Publications using TDT

Aims Major depressive disorder is a severe psychiatric disorder that afflicts ~17% of the world population. Neuroimaging investigations of depressed patients have consistently reported the dysfunction of the basolateral amygdala in the pathophysiology of depression. However, how the BLA and related circuits are implicated in the pathogenesis of depression is poorly understood. Methods Here, we combined fiber photometry, immediate early gene expression (c‐fos), optogenetics, chemogenetics, behavioral analysis, and viral tracing techniques to provide multiple lines of evidence of how the BLA neurons mediate depressive‐like behavior. Results We demonstrated that the aversive stimuli elevated the neuronal activity of the excitatory BLA neurons (BLA CAMKII neurons). Optogenetic activation of CAMKII neurons facilitates the induction of depressive‐like behavior while inhibition of these neurons alleviates the depressive‐like behavior. Next, we found that the chemogenetic inhibition of GABAergic neurons in the BLA (BLA GABA ) increased the firing frequency of CAMKII neurons and mediates the depressive‐like phenotypes. Finally, through fiber photometry recording and chemogenetic manipulation, we proved that the activation of BLA GABA neurons inhibits BLA CAMKII neuronal activity and alleviates depressive‐like behavior in the mice. Conclusion Thus, through evaluating BLA GABA and BLA CAMKII neurons by distinct interaction, the BLA regulates depressive‐like behavior.

Our sense of hearing depends on the function of a specialised class of sensory cells, the hair cells, which are found in the organ of Corti of the mammalian cochlea. The unique physiological environment in which these cells operate is maintained by a syncitium of non‐sensory supporting cells, which are crucial for regulating cochlear physiology and metabolic homeostasis. Despite their importance for cochlear function, the role of these supporting cells in age‐related hearing loss, the most common sensory deficit in the elderly, is poorly understood. Here, we investigated the age‐related changes in the expression and function of metabotropic purinergic receptors (P2Y 1 , P2Y 2 and P2Y 4 ) in the supporting cells of the cochlear apical coil. Purinergic signalling in supporting cells is crucial during the development of the organ of Corti and purinergic receptors are known to undergo changes in expression during ageing in several tissues. Immunolabelling and Ca 2+ imaging experiments revealed a downregulation of P2Y receptor expression and a decrease of purinergic‐mediated calcium responses after early postnatal stages in the supporting cells. An upregulation of P2Y receptor expression was observed in the aged cochlea when compared to 1 month‐old adults. The aged mice also had significantly larger calcium responses and displayed calcium oscillations during prolonged agonist applications. We conclude that supporting cells in the aged cochlea upregulate P2Y 2 and P2Y 4 receptors and display purinergic‐induced Ca 2+ responses that mimic those observed during pre‐hearing stages of development, possibly aimed at limiting or preventing further damage to the sensory epithelium. image Key points Age‐related hearing loss is associated with lower hearing sensitivity and decreased ability to understand speech. We investigated age‐related changes in the expression and function of metabotropic purinergic (P2Y) receptors in cochlear non‐sensory supporting cells of mice displaying early‐onset (C57BL/6N) and late‐onset (C3H/HeJ) hearing loss. The expression of P2Y 1 , P2Y 2 and P2Y 4 receptors in the supporting cells decreased during cochlear maturation, but that of P2Y 2 and P2Y 4 was upregulated in the aged cochlea. P2Y 2 and P2Y 4 receptors were primarily responsible for the ATP‐induced Ca 2+ responses in the supporting cells. The degree of purinergic expression upregulation in aged supporting cells mirrored hearing loss progression in the different mouse strains. We propose that the upregulation of purinergic‐mediated signalling in the aged cochlea is subsequent to age‐related changes in the hair cells and may act as a protective mechanism to limit or to avoid further damage to the sensory epithelium.

