Publications using TDT

To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their Ca V 1.3 calcium channels. Mutations in the CABP2 gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. In Cabp1/2 double-knockout mice, we find strongly enhanced Ca V 1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage- and calcium-dependent inactivation of IHC Ca V 1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding.

Katydids employ acoustic signals to communicate with others of their species and have evolved to generate sounds by coupling the anatomical structures of their forewings. However, some species have evolved to implement an additional resonance mechanism that enhances the transmission and sound pressure of the acoustic signals produced by the primary resonators. Secondary resonators, such as burrow cavities or horn-shaped structures, are found in the surrounding environment but could also occur as anatomical modifications of their bodies. Chamber-like structures have been described in species of katydids with modified pronota or wings. It has been shown that these modified structures directly affect the transmission and filtering of acoustic signals and can function as a Helmholtz resonator that encapsulates the primary sound source. By morphological and acoustic analysis, we describe a new genus of Conocephalinae and investigate the physical properties of their sound production structures for three new species from the Andes of Colombia and Ecuador. Males of the new genus, here described as Tectucantus n. gen., have a characteristic inflated pronotum enclosing the reduced first pair of wings and extending rearward over the first abdominal segments. We test the hypothesis that the pronotal cavity volume correlates with the carrier frequency of specific calls. The cavity of the pronotal chamber acts as a Helmholtz resonator in all three Tectucantus species and, potentially, in other distantly related species, which use similar secondary body resonators.

Mammals can execute intended limb movements despite the fact that spinal reflexes involuntarily modulate muscle activity. To generate appropriate muscle activity, the cortical descending motor output must coordinate with spinal reflexes, yet the underlying neural mechanism remains unclear. We simultaneously recorded activities in motor-related cortical areas, afferent neurons, and forelimb muscles of monkeys performing reaching movements. Motor-related cortical areas, predominantly primary motor cortex (M1), encode subsequent afferent activities attributed to forelimb movement. M1 also encodes a subcomponent of muscle activity evoked by these afferent activities, corresponding to spinal reflexes. Furthermore, selective disruption of the afferent pathway specifically reduced this subcomponent of muscle activity, suggesting that M1 output drives muscle activity not only through direct descending pathways but also through the “transafferent” pathway composed of descending plus subsequent spinal reflex pathways. Thus, M1 provides optimal motor output based on an internal forward model that prospectively computes future spinal reflexes.

Noise-induced hearing loss is a worldwide public health issue that is characterized by temporary or permanent changes in hearing sensitivity. This condition is closely linked to inflammatory responses, and interventions targeting the inflammatory gene tumor necrosis factor-alpha (TNFα) are known to mitigate cochlear noise damage. TNFα-induced proteins (TNFAIPs) are a family of translucent acidic proteins, and TNFAIP6 has a notable association with inflammatory responses. To date, there have been few reports on TNFAIP6 levels in the inner ear. To elucidate the precise mechanism, we generated transgenic mouse models with conditional knockout of Tnfaip6 (Tnfaip6 cKO). Evaluation of hair cell morphology and function revealed no significant differences in hair cell numbers or ribbon synapses between Tnfaip6 cKO and wild-type mice. Moreover, there were no notable variations in hair cell numbers or hearing function in noisy environments. Our results indicate that Tnfaip6 does not have a substantial impact on the auditory system.

The hispid pocket mouse ( C. hispidus ) is a solitary semi-fossorial rodent that has been the subject of various ecological and genetic studies. However, no previous studies have characterized its hearing ability, which is important for its survival and fitness. We collected auditory brainstem responses (ABRs) from C. hispidus and measured craniofacial and pinna morphological features to assess hearing ability and test differences in hearing thresholds, monaural and binaural ABR amplitudes and latencies between the sexes. ABR recordings revealed that similar to other small mammals, C. hispidus displayed the lowest threshold to sounds between 8-16 kHz, indicating best hearing across those frequencies. We found significant differences in auditory thresholds of the ABRs between the sexes, with females showing lower frequency hearing compared to males. However, no significant differences were detected in monaural and binaural ABR amplitudes and latencies between the sexes. We also found no significant differences in craniofacial and pinna dimensions between the sexes. These findings shed novel insights into the auditory systems across species and highlighted for the first time sex differences in auditory thresholds for this rodent species.

