Publications using TDT

Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low-threshold-spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience.

The effect of dextromethorphan (DXM) use in sensorineural hearing loss (SNHL) has not been fully examined. We conducted an animal model and nationwide retrospective matched-cohort study to explore the association between DXM use and SNHL. Eight-week-old CBA/CaJ hearing loss was induced by a white noise 118 dB sound pressure level for 3 h. DXM (30 mg/kg) was administered intraperitoneally for 5 days and boost once round window DXM socking. In population-based study, we examined the medical records over 40 years old in Taiwan’s National Health Insurance Research Database between 2000 and 2015 to establish retrospective matched-cohort to explore the correlation between DXM use and SNHL. Using click auditory brainstem response (ABR), hearing threshold was measured as 48.6 ± 2.9 dB in control mice compared with 42.6 ± 7.0 dB in DXM mice, which differed significantly (p = 0.002) on day 60 after noise exposure with a larger ABR wave I amplitude in DXM mice. In human study, we used a Cox regression hazard model to indicate that a significantly lower percentage individuals developed SNHL compared with and without DXM use (0.44%, 175/39,895 vs. 1.05%, 1675/159,580, p < 0.001). After adjustment for age and other variables [adjusted hazard ratio: 0.725 (95% confidence interval: 0.624–0.803, p < 0.001)], this study also demonstrated that DXM use appeared to reduce the risk of developing SNHL. This animal study demonstrated that DXM significantly attenuated noise-induced hearing loss. In human study, DXM use may have a protective effect against SNHL.

The sensory responses of cortical neuronal populations following training have been extensively studied. However, the spike firing properties of individual cortical neurons following training remain unknown. Here, we have combined two-photon Ca 2+ imaging and single-cell electrophysiology in awake behaving mice following auditory associative training. We find a sparse set (~5%) of layer 2/3 neurons in the primary auditory cortex, each of which reliably exhibits high-rate prolonged burst firing responses to the trained sound. Such bursts are largely absent in the auditory cortex of untrained mice. Strikingly, in mice trained with different multitone chords, we discover distinct subsets of neurons that exhibit bursting responses specifically to a chord but neither to any constituent tone nor to the other chord. Thus, our results demonstrate an integrated representation of learned complex sounds in a small subset of cortical neurons.

This protocol was used to collect data now published in the Journal of Neural Engineering, Sources of off-target effects of vagus nerve stimulation using the helical clinical lead in domestic pigs, see Metadata for citation. Additionally, the dataset is publicly available on Pennsieve 10.26275/qcuk-a8ty.

The contribution of cerebellum to motor learning is often considered to be limited to adaptation, a short-timescale tuning of reflexes and previous learned skills. Yet, the cerebellum is reciprocally connected to two main players of motor learning, the motor cortex and the basal ganglia, via the ventral and midline thalamus respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. In the cerebellar nuclei, we found task-specific neuronal activities during the task, and lasting changes after the task suggesting an offline processing of task-related information. Using pathway-specific inhibition, we found that dentate neurons projecting to the midline thalamus contribute to learning and retrieval, while interposed neurons projecting to the ventral thalamus contribute to the offline consolidation of savings. Our results thus show that two parallel cerebello-thalamic pathways perform distinct computations operating on distinct timescales in motor learning.

The perception of speed is influenced by visual contrast. In primary visual cortex (V1), an early stage in the visual perception pathway, the neural tuning to speed is directly related to the neural tuning to temporal frequency of stimulus changes. The influence of contrast on speed perception can be caused by the joint dependency of neural responses in V1 on temporal frequency and contrast. Here, we investigated how tuning to contrast and temporal frequency in V1 of anesthetized mice are related. We found that temporal frequency tuning is contrast-dependent. V1 was more responsive at lower temporal frequencies than the dLGN, consistent with previous work at high contrast. The temporal frequency tuning moves toward higher temporal frequencies with increasing contrast. The low half-maximum temporal frequency does not change with contrast. The Heeger divisive normalization equation provides a good fit to many response characteristics in V1, but does not fit the dependency of temporal frequency and contrast with set of parameters for all temporal frequencies. Different mechanisms for normalization in the visual cortex may predict different relationships between temporal frequency and contrast non-linearity. Our data could help to make a model selection.

