation (AM) rate separations on stream segregation and its build-up. Sequences of 9 or 3 pairs of A and B narrowband noise (NBN) bursts were presented which differed in either center frequency of the noise band, the AM-rate, or both. In some sequences (delayed sequences), the last B burst was delayed by 35 ms from their otherwise-steady temporal position. In the other sequences (no-delay sequences), the last B bursts were temporally advanced from 0 to 10 ms. A single interval yes/no procedure was utilized to measure participants’ sensitivity ( d ′ ) in identifying delayed vs. no-delay sequences. A higher d ′ value showed the higher ability to segregate the A and B subsequences. For NH listeners, performance improved with each spectral separation. However, for CI users, performance was only significantly better for the condition with the largest spectral separation. Additionally, performance was significantly poorer for the largest AM-rate separation than for the condition with no AM-rate separation for both groups. The significant effect of sequence duration in both groups indicated that listeners made more improvement with lengthening the duration of stimulus sequences, supporting the build-up effect. The results of this study suggest that CI users are less able than NH listeners to segregate NBN bursts into different auditory streams when they are moderately separated in the spectral domain. Contrary to our hypothesis, our results indicate that AM-rate separation may interfere with the segregation of streams of NBN. Additionally, our results add evidence to the literature that CI users build up stream segregation at a rate comparable to NH listeners, when the inter-stream spectral separations are adequately large.

The thalamus controls transmission of sensory signals from periphery to cortex, ultimately shaping perception. Despite this significant role, dynamic thalamic gating and the consequences for downstream cortical sensory representations have not been well studied in the awake brain. We optogenetically modulated the ventro-posterior-medial thalamus in the vibrissa pathway of the awake mouse and measured spiking activity in the thalamus and activity in primary somatosensory cortex (S1) using extracellular electrophysiology and genetically encoded voltage imaging. Thalamic hyperpolarization significantly enhanced thalamic sensory-evoked bursting; however, surprisingly, the S1 cortical response was not amplified, but instead, timing precision was significantly increased, spatial activation more focused, and there was an increased synchronization of cortical inhibitory neurons. A thalamocortical network model implicates the modulation of precise timing of feedforward thalamic population spiking, presenting a highly sensitive, timing-based gating of sensory signaling to the cortex.

Sharp wave/ripples/high frequency events (HFEs) are transient bursts of depolarization in hippocampal subregions CA3 and CA1 that occur during rest and pauses in behavior. Previous studies have reported that CA1 ripples in aged rats have lower frequency than those detected in young animals. While CA1 ripples are thought to be driven by CA3, HFEs in CA3 have not been examined in aged animals. The current study obtained simultaneous recordings from CA1 and CA3 in young and aged rats to examine sharp wave/ripples/HFEs in relation to age. While CA1 ripple frequency was reduced with age, there were no age differences in the frequency of CA3 HFEs, although power and length were lower in old animals. While there was a proportion of CA1 ripples that co-occurred with a CA3 HFE, none of the age-related differences in CA1 ripples could be explained by alterations in CA3 HFE characteristics. These findings suggest that age differences in CA1 are not due to altered CA3 activity, but instead reflect distinct mechanisms of ripple generation with age.

Intra organ of Corti (OC) vibrations differ from those measured at the basilar membrane (BM), with higher amplitudes and a wide-band nonlinearity extending well below a region's best frequency. The vibrations are boosted by the cochlear amplifier, the active processes within the mammalian hearing organ, and are thus sensitive to metabolic or pharmacological manipulation. We introduced salicylate, a known blocker of outer hair cell (OHC) based electromotility, into the perilymphatic space by applying sodium salicylate onto the round window membrane. Vibration patterns of an area of the OC were mapped with phase sensitive optical coherence tomography before and after treatment; distortion product otoacoustic emissions (DPOAEs) were measured at similar times to assess the cochlear condition. Following treatment, all regions showed a loss of vibration amplitude and tuning while OHC-region vibrations retained their wide-band nonlinearity. OC vibrations, which had been relatively confined in a region including OHCs and extending to the BM at the outer pillar foot, became less confined with structures lateral to the OHCs sometimes exhibiting the highest amplitudes. Vibrations and DPOAEs could recover to baseline levels over approximately three hours post treatment. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam.