Foraging is a universal behaviour that has co‐evolved with predation pressure. We investigated the role of the bed nucleus of the stria terminalis (BNST) GABA neurons in robotic and live predator threat processing and their consequences in post‐threat encounter foraging. Both robotic and live predator interactions increased BNST GABA neuron activity. Mice were trained to procure food in a laboratory‐based foraging apparatus in which food pellets were placed at incrementally greater distances from a nest zone. After mice learned to forage, they were exposed to a robotic or live predator threat, while BNST GABA neurons were chemogenetically inhibited. Post‐robotic threat encounter, mice spent more time in the nest zone, but other foraging parameters were unchanged compared with pre‐encounter behaviour. Inhibition of BNST GABA neurons had no effect on foraging behaviour post‐robotic threat encounter. Following live predator exposure, control mice spent significantly more time in the nest zone, increased their latency to successfully forage, and significantly altered their overall foraging performance. Inhibition of BNST GABA neurons during live predator exposure prevented changes in foraging behaviour from developing after a live predator threat. BNST GABA neuron inhibition did not alter foraging behaviour during robotic or live predator threats. We conclude that these results demonstrate that while both robotic and live predator encounters effectively intrude on foraging behaviour, the perceived risk and behavioural consequences of the threat are distinguishable. Additionally, BNST GABA neurons may play a role in the integration of prior innate predator threat experience that results in hypervigilance during post‐encounter foraging behaviour.

With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter ( MORp ) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. MORp constructs designed from promoter regions upstream of the mouse Oprm1 gene ( mMORp ) were validated for transduction efficiency and selectivity in endogenous MOR+ neurons in the brain, spinal cord, and periphery of mice, with additional studies revealing robust expression in rats, shrews, and human induced pluripotent stem cell (iPSC)-derived nociceptors. The use of mMORp for in vivo fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed MORp ( hMORp ) efficiently transduced macaque cortical OPRM1 + cells. Together, our MORp toolkit provides researchers cell type specific genetic access to target and functionally manipulate mu-opioidergic neurons across a range of vertebrate species and translational models for pain, addiction, and neuropsychiatric disorders.

Comparing expectation with experience is an important neural computation performed throughout the brain and is a hallmark of predictive processing. Experiments that alter the sensory outcome of an animal's behavior reveal enhanced neural responses to unexpected self-generated stimuli, indicating that populations of neurons in sensory cortex may reflect prediction errors (PEs), mismatches between expectation and experience. However, enhanced neural responses to self-generated stimuli could also arise through nonpredictive mechanisms, such as the movement-based facilitation of a neuron's inherent sound responses. If sensory prediction error neurons exist in sensory cortex, it is unknown whether they manifest as general error responses, or respond with specificity to errors in distinct stimulus dimensions. To answer these questions, we trained mice of either sex to expect the outcome of a simple sound-generating behavior and recorded auditory cortex activity as mice heard either the expected sound or sounds that deviated from expectation in one of multiple distinct dimensions. Our data reveal that the auditory cortex learns to suppress responses to self-generated sounds along multiple acoustic dimensions simultaneously. We identify a distinct population of auditory cortex neurons that are not responsive to passive sounds or to the expected sound but that encode prediction errors. These prediction error neurons are abundant only in animals with a learned motor-sensory expectation, and encode one or two specific violations rather than a generic error signal. Together, these findings reveal that cortical predictions about self-generated sounds have specificity in multiple simultaneous dimensions and that cortical prediction error neurons encode specific violations from expectation. SIGNIFICANCE STATEMENT Audette et. al record neural activity in the auditory cortex while mice perform a sound-generating forelimb movement and measure neural responses to sounds that violate an animal's expectation in different ways. They find that predictions about self-generated sounds are highly specific across multiple stimulus dimensions and that a population of typically nonsound-responsive neurons respond to sounds that violate an animal's expectation in a specific way. These results identify specific prediction error (PE) signals in the mouse auditory cortex and suggest that errors may be calculated early in sensory processing.