In speech, listeners extract continuously-varying spectrotemporal cues from the acoustic signal to perceive discrete phonetic categories. Spectral cues are spatially encoded in the amplitude of responses in phonetically-tuned neural populations in auditory cortex. It remains unknown whether similar neurophysiological mechanisms encode temporal cues like voice-onset time (VOT), which distinguishes sounds like / b / and/ p /. We used direct brain recordings in humans to investigate the neural encoding of temporal speech cues with a VOT continuum from / ba / to / pa /. We found that distinct neural populations respond preferentially to VOTs from one phonetic category, and are also sensitive to sub-phonetic VOT differences within a population’s preferred category. In a simple neural network model, simulated populations tuned to detect either temporal gaps or coincidences between spectral cues captured encoding patterns observed in real neural data. These results demonstrate that a spatial/amplitude neural code underlies the cortical representation of both spectral and temporal speech cues.

The combined development of new technologies for neuronal recordings and the development of novel sensors for recording both cellular activity and neurotransmitter binding has ushered in a new era for the field of neuroscience. Among these new technologies is fiber photometry, a technique wherein an implanted fiber optic is used to record signals from genetically encoded fluorescent sensors in bulk tissue. Fiber photometry has been widely adapted due to its cost-effectiveness, ability to examine the activity of neurons with specific anatomical or genetic identities, and the ability to use these highly modular systems to record from one or more sensors or brain sites in both superficial and deep-brain structures. Despite these many benefits, one major hurdle for laboratories adopting this technique is the steep learning curve associated with the analysis of fiber photometry data. This has been further complicated by a lack of standardization in analysis pipelines. In the present communication, we present pMAT, a ‘photometry modular analysis tool’ that allows users to accomplish common analysis routines through the use of a graphical user interface. This tool can be deployed in MATLAB and edited by more advanced users, but is also available as an independently deployable, open-source application.

Numerous studies have investigated the cortical representation and time course of responses to auditory signals with and without pitch. However, little is known regarding the responses evoked by pitch changes. To study the spatial as well as temporal characteristics of cortical activity elicited by voice pitch changes, combined functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) data were obtained from normal-hearing listeners presented with continuous vowel sequences in which the prosodic contours either varied between the individual vowels or were the same throughout. The fNIRS topographies and the EEG source reconstructions indicated additional right-hemispheric activity anterior to the primary auditory cortex and in the superior temporal sulcus for sequences with variable prosody. Additionally, the time courses of the fNIRS signals showed that activity was more sustained in response to sequences with changing prosodic contours. The EEG data revealed a similar pattern for the P2 amplitude, which was smaller during the second half for blocks with fixed prosody, whereas the P1 was consistently larger for sequences with variable prosody. Moreover, the sources of the P2, but not the P1, were lateralised to the right, suggesting that the hemispheric asymmetry in the processing of voice pitch changes develops over time.

The ability to acquire a behavior can be facilitated by exposure to a conspecific demonstrator. Such social learning occurs under a range of conditions in nature. Here, we tested the idea that social learning can benefit from any available sensory cue, thereby permitting learning under different natural conditions. The ability of naïve gerbils to learn a sound discrimination task following 5 days of exposure adjacent to a demonstrator gerbil was tested in the presence or absence of visual cues. Naïve gerbils acquired the task significantly faster in either condition, as compared to controls. We also found that exposure to a demonstrator was more potent in facilitating learning, as compared to exposure to the sounds used to perform the discrimination task. Therefore, social learning was found to be flexible and equally efficient in the auditory or visual domains.

The chemotherapeutic agent cisplatin is renowned for its ototoxic effects. While hair cells in the cochlea are established targets of cisplatin, less is known regarding the afferent synapse, which is an essential component in the faithful temporal transmission of sound. The glutamate aspartate transporter (GLAST) shields the auditory synapse from excessive glutamate release, and its loss of function increases the vulnerability to noise, salicylate, and aminoglycosides. Until now, the involvement of GLAST in cisplatin‐mediated ototoxicity remains unknown. Here, we test in mice lacking GLAST the effects of a low‐dose cisplatin known not to cause any detectable change in hearing thresholds. When administered at nighttime, a mild hearing loss in GLAST KO mice was found but not at daytime, revealing a potential circadian regulation of the vulnerability to cisplatin‐mediated ototoxicity. We show that the auditory synapse of GLAST KO mice is more vulnerable to cisplatin administration during the active phase (nighttime) when compared to WT mice and treatment during the inactive phase (daytime). This effect was not related to the abundance of platinum compounds in the cochlea, rather cisplatin had a dose‐dependent impact on cochlear clock rhythms only after treatment at nighttime suggesting that cisplatin can modulate the molecular clock. Our findings suggest that the current protocols of cisplatin administration in humans during daytime may cause a yet undetectable damage to the auditory synapse, more so in already damaged ears, and severely impact auditory sensitivity in cancer survivors.

