Publications using TDT

Social interaction among conspecifics is essential for maintaining adaptive, cooperative, and social behaviors, along with survival among mammals. The 5-hydroxytryptamine (5-HT) neuronal system is an important neurotransmitter system for regulating social behaviors; however, the circadian role of 5-HT in social interaction behaviors is unclear. To investigate whether the circadian nuclear receptor REV-ERBα, a transcriptional repressor of the rate-limiting enzyme tryptophan hydroxylase 2 (Tph2) gene in 5-HT biosynthesis, may affect social interaction behaviors, we generated a conditional knockout (cKO) mouse by targeting Rev-Erbα in dorsal raphe (DR) 5-HT neurons (5-HT DR -specific REV-ERBα cKO) using the CRISPR/Cas9 gene editing system and assayed social behaviors, including social preference and social recognition, with a three-chamber social interaction test at two circadian time (CT) points, i.e., at dawn (CT00) and dusk (CT12). The genetic ablation of Rev-Erbα in DR 5-HTergic neurons caused impaired social interaction behaviors, particularly social preference but not social recognition, with no difference between the two CT points. This deficit of social preference induced by Rev-Erbα in 5-HT DR -specific mice is functionally associated with real-time elevated neuron activity and 5-HT levels at dusk, as determined by fiber-photometry imaging sensors. Moreover, optogenetic inhibition of DR to nucleus accumbens (NAc) 5-HTergic circuit restored the impairment of social preference in 5-HT DR -specific REV-ERBα cKO mice. These results suggest the significance of the circadian regulation of 5-HT levels by REV-ERBα in regulating social interaction behaviors.

Objectives: In the absence of binaural hearing, individuals with single-sided deafness can adapt to use monaural level and spectral cues to improve their spatial hearing abilities. Contralateral routing of signal is the most common form of rehabilitation for individuals with single-sided deafness. However, little is known about how these devices affect monaural localization cues, which single-sided deafness listeners may become reliant on. This study aimed to investigate the effects of contralateral routing of signal hearing aids on localization performance in azimuth and elevation under monaural listening conditions. Design: Localization was assessed in 10 normal hearing adults under three listening conditions: (1) normal hearing (NH), (2) unilateral plug (NH-plug), and (3) unilateral plug and CROS aided (NH-plug + CROS). Monaural hearing simulation was achieved by plugging the ear with E-A-Rsoft™ FX™ foam earplugs. Stimuli consisted of 150 ms high-pass noise bursts (3–20 kHz), presented in a random order from fifty locations spanning ±70° in the horizontal and ±30° in the vertical plane at 45, 55, and 65 dBA. Results: In the unilateral plugged listening condition, participants demonstrated good localization in elevation and a response bias in azimuth for signals directed at the open ear. A significant decrease in performance in elevation occurs with the contralateral routing of signal hearing device on, evidenced by significant reductions in response gain and low r2 value. Additionally, performance in azimuth is further reduced for contralateral routing of signal aided localization compared to the simulated unilateral hearing loss condition. Use of the contralateral routing of signal device also results in a reduction in promptness of the listener response and an increase in response variability. Conclusions: Results suggest contralateral routing of signal hearing aids disrupt monaural spectral and level cues, which leads to detriments in localization performance in both the horizontal and vertical dimensions. Increased reaction time and increasing variability in responses suggests localization is more effortful when wearing the contralateral rerouting of signal device.