In ethological behaviors like parenting, animals innately follow stereotyped patterns of choices to decide between uncertain outcomes but can learn to modify their strategies to incorporate new information. For example, female mice in a T-maze instinctively use spatial-memory to search for pups where they last found them but can learn more efficient strategies employing pup-associated acoustic cues. We uncovered neural correlates for transitioning between these innate and learned strategies. Auditory cortex (ACx) was required during learning. ACx firing at the nest increased with learning and correlated with subsequent search speed but not outcome. Surprisingly, ACx suppression rather than facilitation during search was more prognostic of correct sound-cued outcomes – even before adopting a sound-cued strategy. Meanwhile medial prefrontal cortex encoded the last pup location, but this decayed as the spatial-memory strategy declined. Our results suggest a neural competition between a weakening spatial-memory and strengthening sound-cued neural representation to mediate strategy switches.

Usher syndrome (USH) is the leading cause of combined deafness and blindness, with USH2A being the most prevalent form. The mechanisms responsible for this debilitating sensory impairment remain unclear. This study focuses on characterizing the auditory phenotype in a mouse model expressing the c.2290delG mutation in usherin equivalent to human frameshift mutation c.2299delG. Previously we described how this model reproduces patient’s retinal phenotypes. Here, we present the cochlear phenotype, showing that the mutant usherin, is expressed during early postnatal stages. The c.2290delG mutation results in a truncated protein that is mislocalized within the cell body of the hair cells. The knock-in model also exhibits congenital hearing loss that remains consistent throughout the animal’s lifespan. Structurally, the stereocilia bundles, particularly in regions associated with functional hearing loss, are disorganized. Our findings shed light on the role of usherin in maintaining structural support, specifically in longer inner hair cell stereocilia, during development, which is crucial for proper bundle organization and hair cell function. Overall, we present a genetic mouse model with cochlear defects associated with the c.2290delG mutation, providing insights into the etiology of hearing loss and offering potential avenues for the development of effective therapeutic treatments for USH2A patients.

The therapeutic effects of pharmaceuticals depend on their drug concentrations in the cochlea. Efficient drug delivery from the systemic circulation into the inner ear is limited by the blood‐labyrinth‐barrier (BLB). This study investigated a novel noninvasive sound conditioning (SC) strategy (90 dB SPL, 8–16 kHz, 2 h sound exposure) to temporally enhance BLB permeability in a controllable way, contributing to maximizing the penetration of pharmaceuticals from blood circulation into the cochlea. Trafficking of Fluorescein Isothiocyanate conjugated dextran and bovine serum albumin (FITC‐dextran and FITC‐BSA) demonstrated that paracellular leakage of BLB sustained for 6 h after SC, providing a controllable time window for systemic administration. Cochlear concentrations of dexamethasone (DEX) and dexamethasone phosphate (DEX‐P), respectively transported by transcellular and paracellular pathways, showed a higher content of the latter one after SC, further confirming the key role of paracellular pathway in the SC‐induced hyperpermeability. Results of high‐throughput RNA‐sequencing identified a series of tight junction (TJ)‐associated genes after SC. The expressions of TJ (ZO‐1) were reduced and irregular rearrangements of the junction were observed by transmission electron microscopy after SC. We further determined the inhibiting role of Rab13 in the recruitment of ZO‐1 and later in the regulation of cellular permeability. Meanwhile, no significant change in the quantifications of endothelial caveolae vesicles after SC indicated that cellular transcytosis accounted little for the temporary hyperpermeability after SC. Based on these results, SC enhances the BLB permeability within 6 h and allows systemically applied drugs which tend to be transported by paracellular pathway to readily enter the inner ear, contributing to guiding the clinical medications on hearing loss.