The endogenous dynorphin/kappa opioid receptor (KOR) system in the brain mediates the dysphoric effects of stress, and KOR antagonists may have therapeutic potential for the treatment of drug addiction, depression, and psychosis. One class of KOR antagonists, the long-acting norBNI-like antagonists, have been suggested to act by causing KOR inactivation through a cJun-kinase mechanism rather than by competitive inhibition. In this study, we screened for other opioid ligands that might produce norBNI-like KOR inactivation and found that nalfurafine (a G-biased KOR agonist) and nalmefene (a KOR partial agonist) also produce long-lasting KOR inactivation. Neither nalfurafine nor nalmefene are completely selective KOR ligands, but KOR inactivation was observed at doses 10-100 fold lower than necessary for mu opioid receptor actions. Daily microdosing with nalfurafine or nalmefene blocked KORs responsible for antinociceptive effects, blocked KORs mediating stress-induced aversion, and mitigated the aversion during acute and protracted withdrawal in fentanyl-dependent mice. Both nalfurafine and nalmefene have long histories of safety and use in humans and could potentially be repurposed for the treatment of dynorphin-mediated stress disorders.

Reconstructing perceived speech stimuli from neural recordings is not only advancing the understanding of the neural coding underlying speech processing but also an important building block for brain-computer interfaces and neuroprosthetics. However, previous attempts to directly re-synthesize speech from neural decoding suffer from low re-synthesis quality. With the limited neural data and complex speech representation space, it is hard to build decoding model that directly map neural signal into high-fidelity speech. In this work, we proposed a pre-trained encoder-decoder framework to address these problems. We recorded high-density electrocorticography (ECoG) signals when participants listening to natural speech. We built a pre-trained speech re-synthesizing network that consists of a context-dependent speech encoding network and a generative adversarial network (GAN) for high-fidelity speech synthesis. This model was pre-trained on a large naturalistic speech corpus and can extract critical features for speech re-synthesize. We then built a light-weight neural decoding network that mapped the ECoG signal into the latent space of the pre-trained network, and used the GAN decoder to synthesize natural speech. Using only 20 minutes of intracranial neural data, our neural-driven speech re-synthesis model demonstrated promising performance, with phoneme error rate (PER) at 28.6%, and human listeners were able to recognize 71.6% of the words in the re-synthesized speech. This work demonstrates the feasibility of using pre-trained self-supervised model and feature alignment to build efficient neural-to-speech decoding model.

Bilateral cochlear implant (CI) patients exhibit significant limitations in spatial hearing. Their ability to process interaural time differences (ITDs) is often impaired, while their ability to process interaural level differences (ILDs) remains comparatively good. Clinical studies aiming to identify the causes of these limitations are often plagued by confounds and ethical limitations. Recent behavioral work suggests that rats may be a good animal model for studying binaural hearing under neuroprosthetic stimulation, as rats develop excellent ITD sensitivity when provided with suitable CI stimulation. However, their ability to use ILDs has not yet been characterized. Objective of this study is to address this knowledge gap. Neontally deafened rats were bilaterally fitted with CIs, and trained to lateralize binaural stimuli according to ILD. Their behavioral ILD thresholds were measured at pulse rates from 50 to 2400 pps. CI rats exhibited high sensitivity to ILDs with thresholds of a few dB at all tested pulse rates. We conclude that early deafened rats develop good sensitivity, not only to ITDs but also to ILDs, if provided with appropriate CI stimulation. Their generally good performance, in line with expectations from other mammalian species, validates rats as an excellent model for research on binaural auditory prostheses.

Animacy perception, the ability to discern living from non-living entities, is crucial for survival and social interaction, as it includes recognizing abstract concepts such as movement, purpose, and intentions. This process involves interpreting cues that may suggest the intentions or actions of others. It engages the temporal cortex (TC), particularly the superior temporal sulcus (STS) and the adjacent region of the inferior temporal cortex (ITC), as well as the dorsomedial prefrontal cortex (dmPFC). However, it remains unclear how animacy is dynamically encoded over time in these brain areas and whether its processing is distributed or localized. In this study, we addressed these questions by employing a symbolic categorization task involving animate and inanimate objects using natural movie stimuli. Simultaneously, electrocorticography were conducted in both the TC and dmPFC. Time-frequency analysis revealed region-specific frequency representations throughout the observation of the movies. Spatial searchlight decoding analysis demonstrated that animacy processing is represented in a distributed manner. Regions encoding animacy information were found to be dispersed across the fundus and lip of the STS, as well as in the ITC. Next, we examined whether these dispersed regions form functional networks. Independent component analysis revealed that the spatial distribution of the component with the most significant animacy information corresponded with the dispersed regions identified by the spatial decoding analysis. Furthermore, Granger causality analysis indicated that these regions exhibit frequency-specific directional functional connectivity, with a general trend of causal influence from the ITC to STS across multiple frequency bands. Notably, a prominent feedback flow in the alpha band from the ITC to both the ventral bank and fundus of the STS was identified. These findings suggest a distributed and functionally interconnected neural substrate for animacy processing across the STS and ITC.