Defining the relationship between maternal care, sensory development and brain gene expression in neonates is important to understand the impact of environmental challenges during sensitive periods in early life. In this study, we used a selection approach to test the hypothesis that variation in maternal licking and grooming (LG) during the first week of life influences sensory development in Wistar rat pups. We tracked the onset of the auditory brainstem response (ABR), the timing of eye opening (EO), middle ear development with micro-CT X-ray tomography, and used qRT-PCR to monitor changes in gene expression of the hypoxia-sensitive pathway and neurotrophin signaling in pups reared by low-LG or high-LG dams. The results show the first evidence that the transcription of genes involved in the hypoxia-sensitive pathway and neurotrophin signaling is regulated during separate sensitive periods that occur before and after hearing onset, respectively. Although the timing of ABR onset, EO, and the relative mRNA levels of genes involved in the hypoxia-sensitive pathway did not differ between pups from different LG groups, we found statistically significant increases in the relative mRNA levels of four genes involved in neurotrophin signaling in auditory brain regions from pups of different LG backgrounds. These results suggest that sensitivity to hypoxic challenge might be widespread in the auditory system of neonate rats before hearing onset, and that maternal LG may affect the transcription of genes involved in experience-dependent neuroplasticity.

The nascent field of bioelectronic medicine seeks to decode and modulate peripheral nervous system signals to obtain therapeutic control of targeted end organs and effectors. Current approaches rely heavily on electrode-based devices, but size scalability, material and microfabrication challenges, limited surgical accessibility, and the biomechanically dynamic implantation environment are significant impediments to developing and deploying peripheral interfacing technologies. Here, we present a microscale implantable device – the nanoclip – for chronic interfacing with fine peripheral nerves in small animal models that begins to meet these constraints. We demonstrate the capability to make stable, high signal-to-noise ratio recordings of behaviorally-linked nerve activity over multi-week timescales. In addition, we show that multi-channel, current-steering-based stimulation within the confines of the small device can achieve multi-dimensional control of a small nerve. These results highlight the potential of new microscale design and fabrication techniques for realizing viable devices for long-term peripheral interfacing.

Congenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by “hidden hearing loss” that is not assessed on standard audiological exams, such as reduced temporal processing acuity. To assess whether sound therapy may improve these hidden deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. Peripheral function and sound sensitivity in auditory midbrain neurons improved following exposure to both types of AAE. However, only exposure to a novel, temporally complex AAE significantly improved a measure of temporal processing acuity, neural gap-in-noise detection in the auditory midbrain. These experiments suggest that targeted sound therapy may improve hearing outcomes for children suffering from congenital SNHL.

Processing of olfactory information is modulated by centrifugal projections from cortical areas, yet their behavioral relevance and underlying neural mechanisms remain unclear in most cases. The anterior olfactory nucleus (AON) is part of the olfactory cortex, and its extensive connections to multiple upstream and downstream brain centers place it in a prime position to modulate early sensory information in the olfactory system. Here, we show that optogenetic activation of AON neurons in awake male and female mice was not perceived as an odorant equivalent cue. However, AON activation during odorant presentation reliably suppressed behavioral odor responses. This AON-mediated effect was fast and constant across odors and concentrations. Likewise, activation of glutamatergic AON projections to the olfactory bulb (OB) transiently inhibited the excitability of mitral/tufted cells (MTCs) that relay olfactory input to the cortex. Single-unit MTC recordings revealed that optogenetic activation of glutamatergic AON terminals in the OB transiently decreased sensory-evoked MTC spiking, regardless of the strength or polarity of the sensory response. The reduction in MTC firing during optogenetic stimulation was confirmed in recordings in awake mice. These findings suggest that glutamatergic AON projections to the OB impede early olfactory signaling by inhibiting OB output neurons, thereby dynamically gating sensory throughput to the cortex.SIGNIFICANCE STATEMENT The anterior olfactory nucleus (AON) as an olfactory information processing area sends extensive projections to multiple brain centers, but the behavioral consequences of its activation have been scarcely investigated. Using behavioral tests in combination with optogenetic manipulation, we show that, in contrast to what has been suggested previously, the AON does not seem to form odor percepts but instead suppresses behavioral odor responses across odorants and concentrations. Furthermore, this study shows that AON activation inhibits olfactory bulb output neurons in both anesthetized as well as awake mice, pointing to a potential mechanism by which the olfactory cortex can actively and dynamically gate sensory throughput to higher brain centers.