The GJB2 gene, encoding Connexin26 (Cx26), is one of the most common causes of inherited deafness. Clinically, mutations in GJB2 cause congenital deafness or late‐onset progressive hearing loss. Recently, it has been reported that Cx26 haploid deficiency accelerates the development of age‐related hearing loss (ARHL). However, the roles of cochlear Cx26 in the hearing function of aged animals remain unclear. In this study, we revealed that the Cx26 expression was significantly reduced in the cochleae of aged mice, and further explored the underlying molecular mechanism for Cx26 degradation. Immunofluorescence co‐localization results showed that Cx26 was internalized and degraded by lysosomes, which might be one of the important ways for Cx26 degradation in the cochlea of aged mice. Currently, whether the degradation of Cx26 in the cochlea leads directly to ARHL, as well as the mechanism of Cx26 degradation‐related hearing loss are still unclear. To address these questions, we generated mice with Cx26 knockout in the adult cochlea as a model for the natural degradation of Cx26. Auditory brainstem response (ABR) results showed that Cx26 knockout mice exhibited high‐frequency hearing loss, which gradually progressed over time. Pathological examination also revealed the degeneration of hair cells and spiral ganglions, which is similar to the phenotype of ARHL. In summary, our findings suggest that degradation of Cx26 in the cochlea accelerates the occurrence of ARHL, which may be a novel mechanism of ARHL.

Background Aminoglycoside antibiotics are used for treating certain acute infections. However, these drugs cause ototoxicity by inducing inner ear hair cell death. Aims/Objectives We investigated the protective effect of a nanoemulsion of the carotenoid astaxanthin on mammalian inner ear hair cells against neomycin-induced ototoxicity. Material and Methods Dose-response relationship, quantification of hair cell loss, and reactive oxygen species production were assayed in response to neomycin with and without astaxanthin in cultured utricles of CBA/N mice. In addition, auditory brain response (ABR) and hair cell loss after exposure to the nanoformulation and loud noise were examined in vivo in guinea pigs. Results Astaxanthin suppressed neomycin-induced reduction of hair cells by reducing the production of hydroxy radicals. Furthermore, hair cell loss in the second rotation of the cochlea was significantly lower in the astaxanthin group than in the noise-only group. Conclusions and Significance The blood-labyrinth barrier limits the successful delivery of drugs for inner ear complications. However, in the nanoemulsion form, astaxanthin can penetrate the round window (fenestra ovale) membrane, enabling topical administration. Thus, astaxanthin nanoemulsion could be useful in treating ototoxicity in individuals with inner ear complications.

Introduction Neuronal hyperactivity has been associated with many brain diseases. In the auditory system, hyperactivity has been linked to hyperacusis and tinnitus. Previous research demonstrated the development of hyperactivity in inferior colliculus (IC) neurons after sound overexposure, but the underlying mechanism of this hyperactivity remains unclear. The main goal of this study was to determine the mechanism of this hyperactivity. Methods Experiments were performed on CBA/CaJ mice in a restrained, unanesthetized condition using intracellular recordings with sharp microelectrodes. Recordings were obtained from control (unexposed) and unilaterally sound overexposed groups of mice. Results Our data suggest that sound exposure-induced hyperactivity was due to a depolarizing shift of the resting membrane potential (RMP) in the hyperactive neurons. The half width of action potentials in these neurons was also decreased after sound exposure. Surprisingly, we also found an RMP gradient in which neurons have more hyperpolarized RMPs with increasing depth in the IC. This gradient was altered in the overexposed animals.

Introduction Repeatedly pairing a tone with vagus nerve stimulation (VNS) alters frequency tuning across the auditory pathway. Pairing VNS with speech sounds selectively enhances the primary auditory cortex response to the paired sounds. It is not yet known how altering the speech sounds paired with VNS alters responses. In this study, we test the hypothesis that the sounds that are presented and paired with VNS will influence the neural plasticity observed following VNS-sound pairing. Methods To explore the relationship between acoustic experience and neural plasticity, responses were recorded from primary auditory cortex (A1) after VNS was repeatedly paired with the speech sounds ‘rad’ and ‘lad’ or paired with only the speech sound ‘rad’ while ‘lad’ was an unpaired background sound. Results Pairing both sounds with VNS increased the response strength and neural discriminability of the paired sounds in the primary auditory cortex. Surprisingly, pairing only ‘rad’ with VNS did not alter A1 responses. Discussion These results suggest that the specific acoustic contrasts associated with VNS can powerfully shape neural activity in the auditory pathway. Methods to promote plasticity in the central auditory system represent a new therapeutic avenue to treat auditory processing disorders. Understanding how different sound contrasts and neural activity patterns shape plasticity could have important clinical implications.

