Publications using TDT

To survive, animals must rapidly learn to avoid predictable threats. Such learning depends on detecting reliable cue-outcome relationships that efficiently drive behavioral adaptations. The medial prefrontal cortex (mPFC) integrates learned information about the environment to guide adaptive behaviors1,2,3,4,5,6,7 and is critical for threat avoidance.8,9,10,11,12,13,14 However, most studies focused on well-learned threat avoidance strategies, and the specific inputs that signal avoidability and drive rapid avoidance learning remain poorly understood. Dopamine (DA) inputs from the ventral tegmental area (VTA) potently modulate prefrontal function and are preferentially engaged by aversive stimuli.15,16,17,18,19,20,21 Pharmacological blockade, DA depletion, and microdialysis experiments implicated DA in threat avoidance22,23,24,25 but lacked the spatiotemporal resolution required to define the timing of mPFC DA signals during avoidance learning. We used high-resolution tools to dissect the role of the VTA-mPFC DA circuit in rapid avoidance learning. Optogenetic suppression of VTA DA terminals in mPFC selectively slowed learning of a cued avoidance response without affecting cue-shock association learning, reactive escape behaviors, or expression of previously learned avoidance. Using a fluorescent DA sensor, we observed rapid, event-locked DA activity that emerged transiently during learning initiation. Increased DA encoded aversive outcomes and their predictive cues, while decreased DA encoded their omission and predicted how quickly mice learned to avoid. In yoked mice lacking control over shock omission, these dynamics were largely absent. Together, these findings demonstrate that the VTA-mPFC DA circuit is necessary for rapid acquisition of proactive avoidance behaviors and reveal transient event-related DA signals underlying this form of learning.

Age-related hearing loss (ARHL) is a major public health concern, driven by the interplay of multiple factors. Here, we reveal spatiotemporal metabolic shifts in murine inner ears mirroring erythrocytes and plasma. Isotope-labeled glucose tracing demonstrates a metabolic rerouting favoring glycolysis over the pentose phosphate pathway, alongside downregulation of the tricarboxylic acid cycle, indicating impaired energy production and redox homeostasis. Accumulation of medium- and long-chain acylcarnitines further exacerbates lipotoxicity. Notably, age-dependent depletion of arginine, lysine, proline, and glycine disrupts the arginine-polyamine-urea cycle. Translationally, UK Biobank plasma metabolomics links omega-6 fatty acids, linoleic acid, glycine, and albumin to ARHL resilience, while branched-chain amino acids, tyrosine, creatinine, glycoprotein acetyls and urea confer risk. Sex differences in ARHL were linked to fatty acid metabolism divergence. These bioenergetic disruptions in the inner ear are mirrored in erythrocytes and plasma, highlighting potential biomarkers for early ARHL diagnosis and treatment.

Nicotine is one of the most widely used addictive substances, yet its primary reinforcing effects are relatively weak. Nicotine's ability to potentiate responding for conditioned reinforcers is thought to drive persistent drug use. Here, we show that nicotine failed to alter responding maintained by a primary sucrose reinforcer (under a variable-ratio [VR] 11 schedule) across a broad dose range (0.01-1.0 mg/kg). Yet, nicotine enhanced operant behavior under a second-order reinforcement schedule in which responses produced sucrose-associated cues and were only intermittently reinforced by sucrose itself. Together, we demonstrate that nicotine selectively augments behavior maintained by conditioned reinforcers (sucrose-associated cues) in a rate-dependent manner, increasing responding only in mice with low rates of reinforcement behavior at baseline. Using fiber photometry, we demonstrate that nicotine selectively amplified cue-evoked dopamine release in the dorsolateral striatum-but only in low baseline responders-while having no effect on dopamine signaling in the nucleus accumbens. These effects were blocked by the nicotinic receptor antagonist mecamylamine. Further, nicotine's influence on behavior was abolished when the contingency between action and conditioned stimuli was disrupted, indicating that nicotine strengthens cue control of behavior rather than increasing motivation generally. Collectively, these findings reveal that nicotine's behavioral actions emerge through an interaction between pharmacological mechanisms, behavioral contingencies, and individual differences in baseline behavioral control. SIGNIFICANCE STATEMENT: Nicotine strengthens the impact of environmental cues on behavior by amplifying dopamine signals in specific projection targets, but only in individuals with specific behavioral traits. This reveals how nicotine hijacks learning processes to promote persistent, cue-driven actions.