Local field potential (LFP) recording is a valuable method for assessing brain systems communication. Multiple methods have been developed to collect LFP data to study the rhythmic activity of the brain. These methods range from the use of single or bundled metal electrodes to electrode arrays that can target multiple brain regions. Although these electrodes are efficient in collecting LFP activity, they can be expensive, difficult to build, and less adaptable to different applications, which may include targeting multiple brain regions simultaneously. Here, the building process for a 16-channel customizable multielectrode array (CMEA) that can be used to collect LFP data from different brain regions simultaneously in rats is described. These CMEA electrode arrays are lightweight (<1 g), take little time to build (<1 h), and are affordable ($15 Canadian). The CMEA can also be modified to record single-unit and multiunit activity in addition to LFP activity using both wired and wireless neural data acquisition systems. Moreover, these CMEAs can be used to explore neural activity (LFP and single-unit/multiunit activity) in preliminary studies, before purchasing more expensive electrodes for targeted studies. Together, these characteristics make the described CMEA a competitive alternative to the commercially available multielectrode arrays for its simplicity, low cost, and efficiency in collecting LFP data in freely behaving animals.

Synaptic zinc signaling modulates synaptic activity and is present in specific populations of cortical neurons, suggesting that synaptic zinc contributes to the diversity of intracortical synaptic microcircuits and their functional specificity. To understand the role of zinc signaling in the cortex, we performed whole-cell patch-clamp recordings from intratelencephalic (IT)-type neurons and pyramidal tract (PT)-type neurons in layer 5 of the mouse auditory cortex during optogenetic stimulation of specific classes of presynaptic neurons. Our results show that synaptic zinc potentiates AMPA receptor (AMPAR) function in a synapse-specific manner. We performed in vivo 2-photon calcium imaging of the same classes of neurons in awake mice and found that changes in synaptic zinc can widen or sharpen the sound-frequency tuning bandwidth of IT-type neurons but only widen the tuning bandwidth of PT-type neurons. These results provide evidence for synapse- and cell-type-specific actions of synaptic zinc in the cortex.

Dopamine release in the nucleus accumbens (NAc) is causally linked to adaptive aversive learning, and its dysregulation is a core phenotype in anxiety and stress disorders. Here, we record NAc core dopamine during a task where mice learn to discriminate between cues signaling two types of outcomes: (1) footshock presentation and (2) footshock omission. We show that dopamine release is evoked by footshock omission. This dopamine response is largest when the omission is unexpected and decreases over learning, and artificially increasing this signal disrupts discrimination learning. Conversely, optogenetic inhibition of dopamine responses to the footshock itself impairs learning. Finally, theory-driven computational modeling suggests that these effects can be explained by dopamine signaling the perceived saliency of predicted aversive events. Together, we elucidate the role of NAc dopamine in aversive learning and offer potential avenues for understanding the neural mechanisms involved in anxiety and stress disorders.

Background Niemann–Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear. Methods We estimated CD–UC complexation for nine CD derivatives derived from native α‐, β‐, and γ‐CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models. Findings We found that shuttle and sink activities of CDs are dependent on cavity size‐dependent stoichiometry and substituent‐associated stability of CD–UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability. Conclusions Our findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC.

Social decision making requires the integration of reward valuation and social cognition systems, both dependent on the orbitofrontal cortex (OFC). How these two OFC functions interact is largely unknown. We recorded intracranial activity from the OFC of ten patients making choices in a social context where reward inequity with a social counterpart varied and could be either advantageous or disadvantageous. We find that OFC high-frequency activity (HFA; 70-150 Hz) encodes self-reward, consistent with previous reports. We also observe encoding of the social counterpart's reward, as well as the type of inequity being experienced. Additionally, we find evidence of inequity-dependent reward encoding: depending on the type of inequity, electrodes rapidly and reversibly switch between different reward-encoding profiles. These results provide direct evidence for encoding of self- and other rewards in the human OFC and highlight the dynamic nature of encoding in the OFC as a function of social context.