Purpose: Multiple dimensions of language dominance, such as language proficiency and demand for language use, can be reflected in bilinguals’ speech-in-speech recognition scores. This paper explores the feasibility of using a novel measure to estimate language dominance for bilinguals: relative speech-in-speech recognition thresholds (SRTs) or the within-person difference in SRTs between their two languages. Method: Participants were 25 Spanish/English bilingual adults ( M age = 30 years). SRTs for sentence recognition in a language-matched two-talker masker were measured in English and in Spanish using an adaptive, open-set task. Relative SRTs were calculated by subtracting the Spanish SRT from the English SRT. Language dominance and proficiency were assessed by established measures. Analysis: Spearman correlations were used to assess the association between measures. Findings: Relative SRTs were correlated with dominance scores derived from both a questionnaire ( r s = −.80) and standardized testing ( r s = −.80). Originality: We tested and validated a novel measure, relative SRTs, to predict language dominance in bilingual adults. This time-efficient method could be used by bilingual researchers interested in assessing language dominance for descriptive or experimental purposes. Significance: Relative SRTs show promise as a valid method to assess language dominance in Spanish/English bilingual adults.

The sensitivity of neurons to small time differences in sustained sounds to both ears is important for binaural hearing, and this sensitivity is critically dependent on phase-locking in the monaural pathways. Although studies in cat showed a marked improvement in phase-locking from the peripheral to the central auditory nervous system, the evidence in rodents is mixed. Here, we recorded from AN and TB of chinchilla and found temporal enhancement, though more limited than in cat.

Importance Unexplained chronic cough is common and has substantial negative quality-of-life implications, yet its causes are not well understood. A better understanding of how peripheral and central neural processes contribute to chronic cough is essential for treatment design. Objective To determine if people with chronic cough exhibit signs of abnormal neural processing over laryngeal sensorimotor cortex during voluntary laryngeal motor activity such as vocalization. Design, Setting, and Participants This was a cross-sectional study of a convenience sample of participants with chronic cough and healthy participants. Testing was performed in an acoustically and electromagnetically shielded chamber. In a single visit, electroencephalographic (EEG) signals were recorded from participants with chronic cough and healthy participants during voice production. The chronic cough group participants presented with unexplained cough of 8 weeks or longer duration with prior medical evaluation including negative results of chest imaging. None of the participants had a history of any neurologic disease known to impair vocalization or swallowing. Data collection for the healthy control group occurred from February 2 to June 28, 2018, and for the chronic cough group, from November 22, 2021, to June 21, 2022. Data analysis was performed from May 1 to October 30, 2022. Exposure Participants with or without chronic cough. Main Outcome Measures Event-related spectral perturbation over the laryngeal area of somatosensory-motor cortex from 0 to 30 Hz (ie, θ, α, and β bands) and event-related coherence as a measure of synchronous activity between somatosensory and motor cortical regions. Results The chronic cough group comprised 13 participants with chronic cough (mean [SD] age, 63.5 [7.8] years; 9 women and 4 men) and the control group, 10 healthy age-matched individuals (mean [SD] age, 60.3 [13.9] years; 6 women and 4 men). In the chronic cough group, the typical movement-related desynchronization over somatosensory-motor cortex during vocalization was significantly reduced across θ, α, and β frequency bands when compared with the control group. Conclusions and Relevance This cross-sectional study found that the typical movement-related suppression of brain oscillatory activity during vocalization is weak or absent in people with chronic cough. Thus, chronic cough affects sensorimotor cortical activity during the asymptomatic voluntary activation of laryngeal muscles.