Video recording is essential for behavioral neuroscience research, but the majority of available systems suffer from poor cost-to-functionality ratio. Commercial options frequently come at high financial cost that prohibits scalability and throughput, whereas DIY solutions often require significant expertise and time investment unaffordable to many researchers. To address this, we combined a low-cost Raspberry Pi microcomputer, DIY electronics peripherals, freely available open-source firmware, and custom 3D-printed casings to create Pi USB Cam, a simple yet powerful and highly versatile video recording solution. Pi USB Cam is constructed using affordable and widely available components and requires no expertise to build and implement. The result is a system that functions as a plug-and-play USB camera that can be easily installed in various animal testing and housing sites and is readily compatible with popular behavioral and neural recording software. Here, we provide a comprehensive parts list and step-by-step instructions for users to build and implement their own Pi USB Cam system. In a series of benchmark comparisons, Pi USB Cam was able to capture ultra-wide fields of view of behaving rats given limited object distance and produced high image quality while maintaining consistent frame rates even under low-light and no-light conditions relative to a standard, commercially available USB camera. Video recordings were easily scaled using free, open-source software. Altogether, Pi USB Cam presents an elegant yet simple solution for behavioral neuroscientists seeking an affordable and highly flexible system to enable quality video recordings.

The brain propagates neuronal signals accurately and rapidly. Nevertheless, whether and how a pool of cortical neurons transmits an undistorted message to a target remains unclear. We apply optogenetic white noise signals to small assemblies of cortical pyramidal cells (PYRs) in freely moving mice. The directly activated PYRs exhibit a spike timing precision of several milliseconds. Instead of losing precision, interneurons driven via synaptic activation exhibit higher precision with respect to the white noise signal. Compared with directly activated PYRs, postsynaptic interneuron spike trains allow better signal reconstruction, demonstrating error correction. Data-driven modeling shows that nonlinear amplification of coincident spikes can generate error correction and improved precision. Over multiple applications of the same signal, postsynaptic interneuron spiking is most reliable at timescales ten times shorter than those of the presynaptic PYR, exhibiting temporal coding. Similar results are observed in hippocampal region CA1. Coincidence detection of convergent inputs enables messages to be precisely propagated between cortical PYRs and interneurons.

The prefrontal cortex (PFC) is a hub for cognitive control, and dopamine profoundly influences its functions. In other brain regions, astrocytes sense diverse neurotransmitters and neuromodulators and, in turn, orchestrate regulation of neuroactive substances. However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to and how they contribute to PFC function, is unclear. Here, we characterize divergent signaling signatures in mouse astrocytes of the PFC and primary sensory cortex, which show differential responsiveness to locomotion. We find that PFC astrocytes express receptors for dopamine but are unresponsive through the Gs/Gi-cAMP pathway. Instead, fast calcium signals in PFC astrocytes are time locked to dopamine release and are mediated by α1-adrenergic receptors both ex vivo and in vivo. Further, we describe dopamine-triggered regulation of extracellular ATP at PFC astrocyte territories. Thus, we identify astrocytes as active players in dopaminergic signaling in the PFC, contributing to PFC function though neuromodulator receptor crosstalk.

Given its inputs from auditory structures and neuromodulatory systems, the posterior tail of the striatum is ideally positioned to influence behavioral responses to acoustic stimuli according to context and previous rewards. Results from previous studies indicate that neurons in this striatal region display selective responses to sounds. However, it is not clear whether different striatal cell classes code for distinct features of sounds or how different striatal output pathways may use acoustic information to guide behavior. Here we compared the sound-evoked responses of posterior striatal neurons that form the striatal direct pathway (and express the dopamine receptor D 1 ) to the responses of neighboring neurons in naive mice. We achieved this via optogenetic photo-identification of D 1 -expressing neurons during extracellular electrophysiological recordings in awake head-fixed mice of both sexes. We found that the frequency tuning of sound-responsive direct-pathway striatal neurons is comparable with that of their sound-responsive neighbors. Moreover, we found that both populations encode amplitude-modulated sounds in a similar fashion. These results suggest that different classes of neurons in the posterior striatum of naive animals have similar access to acoustic features conveyed by the auditory system even outside the context of an auditory task.