Usher syndrome type 1F (USH1F), characterized by congenital lack of hearing and balance and progressive loss of vision, is caused by mutations in the PCDH15 gene. In the Ashkenazi population, a recessive truncation mutation accounts for a large proportion of USH1F cases. The truncation is caused by a single C→T mutation, which converts an arginine codon to a stop (R245X). To test the potential for base editors to revert this mutation, we developed a humanized Pcdh15R245X mouse model for USH1F. Mice homozygous for the R245X mutation were deaf and exhibited profound balance deficits, while heterozygous mice were unaffected. Here we show that an adenine base editor (ABE) is capable of reversing the R245X mutation to restore the PCDH15 sequence and function. We packaged a split-intein ABE into dual adeno-associated virus (AAV) vectors and delivered them into cochleas of neonatal USH1F mice. Hearing was not restored in a Pcdh15 constitutive null mouse despite base editing, perhaps because of early disorganization of cochlear hair cells. However, injection of vectors encoding the split ABE into a late-deletion conditional Pcdh15 knockout rescued hearing. This study demonstrates the ability of an ABE to correct the PCDH15 R245X mutation in the cochlea and restore hearing.

Schroeder-phase harmonic tone complexes can have a flat temporal envelope and rising or falling instantaneous-frequency sweeps within F0 periods, depending on the phase-scaling parameter C. Human tone-detection thresholds in a concurrent Schroeder masker are 10-15 dB lower for positive C values (rising frequency sweeps) compared to negative (falling sweeps), potentially due to cochlear mechanics, though this hypothesis remains controversial. Birds provide an interesting model for studies of Schroeder masking because many species produce vocalizations containing frequency sweeps. Prior behavioral studies in birds suggest less behavioral threshold difference between maskers with opposite C values than in humans, but focused on low masker F0s and did not explore neural mechanisms. We performed behavioral Schroeder-masking experiments in budgerigars (Melopsittacus undulatus) using a wide range of masker F0 and C values. Signal frequency was 2800 Hz. Neural recordings from the midbrain characterized encoding of behavioral stimuli in awake animals. Behavioral thresholds increased with increasing masker F0 and showed minimal difference between opposite C values, consistent with prior budgerigar studies. Midbrain recordings showed prominent temporal and rate-based encoding of Schroeder F0, and in many cases, marked asymmetry in Schroeder responses between C polarities. Neural thresholds for Schroeder-masked tone detection were often based on a response decrement compared to the masker alone, consistent with prominent modulation tuning in midbrain neurons, and were generally similar between opposite C values. The results highlight the likely importance of envelope cues in Schroeder masking and show that differences in supra-threshold Schroeder responses do not necessarily result in neural threshold differences.

Strong expression of the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1) in ventral tegmental area (VTA) dopamine (DA) neurons and terminals makes it an attractive target to modulate DA neuron activity and normalize DA-related pathologies. Recent studies have identified a novel class of NTR1 ligand that shows promising effects in preclinical models of addiction. A lead molecule, SBI-0654553 (SBI-553), can act as a positive allosteric modulator of NTR1 β-arrestin recruitment while simultaneously antagonizing NTR1 Gq protein signaling. Using cell-attached recordings from mouse VTA DA neurons we discovered that, unlike neurotensin (NT), SBI-553 did not independently increase spontaneous firing. Instead, SBI-553 blocked the NT-mediated increase in firing. SBI-553 also antagonized the effects of NT on dopamine D2 auto-receptor signaling, potentially through its inhibitory effects on G-protein signaling. We also measured DA release directly, using fast-scan cyclic voltammetry in the nucleus accumbens and observed antagonist effects of SBI-553 on an NT-induced increase in DA release. Further, in vivo administration of SBI-553 did not notably change basal or cocaine-evoked DA release measured in NAc using fiber photometry. Overall, these results indicate that SBI-553 blunts NT's effects on spontaneous DA neuron firing, D2 auto-receptor function, and DA release, without independently affecting these measures. In the presence of NT, SBI-553 has an inhibitory effect on mesolimbic DA activity, which could contribute to its efficacy in animal models of psychostimulant use.