Little is known about how populations of neurons within cortical circuits encode sensory stimuli in the presence of competing stimuli at other spatial locations. Here, we investigate this problem in auditory cortex using a recently proposed information-theoretic approach. We find a small subset of neurons nearly maximizes information about target sounds in the presence of competing maskers, approaching information levels for isolated stimuli, and provides a noise-robust code for sounds in a complex auditory scene.

Despite lacking ears, the nematode C. elegans senses airborne sound and engages in phonotaxis behavior, enabling it to locate and avoid sound sources.1 How worms sense sound, however, is not well understood. Here, we report an interesting observation that worms respond only to sounds emitted by small but not large speakers, indicating that they preferentially respond to localized sound sources. Notably, sounds emitted by small speakers form a sharp sound pressure gradient across the worm body, while sounds from large speakers do not, suggesting that worms sense sound pressure gradients rather than absolute sound pressure. Analysis of phonotaxis behavior, sound-evoked skin vibration, and sound-sensitive neuron activities further support this model. We suggest that the ability to sense sound pressure gradients provides a potential mechanism for worms to distinguish sounds generated by their predators, which are typically small animals, from those produced by large animals or background noise. As vertebrate cochlea and some insect ears can also detect sound pressure gradients, our results reveal that sensing of sound pressure gradients may represent a common mechanism in auditory sensation across animal phyla. VIDEO ABSTRACT.

Context modulates how information is processed in the mammalian brain. For example, brain responses are amplified to contextually unusual stimuli. This phenomenon, known as "deviance detection,"1,2 is well documented in early, primary sensory cortex, where large responses are generated to simple stimuli that deviate from their context in low-order properties, such as line orientation, size, or pitch.2,3,4,5 However, the extent to which neural deviance detection manifests (1) in broader cortical networks and (2) to simple versus complex stimuli, which deviate only in their higher-order, multisensory properties, is not known. Consistent with a predictive processing framework,6,7 we hypothesized that deviance detection manifests in a hierarchical manner across cortical networks,8,9 emerging later and further downstream when stimulus deviance is complex. To test this, we examined brain responses of awake mice to simple unisensory deviants (e.g., visual line gratings, deviating from context in their orientation alone) versus complex multisensory deviants (i.e., audiovisual pairs, deviating from context only in their audiovisual pairing but not visual or auditory content alone). We find that mouse parietal associative area-a higher cortical region-displays robust multisensory deviance detection. In contrast, primary visual cortex exhibits strong unisensory visual deviance detection but weaker multisensory deviance detection. These results suggest that deviance detection signals in the cortex may be conceptualized as "prediction errors," which are primarily fed forward-or downstream-in cortical networks.6,7.

The ventral tegmental area (VTA) has been proposed to play a role in pain, but the brain structures modulating VTA activity in response to nociceptive stimuli remain unclear. Here, we demonstrate that the lateral preoptic area (LPO) glutamate neurons relay nociceptive information to the VTA. These LPO glutamatergic neurons synapsing on VTA neurons respond to nociceptive stimulation and conditioned stimuli predicting nociceptive stimulation and also mediate aversion. In contrast, LPO GABA neurons synapsing in the VTA mediate reward. By ultrastructural quantitative synaptic analysis, ex vivo electrophysiology, and functional neuroanatomy we identify a complex circuitry between LPO glutamatergic and GABAergic neurons and VTA dopaminergic, GABAergic, and glutamatergic neurons. We conclude that LPO glutamatergic neurons play a causal role in the processing of nociceptive stimuli and in relaying information about nociceptive stimuli. The pathway from LPO glutamatergic neurons to the VTA represents an unpredicted interface between peripheral nociceptive information and the limbic system.

Study of the inferior colliculus (IC) has largely focused on the central nucleus, with little exploration of the outer cortices. Here, we systematically assessed the acoustic response properties from over 2,000 locations in different subregions of the IC. The results revealed spatial trends in temporal response patterns that span all subregions. Furthermore, two populations of temporal response types emerged for neurons in the outer cortices that may contribute to their functional roles in auditory tasks.