The mammalian auditory system encodes sounds with subtypes of spiral ganglion neurons (SGNs) that differ in sound level sensitivity, permitting discrimination across a wide range of levels. Recent work suggests the physiologically defined SGN subtypes correspond to at least three molecular subtypes. It is not known how information from the different subtypes converges within the cochlear nucleus. We examined this issue using transgenic mice of both sexes that express Cre recombinase in SGNs that are positive for markers of two subtypes: CALB2 (calretinin) in type 1a SGNs and LYPD1 in type 1c SGNs, which correspond to high- and low-sensitivity subtypes, respectively. We crossed these with mice expressing floxed channelrhodopsin, which allowed specific activation of axons from type 1a or 1c SGNs using optogenetics. We made voltage-clamp recordings from bushy cells in the anteroventral cochlear nucleus (AVCN) and found that the synapses formed by CALB2- and LYPD1-positive SGNs had similar EPSC amplitudes and short-term plasticity. Immunohistochemistry revealed that individual bushy cells receive a mix of 1a, 1b, and 1c synapses with VGluT1-positive puncta of similar sizes. We used optogenetic stimulation during in vivo recordings to classify chopper and primary-like units as receiving versus nonreceiving 1a- or 1c-type inputs. These groups showed no significant difference in threshold or spontaneous rate, suggesting the subtypes do not segregate into distinct processing streams in the AVCN. Our results indicate that principal cells in the AVCN integrate information from all SGN subtypes with extensive convergence, which could optimize sound encoding across a large dynamic range.

Women are disproportionately affected by chronic pain compared with men. While societal and environmental factors contribute to this disparity, sex-based biological differences in the processing of pain are also believed to play significant roles. The central lateral nucleus of the amygdala (CeLC) is a key region for the emotional-affective dimension of pain, and a prime target for exploring sex differences in pain processing since a recent study demonstrated sex differences in CGRP actions in this region. Inputs to CeLC from the parabrachial nucleus (PB) play a causal role in aversive processing and release both glutamate and calcitonin gene-related peptide (CGRP). CGRP is thought to play a crucial role in chronic pain by potentiating glutamatergic signaling in CeLC. However, it is not known if this CGRP-mediated synaptic plasticity occurs similarly in males and females. Here, we tested the hypothesis that female CeLC neurons experience greater potentiation of glutamatergic signaling than males following endogenous CGRP exposure. Using trains of optical stimuli to evoke transient CGRP release from PB terminals in CeLC, we find that subsequent glutamatergic responses are preferentially potentiated in CeLC neurons from female mice. This potentiation was CGRP dependent and involved a postsynaptic mechanism. This sex difference in CGRP sensitivity may explain sex differences in affective pain processing.

Exposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response (UPR), have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways have been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice. We used a genetically encoded calcium indicator mouse model in which GCaMP6f is expressed specifically in hair cells or supporting cells under control of Myo15Cre or Sox2Cre, respectively. We performed live calcium imaging and UPR gene expression analysis in 8-week-old mice exposed to levels of noise that cause cochlear synaptopathy (98 db sound pressure level [SPL]) or permanent hearing loss (106 dB SPL). UPR activation occurred immediately after noise exposure, and the pattern of UPR activation was dependent on noise level, with the proapoptotic pathway upregulated only after 106 dB noise exposure. Spontaneous calcium transients in hair cells and intercellular calcium waves in supporting cells, which are present in neonatal cochleae, were quiescent in mature-hearing cochleae but reactivated upon noise exposure. Noise exposure of 106 dB was associated with more persistent and expansive intercellular Ca 2+ signaling wave activity. These findings demonstrate a strong and dose-dependent association between noise exposure, UPR activation, and changes in calcium homeostasis in hair cells and supporting cells, suggesting that targeting these pathways may be effective to develop treatments for noise-induced hearing loss.