So-called duplex speech stimuli with perceptually ambiguous spectral cues to one ear and isolated low- versus high-frequency third formant “chirp” to the opposite ear yield a coherent percept supporting their phonetic categorization. Critically, such dichotic sounds are only perceived categorically upon binaural integration. Here, we used frequency-following responses (FFRs), scalp-recorded potentials reflecting phase-locked subcortical activity, to investigate brainstem responses to fused speech percepts and to determine whether FFRs reflect binaurally integrated category-level representations. We recorded FFRs to diotic and dichotic stop-consonants (/da/, /ga/) that either did or did not require binaural fusion to properly label along with perceptually ambiguous sounds without clear phonetic identity. Behaviorally, listeners showed clear categorization of dichotic speech tokens confirming they were heard with a fused, phonetic percept. Neurally, we found FFRs were stronger for categorically perceived speech relative to category-ambiguous tokens but also differentiated phonetic categories for both diotically and dichotically presented speech sounds. Correlations between neural and behavioral data further showed FFR latency predicted the degree to which listeners labeled tokens as “da” versus “ga.” The presence of binaurally integrated, category-level information in FFRs suggests human brainstem processing reflects a surprisingly abstract level of the speech code typically circumscribed to much later cortical processing.

Background Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception and language development. Abnormal development of temporal processing may account for the language impairments associated with ASD. Very little is known about the development of temporal processing in any animal model of ASD. Methods In the current study, we quantify auditory temporal processing throughout development in the Fmr1 knock-out (KO) mouse model of Fragile X Syndrome (FXS), a leading genetic cause of intellectual disability and ASD-associated behaviors. Using epidural electrodes in awake and freely moving wildtype (WT) and KO mice, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (gap-ASSR) paradigm. Mice were recorded at three different ages in a cross sectional design: postnatal (p)21, p30 and p60. Recordings were obtained from both auditory and frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses to gaps of different widths embedded in noise, providing an objective measure of temporal processing across genotypes and age groups. Results We present evidence that the frontal, but not auditory, cortex shows significant temporal processing deficits at p21 and p30, with poor ability to phase lock to rapid gaps in noise. Temporal processing was similar in both genotypes in adult mice. ERP amplitudes were larger in Fmr1 KO mice in both auditory and frontal cortex, consistent with ERP data in humans with FXS. Conclusions These data indicate cortical region-specific delays in temporal processing development in Fmr1 KO mice. Developmental delays in the ability of frontal cortex to follow rapid changes in sounds may shape language delays in FXS, and more broadly in ASD.

We have recently reported that the central nucleus of the inferior colliculus (the auditory midbrain) is innervated by glutamatergic pyramidal cells originating not only in auditory cortex (AC) but also in multiple ‘non-auditory’ regions of the cerebral cortex. Using optogenetics and electrical stimulation, we investigated the functional properties of these descending connections in vivo in anaesthetised rats. A retrograde virus encoding green fluorescent protein (GFP) and channelrhodopsin (ChR2) injected into the central nucleus of the inferior colliculus (ICC), labelled discrete groups of cells in multiple areas of the cerebral cortex. Light stimulation of AC and M1 caused local activation of cortical neurones and increased the firing rate of neurones in ICc indicating a direct excitatory input from AC and M1 to ICC. Electrical stimulation of M1, secondary motor, somatosensory and prefrontal cortical regions evoked short, fixed latency firing events in ICC as well as longer latency, longer duration increases in firing activity. The short latency events were singular spikes of consistent shape and size likely resulting from monosynaptic excitation of individual ICC units. The longer latency responses comprised multiple units and spikes occurred with significant temporal jitter suggesting polysynaptic activation of local circuits within the ICC. The probability of the monosynaptic event, the magnitude of the polysynaptic response, and the area of ICC affected were dependent on the stimulus current. Our data are consistent with cortical regions exerting an important excitatory direct and indirect regulation of ICc neurones. Significance statement We have recently described inputs from motor, somatosensory, and executive cortices to the inferior colliculus (IC, auditory midbrain). Here we provide functional evidence for such connections. Optogenetics, using a retrograde virus encoding channelrhodopsin injected into IC revealed a direct excitatory influence of neurones in auditory and motor cortices on firing in IC. Electrical stimulation of discrete cortical regions revealed that multiple non-auditory cortical regions have a direct monosynaptic excitatory influence on neurones in the IC which, in turn, activates local circuits increasing the firing probability of multiple neurones in the IC. This is the first evidence for circuitry by which auditory processing can be influenced at an early stage by activity in the sensory, motor and executive domains.