Alcohol seeking during abstinence is mediated in part by strong associations between the pharmacological effects of alcohol and the environment within which alcohol is administered. The amygdala, particularly the basolateral amygdala (BLA), is a key neural substrate of environmental cue and reward associations since it is involved in associative learning and memory recall. However, we still lack a clear understanding of how alcohol affects the activity of BLA neurons, which may encode information that drives environmental cue-dependent, alcohol-related behaviors. We previously demonstrated that a subset of BLA neurons which express the calcium/calmodulin-dependent protein kinase II (CaMKII) and thymus cell antigen 1 (Thy1) markers project preferentially to the nucleus accumbens (NAcc), rather than the central amygdala; and these neurons mediate fear inhibition rather than fear acquisition or expression, suggesting a specific role in positive valence processing. We now demonstrate that Pavlovian conditioning with alcohol administration increases the activity of these Thy1-expressing (Thy1+) excitatory neurons in mouse BLA, which is necessary for the conditioned appetitive response. In vivo calcium imaging indicates that the temporal activity profile of these neurons is also correlated with alcohol-induced motivated behavior in response to environmental cues. Optogenetic inhibition of BLA Thy1+ neuronal activity at cell body disrupts both the formation and expression of alcohol-induced conditioned place preference. Furthermore, selective axonal inhibition of BLA-Thy1+ efferents reveals that the activity of their NAcc and prefrontal cortex (PFC) projections are differentially necessary for alcohol cue association vs. recall, respectively. Together, these findings provide insights into a molecularly distinct subset of BLA neurons that regulates environmental cue-reward associations and drives alcohol-induced motivated behaviors in a projection-specific manner.

The ability to recognize speakers by their voice despite acoustical variation plays a substantial role in primate social interactions. Although neurons in the macaque anterior temporal lobe (ATL) show invariance to face viewpoint, whether they also encode abstract representations of caller identity is not known. Here, we demonstrate that neurons in the voice-selective ATL of two macaques support invariant voice identity representations through dynamic population-level coding. These representations minimize neural distances across different vocalizations from the same individual while preserving distinct trajectories for different callers. This structure emerged from the coordinated activity of the broader neuronal ensemble, although a small subset of highly identity-selective neurons carried high identity information. Our findings provide a neural basis for voice identity recognition in primates and highlight the ATL as a key hub for integrating perceptual voice features into higher-level identity representations.

Chemical feedback is ubiquitous in physiology but is challenging to study without perturbing basal functions. One example is addictive drugs, which elicit a positive-feedback cycle of drug-seeking and ingestion by acting on the brain to increase dopamine signalling 1–3 . However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness 4 . Here, inspired by physiological control systems, we developed a highly selective synthetic physiology approach to interfere with the positive-feedback cycle of addiction by installing a cocaine-dependent opposing signalling process into this body–brain signalling loop. We used protein engineering to create cocaine-gated ion channels that are selective for cocaine over other drugs and endogenous molecules. Expression of an excitatory cocaine-gated channel in the rat lateral habenula, a brain region that is normally inhibited by cocaine, suppressed cocaine self-administration without affecting food motivation. This artificial cocaine-activated chemogenetic process reduced the cocaine-induced extracellular dopamine rise in the nucleus accumbens. Our results show that cocaine chemogenetics is a selective approach for countering drug reinforcement by clamping dopamine release in the presence of cocaine. In the future, chemogenetic receptors could be developed for additional addictive drugs or hormones and metabolites, which would facilitate efforts to probe their neural circuit mechanisms using a synthetic physiology approach. As these chemogenetic ion channels are specific for cocaine over natural rewards, they may also offer a route towards gene therapies for cocaine addiction.