In the mammalian cochlea, sensory hair cells are crucial for the transduction of acoustic stimuli into electrical signals, which are then relayed to the central auditory pathway via spiral ganglion neuron (SGN) afferent dendrites. The SGN output is directly modulated by inhibitory cholinergic axodendritic synapses from the efferent fibers originating in the superior olivary complex. When the adult cochlea is subjected to noxious stimuli or aging, the efferent system undergoes major rewiring, such that it reestablishes direct axosomatic contacts with the inner hair cells (IHCs), which occur only transiently during prehearing stages of development. The trigger, origin, and degree of efferent plasticity in the cochlea remains largely unknown. Using functional and morphological approaches, we demonstrate that efferent plasticity in the adult cochlea occurs as a direct consequence of mechanoelectrical transducer current dysfunction. We also show that, different from prehearing stages of development, the lateral olivocochlear — but not the medial olivocochlear — efferent fibers are those that form the axosomatic synapses with the IHCs. The study also demonstrates that in vivo restoration of IHC function using AAV- Myo7a rescue reestablishes the synaptic profile of adult IHCs and improves hearing, highlighting the potential of using gene-replacement therapy for progressive hearing loss.

The class C orphan G-protein-coupled receptor (GPCR) GPR156, which lacks the large extracellular region, plays a pivotal role in auditory function through Gi2/3. Here, we firstly demonstrate that GPR156 with high constitutive activity is essential for maintaining auditory function, and further reveal the structural basis of the sustained role of GPR156. We present the cryo-EM structures of human apo GPR156 and the GPR156-Gi3 complex, unveiling a small extracellular region formed by extracellular loop 2 (ECL2) and the N-terminus. The GPR156 dimer in both apo state and Gi3 protein-coupled state adopt a transmembrane (TM)5/6-TM5/6 interface, indicating the high constitutive activity of GPR156 in the apo state. Furthermore, C-terminus in G-bound subunit of GPR156 plays a dual role in promoting G protein binding within G-bound subunit while preventing the G-free subunit from binding to additional G protein. Together, these results explain how GPR156 constitutive activity is maintained through dimerization and provide a mechanistic insight into the sustained role of GPR156 in maintaining auditory function.

The brain predicts regularities in sensory inputs at multiple complexity levels, with neuronal mechanisms that remain elusive. Here, we monitored auditory cortex activity during the local-global paradigm, a protocol nesting different regularity levels in sound sequences. We observed that mice encode local predictions based on stimulus occurrence and stimulus transition probabilities, because auditory responses are boosted upon prediction violation. This boosting was due to both short-term adaptation and an adaptation-independent surprise mechanism resisting anesthesia. In parallel, and only in wakefulness, VIP interneurons responded to the omission of the locally expected sound repeat at the sequence ending, thus providing a chunking signal potentially useful for establishing global sequence structure. When this global structure was violated, by either shortening the sequence or ending it with a locally expected but globally unexpected sound transition, activity slightly increased in VIP and PV neurons, respectively. Hence, distinct cellular mechanisms predict different regularity levels in sound sequences.

Neural implantable devices serve as electronic interfaces facilitating communication between the body and external electronic systems. These bioelectronic systems ideally possess stable electrical conductivity, flexibility, and stretchability to accommodate dynamic movements within the body. However, achieving both high electrical conductivity and mechanical compatibility remains a challenge. Effective electrical conductors tend to be rigid and stiff, leading to a substantial mechanical mismatch with bodily tissues. On the other hand, highly stretchable polymers, while mechanically compatible, often suffer from limited compatibility with lithography techniques and reduced electrical stability. Therefore, there exists a pressing need to develop electromechanically stable neural interfaces that enable precise communication with biological tissues. In this study, a polymer that is softening, flexible, conformal, and compatible with lithography to microfabricate perforated thin‐film architectures is utilized. These architectures offer stretchability and improved mechanical compatibility. Three distinct geometries are evaluated both mechanically and electrically under in vitro conditions that simulate physiological environments. Notably, the Peano structure demonstrates minimal changes in resistance, varying less than 1.5× even when subjected to ≈150% strain. Furthermore, devices exhibit a maximum mechanical elongation before fracture, reaching 220%. Finally, the application of multi‐electrode spinal cord leads employing titanium nitride for neural stimulation in rat models is demonstrated.