Objectives: Speech perception training can be a highly effective intervention to improve perception and language abilities in children who are deaf or hard of hearing. Most studies of speech perception training, however, only measure gains immediately following training. Only a minority of cases include a follow-up assessment after a period without training. A critical unanswered question was whether training-related benefits are retained for a period of time after training has stopped. A primary goal of this investigation was to determine whether children retained training-related benefits 4 to 6 weeks after they completed 16 hours of formal speech perception training. Training was comprised of either auditory or speechreading training, or a combination of both. Also important is to determine if “booster” training can help increase gains made during the initial intensive training period. Another goal of the study was to investigate the benefits of providing home-based booster training during the 4- to 6-week interval after the formal training ceased. The original investigation (Tye-Murray et al. 2022) compared the effects of talker familiarity and the relative benefits of the different types of training. We predicted that the children who received no additional training would retain the gains after the completing the formal training. We also predicted that those children who completed the booster training would realize additional gains. Design: Children, 6 to 12 years old, with hearing loss who had previously participated in the original randomized control study returned 4 to 6 weeks after the conclusion to take a follow-up speech perception assessment. The first group (n = 44) returned after receiving no formal intervention from the research team before the follow-up assessment. A second group of 40 children completed an additional 16 hours of speech perception training at home during a 4- to 6-week interval before the follow-up speech perception assessment. The home-based speech perception training was a continuation of the same training that was received in the laboratory formatted to work on a PC tablet with a portable speaker. The follow-up speech perception assessment included measures of listening and speechreading, with test items spoken by both familiar (trained) and unfamiliar (untrained) talkers. Results: In the group that did not receive the booster training, follow-up testing showed retention for all gains that were obtained immediately following the laboratory-based training. The group that received booster training during the same interval also maintained the benefits from the formal training, with some indication of minor improvement. Conclusions: Clinically, the present findings are extremely encouraging; the group that did not receive home-based booster training retained the benefits obtained during the laboratory-based training regimen. Moreover, the results suggest that self-paced booster training maintained the relative training gains associated with talker familiarity and training type seen immediately following laboratory-based training. Future aural rehabilitation programs should include maintenance training at home to supplement the speech perception training conducted under more formal conditions at school or in the clinic.

Sensorineural hearing loss is associated with dysfunction of cochlear cells. Although immune cells play a critical role in maintaining the inner ear microenvironment, the precise immune-related molecular mechanisms underlying the pathophysiology of hearing loss remain unclear. The complement cascade contributes to the regulation of immune cell activity. Additionally, activation of the complement cascade can lead to the cellular opsonization of cells and pathogens, resulting in their engulfment and elimination by phagocytes. Complement factor B (fB) is an essential activator protein in the alternative complement pathway, and variations in the fB gene are associated with age-related macular degeneration. Here we show that mice of both sexes deficient in fB functional alleles (fB −/− ) demonstrate progressive hearing impairment. Transcriptomic analysis of auditory nerves from adult mice detected 706 genes that were significantly differentially expressed between fB −/− and wild-type control animals, including genes related to the extracellular matrix and neural development processes. Additionally, a subset of differentially expressed genes was related to myelin function and neural crest development. Histological and immunohistochemical investigations revealed pathological alterations in auditory nerve myelin sheathes of fB −/− mice. Pathological alterations were also seen in the stria vascularis of the cochlear lateral wall in these mice. Our results implicate fB as an integral regulator of myelin maintenance and stria vascularis integrity, underscoring the importance of understanding the involvement of immune signaling pathways in sensorineural hearing loss.