The functional role of spontaneous brain activity, especially in relation to external events, is a longstanding key question in neuroscience. Intrinsic and externally-evoked activities were suggested to be anticorrelated, yet inferring an antagonistic mechanism between them remains a challenge. Here, we used beta-band (15-30 Hz) power as a proxy of spontaneous activity in the rat somatosensory cortex during a detection task. Beta-power anticorrelated with sensory-evoked-responses, and high rates of spontaneously occurring beta-bursts predicted reduced detection. By applying a burst-rate detection algorithm in real-time and trial-by-trial stimulus-intensity adjustment, this influence could be counterbalanced. Mechanistically, bursts in all bands indicated transient synchronization of cell assemblies, but only beta-bursts were followed by a reduction in firing-rate. Our findings reveal that spontaneous beta-bursts reflect a dynamic state that competes with external stimuli.

Temporal resolution is essential for processing complex auditory information such as speech. In hearing impaired persons, temporal resolution, often assessed by detection of brief gaps in continuous sound stimuli, is typically poorer than in individuals with normal hearing. At low stimulus presentation levels, hearing impaired individuals perform poorly but the deficits are greatly reduced when the sensation level of the stimuli are adjusted to match their normal hearing peers. In the present study, we evaluated the effect of selective inner hair cell loss on gap detection in chinchillas treated with carboplatin, an anticancer drug that selectively damages inner hair cells and afferents in this species. Treatment with carboplatin-induced inner hair cell loss of ~ 70 % but had little effect on audiometric thresholds in quiet and produced no evidence of outer hair cell loss. In contrast, selective inner hair cell loss had a significant effect on gap detection ability across a wide range of presentation levels. These results suggest that gap detection tasks are more sensitive to inner hair cell pathology than audiometric thresholds.

Key points Age‐related hearing loss (ARHL) is associated with the loss of inner hair cell (IHC) ribbon synapses, lower hearing sensitivity and decreased ability to understand speech, especially in a noisy environment. Little is known about the age‐related physiological and morphological changes that occur at ribbon synapses. We show that the differing degrees of ARHL in four selected mouse stains is correlated with the loss of ribbon synapses, being most severe for the strains C57BL/6NTac and C57BL/6J, less so for C57BL/6NTac Cdh23+ ‐Repaired and lowest for C3H/HeJ. Despite the loss of ribbon synapses with age, the volume of the remaining ribbons increased and the size and kinetics of Ca 2+ ‐dependent exocytosis in IHCs was unaffected, indicating the presence of a previously unknown degree of functional compensation at ribbon synapses. Although the age‐related morphological changes at IHC ribbon synapses contribute to the different progression of ARHL, without the observed functional compensation hearing loss could be greater. Abstract Mammalian cochlear inner hair cells (IHCs) are specialized sensory receptors able to provide dynamic coding of sound signals. This ability is largely conferred by their ribbon synapses, which tether a large number of vesicles at the IHC's presynaptic active zones, allowing high rates of sustained synaptic transmission onto the afferent fibres. How the physiological and morphological properties of ribbon synapses change with age remains largely unknown. Here, we have investigated the biophysical and morphological properties of IHC ribbon synapses in the ageing cochlea (9–12 kHz region) of four mouse strains commonly used in hearing research: early‐onset progressive hearing loss (C57BL/6J and C57BL/6NTac) and ‘good hearing’ strains (C57BL/6NTac Cdh23+ and C3H/HeJ). We found that with age, both modiolar and pillar sides of the IHC exhibited a loss of ribbons, but there was an increased volume of those that remained. These morphological changes, which only occurred after 6 months of age, were correlated with the level of hearing loss in the different mouse strains, being most severe for C57BL/6NTac and C57BL/6J, less so for C57BL/6NTac Cdh23+ and absent for C3H/HeJ strains. Despite the age‐related reduction in ribbon number in three of the four strains, the size and kinetics of Ca 2+ ‐dependent exocytosis, as well as the replenishment of synaptic vesicles, in IHCs was not affected. The degree of vesicle release at the fewer, but larger, individual remaining ribbon synapses colocalized with the post‐synaptic afferent terminals is likely to increase, indicating the presence of a previously unknown degree of functional compensation in the ageing mouse cochlea.

BHA (aka high gamma) correlates with neuronal firing, but is generated mainly by dendritic processes separable from firing.

Decades-old model of slow adaptation in sensory hair cells of the auditory and vestibular systems requires revamp.