Acoustic information in speech changes continuously, yet listeners form discrete perceptual categories to ease the demands of perception. Being a more continuous/gradient as opposed to a more discrete/categorical listener may be further advantageous for understanding speech in noise by increasing perceptual flexibility and resolving ambiguity. The degree to which a listener's responses to a continuum of speech sounds are categorical versus continuous can be quantified using visual analog scaling (VAS) during speech labeling tasks. Here, we recorded event-related brain potentials (ERPs) to vowels along an acoustic-phonetic continuum (/u/ to /a/) while listeners categorized phonemes in both clean and noise conditions. Behavior was assessed using standard two alternative forced choice (2AFC) and VAS paradigms to evaluate categorization under task structures that promote discrete vs. continuous hearing, respectively. Behaviorally, identification curves were steeper under 2AFC vs. VAS categorization but were relatively immune to noise, suggesting robust access to abstract, phonetic categories even under signal degradation. Behavioral slopes were correlated with listeners' QuickSIN scores; shallower slopes corresponded with better speech in noise performance, suggesting a perceptual advantage to noise degraded speech comprehension conferred by a more gradient listening strategy. At the neural level, P2 amplitudes and latencies of the ERPs were modulated by task and noise; VAS responses were larger and showed greater noise-related latency delays than 2AFC responses. More gradient responders had smaller shifts in ERP latency with noise, suggesting their neural encoding of speech was more resilient to noise degradation. Interestingly, source-resolved ERPs showed that more gradient listening was also correlated with stronger neural responses in left superior temporal gyrus. Our results demonstrate that listening strategy modulates the categorical organization of speech and behavioral success, with more continuous/gradient listening being advantageous to sentential speech in noise perception.

Fetal Alcohol Spectrum Disorders (FASD) are one of the most common causes of mental disability in the world. Despite efforts to increase public awareness of the risks of drinking during pregnancy, epidemiological studies indicate a prevalence of 1-6% in all births. There is growing evidence that deficits in sensory processing may contribute to social problems observed in FASD. Multisensory (MS) integration occurs when a combination of inputs from two sensory modalities leads to enhancement or suppression of neuronal firing. MS enhancement is usually linked to processes that facilitate cognition and reaction time, whereas MS suppression has been linked to filtering unwanted sensory information. The rostral portion of the posterior parietal cortex (PPr) of the ferret is an area that shows robust visual-tactile integration and displays both MS enhancement and suppression. Recently, our lab demonstrated that ferrets exposed to alcohol during the "third trimester equivalent" of human gestation show less MS enhancement and more MS suppression in PPr than controls. Here we complement these findings by comparing in vivo electrophysiological recordings from channels located in shallow and deep cortical layers. We observed that while the effects of alcohol (less MS enhancement and more MS suppression) were found in all layers, the magnitude of these effects was more pronounced in putative layers V-VI. These findings extend our knowledge of the sensory deficits of FASD.

Objective . Intracortical microelectrode arrays often fail to deliver reliable signal quality over chronic recordings, and the effect of an implanted recording array on local neural circuits is not completely understood. Approach . In this work we examined the degree of correlation and the spatial dependence of that relationship between widefield calcium imaging and electrophysiology in awake mice from 4 to 44 d post-implantation. Both correlation maps and spike-triggered averaging (STA) are used to characterize the relationship. Main results . We find that calcium imaging and electrophysiological signal are highly correlated in all animals, however, spatial variability in the correlation is affected by inherent correlation in the calcium imaging signal. Some animals exhibit a high degree of apparent neuronal synchrony in the vicinity of the probe at 4 d, while more diversity of response is detected at later time points. Significance . Degree of synchrony appears to be related to the acute injury response to the implanted electrode, with later time points displaying less synchrony. STA may be used to uncover the diverse cortical connections of spiking units.

Because bats emit ultrasound and listen to echoes to perceive their surroundings, presenting phantom echoes is useful for understanding their perception of echolocation. Here, we present a protocol for the real-time playback of phantom echoes, especially from approaching objects. We describe steps for presenting virtual objects using a microphone, digital signal processor, and loudspeaker to induce the escape behavior of bats. We then detail procedures for clarifying their detection algorithm for approaching objects. For complete details on the use and execution of this protocol, please refer to Yoshida et al.1.