To understand how the brain produces behavior, we must elucidate the relationships between neuronal connectivity and function. The medial prefrontal cortex (mPFC) is critical for complex functions including decision-making and mood. mPFC projection neurons collateralize extensively, but the relationships between mPFC neuronal activity and brain-wide connectivity are poorly understood. We performed whole-brain connectivity mapping and fiber photometry to better understand the mPFC circuits that control threat avoidance in male and female mice. Using tissue clearing and light sheet fluorescence microscopy (LSFM), we mapped the brain-wide axon collaterals of populations of mPFC neurons that project to nucleus accumbens (NAc), ventral tegmental area (VTA), or contralateral mPFC (cmPFC). We present DeepTraCE (deep learning-based tracing with combined enhancement), for quantifying bulk-labeled axonal projections in images of cleared tissue, and DeepCOUNT (deep-learning based counting of objects via 3D U-net pixel tagging), for quantifying cell bodies. Anatomical maps produced with DeepTraCE aligned with known axonal projection patterns and revealed class-specific topographic projections within regions. Using TRAP2 mice and DeepCOUNT, we analyzed whole-brain functional connectivity underlying threat avoidance. PL was the most highly connected node with functional connections to subsets of PL-cPL, PL-NAc, and PL-VTA target sites. Using fiber photometry, we found that during threat avoidance, cmPFC and NAc-projectors encoded conditioned stimuli, but only when action was required to avoid threats. mPFC-VTA neurons encoded learned but not innate avoidance behaviors. Together our results present new and optimized approaches for quantitative whole-brain analysis and indicate that anatomically defined classes of mPFC neurons have specialized roles in threat avoidance. SIGNIFICANCE STATEMENT Understanding how the brain produces complex behaviors requires detailed knowledge of the relationships between neuronal connectivity and function. The medial prefrontal cortex (mPFC) plays a key role in learning, mood, and decision-making, including evaluating and responding to threats. mPFC dysfunction is strongly linked to fear, anxiety and mood disorders. Although mPFC circuits are clear therapeutic targets, gaps in our understanding of how they produce cognitive and emotional behaviors prevent us from designing effective interventions. To address this, we developed a high-throughput analysis pipeline for quantifying bulk-labeled fluorescent axons [DeepTraCE (deep learning-based tracing with combined enhancement)] or cell bodies [DeepCOUNT (deep-learning based counting of objects via 3D U-net pixel tagging)] in intact cleared brains. Using DeepTraCE, DeepCOUNT, and fiber photometry, we performed detailed anatomic and functional mapping of mPFC neuronal classes, identifying specialized roles in threat avoidance.

Hyperacusis, i.e., an increased sensitivity to sounds, is described in several neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS). The mechanisms underlying hyperacusis in FXS are still largely unknown and effective therapies are lacking. Big conductance calcium-activated potassium (BKCa) channels were proposed as a therapeutic target to treat several behavioral disturbances in FXS preclinical models, but their role in mediating their auditory alterations was not specifically addressed. Furthermore, studies on the acoustic phenotypes of FXS animal models mostly focused on central rather than peripheral auditory pathways. Here, we provided an extensive characterization of the peripheral auditory phenotype of the Fmr1-knockout (KO) mouse model of FXS at adulthood. We also assessed whether the acute administration of Chlorzoxazone, a BKCa agonist, could rescue the auditory abnormalities of adult mutant mice. Fmr1-KO mice both at 3 and 6 months showed a hyperacusis-like startle phenotype with paradoxically reduced auditory brainstem responses associated with a loss of ribbon synapses in the inner hair cells (IHCs) compared to their wild-type (WT) littermates. BKCa expression was markedly reduced in the IHCs of KOs compared to WT mice, but only at 6 months, when Chlorzoxazone rescued mutant auditory dysfunction. Our findings highlight the age-dependent and progressive contribution of peripheral mechanisms and BKCa channels to adult hyperacusis in FXS, suggesting a novel therapeutic target to treat auditory dysfunction in NDDs.

Cochlear inner hair cells (IHCs) form specialized ribbon synapses with spiral ganglion neurons that tirelessly transmit sound information at high rates over long time periods with extreme temporal precision. This functional specialization is essential for sound encoding and is attributed to a distinct molecular machinery with unique players or splice variants compared to conventional neuronal synapses. Among these is the active zone (AZ) scaffold protein piccolo/aczonin, which is represented by its short splice variant piccolino at cochlear and retinal ribbon synapses. While the function of piccolo at synapses of the central nervous system has been intensively investigated, the role of piccolino at IHC synapses remains unclear. In this study, we characterize the structure and function of IHC synapses in piccolo gene-trap mutant rats (Pclogt/gt ). We find a mild hearing deficit with elevated thresholds and reduced amplitudes of auditory brainstem responses. Ca2+ channel distribution and ribbon morphology are altered in apical IHCs, while their presynaptic function seems to be unchanged. We conclude that piccolino contributes to the AZ organization in IHCs and is essential for normal hearing.

Cortical representations supporting many cognitive abilities emerge from underlying circuits comprised of several different cell types. However, cell type-specific contributions to rate and timing-based cortical coding are not well-understood. Here, we investigated the role of parvalbumin neurons in cortical complex scene analysis. Many complex scenes contain sensory stimuli which are highly dynamic in time and compete with stimuli at other spatial locations. Parvalbumin neurons play a fundamental role in balancing excitation and inhibition in cortex and sculpting cortical temporal dynamics; yet their specific role in encoding complex scenes via timing-based coding, and the robustness of temporal representations to spatial competition, has not been investigated. Here, we address these questions in auditory cortex of mice using a cocktail party-like paradigm, integrating electrophysiology, optogenetic manipulations, and a family of spike-distance metrics, to dissect parvalbumin neurons’ contributions towards rate and timing-based coding. We find that suppressing parvalbumin neurons degrades cortical discrimination of dynamic sounds in a cocktail party-like setting via changes in rapid temporal modulations in rate and spike timing, and over a wide range of time-scales. Our findings suggest that parvalbumin neurons play a critical role in enhancing cortical temporal coding and reducing cortical noise, thereby improving representations of dynamic stimuli in complex scenes.

Coordinated functioning of the two cortical hemispheres is crucial for perception. The human auditory cortex (ACx) shows functional lateralization with the left hemisphere specialized for processing speech, whereas the right analyzes spectral content. In mice, virgin females demonstrate a left-hemisphere response bias to pup vocalizations that strengthens with motherhood. However, how this lateralized function is established is unclear. We developed a widefield imaging microscope to simultaneously image both hemispheres of mice to bilaterally monitor functional responses. We found that global ACx topography is symmetrical and stereotyped. In both male and virgin female mice, the secondary auditory cortex (A2) in the left hemisphere shows larger responses than right to high-frequency tones and adult vocalizations; however, only virgin female mice show a left-hemisphere bias in A2 in response to adult pain calls. These results indicate hemispheric bias with both sex-independent and -dependent aspects. Analyzing cross-hemispheric functional correlations showed that asymmetries exist in the strength of correlations between DM-AAF and A2-AAF, while other ACx areas showed smaller differences. We found that A2 showed lower cross-hemisphere correlation than other cortical areas, consistent with the lateralized functional activation of A2. Cross-hemispheric activity correlations are lower in deaf, otoferlin knockout (OTOF −/− ) mice, indicating that the development of functional cross-hemispheric connections is experience dependent. Together, our results reveal that ACx is topographically symmetric at the macroscopic scale but that higher-order A2 shows sex-dependent and independent lateralized responses due to asymmetric intercortical functional connections. Moreover, our results suggest that sensory experience is required to establish functional cross-hemispheric connectivity.