Sound harmonicity is foundational in complex auditory stimuli like music and vocalizations but it remains unclear how such spectrally complex stimuli are processed in the auditory cortex (ACtx). Subregions of the auditory cortex process are thought to process harmonic stimuli differently, and secondary ACtx (A2) layer (L) 2/3 is believed to be the most selective. Selective responses to sound features in ACtx are thought to emerge hierarchically starting from A1 L4. Since the spectral complexity of harmonic stacks can range from two to more than ten components, harmonic selectivity and sensitivity might also arise hierarchically across layers and areas. We studied responses to simple and complex harmonic stacks across A1 L4, A1 L2/3, and A2 L2/3 in adult mice using in vivo two-photon microscopy. We found harmonic-sensitive neurons (HN) responding only to harmonic stacks but not to their pure-tone components in all areas at similar proportions. HNs showed non-linear processing of component tones with onset-responsive HNs showing greater nonlinearity, which decreased with harmonic complexity. Co-tuned HNs in A1 L4 exhibited the highest signal correlation, regardless of harmonic complexity. A1 L4 HNs also showed the lowest noise correlation with other neurons. Moreover, A1 L4 HNs achieve robust spectral integration and harmonic sensitivity by receiving diverse inputs and maintaining high signal correlation, ensuring independent, strong responses to harmonic stimuli. Therefore, harmonic sensitivity is present in A1 L4 and is not a unique feature of A2. Thus, tuning to complex spectral sounds is a fundamental property of ACtx and is already established in A1 L4. Significance statement Harmonics are essential in auditory perception, influencing how we process complex sounds like music and speech. This study reveals that neurons in the primary auditory cortex (A1) and secondary auditory cortex (A2) integrate simple and complex harmonic structures with distinct mechanisms of neuronal recruitment. A1 L4 harmonic-sensitive neurons (HNs) demonstrated strong, independent responses through high signal correlation and minimal noise correlation, suggesting a robust mechanism for spectral integration. Our results show that harmonic relationships are already extracted at the input layers of A1, and that HNs show non-linear facilitative integration. Thus, tuning to sounds of complex spectral contents might be a fundamental processing function of the auditory cortex and is already established in A1 L4, which receives major thalamic inputs.

Behavioral outcomes are rarely certain, requiring subjects to discriminate between available choices by using feedback to guide future decisions. Probabilistic reversal learning (PRL) tasks test subjects’ ability to learn and flexibly adapt to changes in reward contingencies. Cortico-striatal circuitry has been broadly implicated in flexible decision-making—though what role these circuits play remains complicated. In this study we leveraged the fast temporal dynamics of local field potentials to precisely identify the role that cortico-striatal networks play during PRL reward feedback. We measured widespread (32-CH) local field potential activity of male Long–Evans rats during a PRL task wherein a target response delivered reward on 80% of trials while a non-target response delivered reward on 20% of trials. When subjects learned those reward probabilities, contingencies were reversed. We found that reward-evoked oscillations at beta (15–30 Hz) and high gamma (>70 Hz) frequencies marked positive reward valence and reflected probability of reward. Activity and connectivity at beta frequencies between orbitofrontal cortex, anterior insula, medial prefrontal cortex, and ventral striatum during expected rewards were correlated with behavioral performance and specific aspects of value/exploitative behavior as defined by a reinforcement learning computational model. Finally, we found that modulating beta activity in orbitofrontal cortex with optogenetic (20 Hz) stimulation promoted maladaptive behavior when stimulation was provided during non-target responses, consistent with our data and computational model predictions. Reward-evoked beta oscillations may reflect a crucial component underlying reward learning, and erroneous elevations in this physiological signal may contribute to maladaptive task performance and behavioral disruptions.

Adeno-associated virus-based gene therapy offers a promising treatment paradigm for inner ear diseases; however, the genetic heterogeneity of hereditary deafness requires gene-specific strategies and optimization of current approaches to identify the range of treatable conditions and improve therapeutic outcomes. To consider the therapeutic potential for a hearing loss gene not previously explored, we investigated the gene encoding the chloride intracellular channel protein CLIC5, mutations in which lead to DFNB103 in humans and deafness and circling behavior in a Clic5 -deficient mouse model. In this study, we utilized two constructs to deliver the wild-type Clic5 coding sequence into Clic5 -deficient mice: single-stranded and self-complementary adeno-associated virus, the latter known for rapid onset of transgene expression. We report a robust restoration of CLIC5 expression using either construct, including prevention of morphological degeneration and preserving auditory and vestibular function. Interestingly, the self-complementary construct achieved comparable functional recovery to single-stranded construct but at a lower titer. These findings highlight the potential of self-complementary adeno-associated virus to reduce dose requirements, minimize toxicity and broaden clinical utility for inner ear therapies.

Olfactory perception of food odors is a key determinant of eating behavior, including triggering appetite, facilitating food seeking and influencing food choice. While transient food-related olfactory cues stimulate appetite and provoke cravings in states of hunger, emerging evidence implies that prolonged and sustained exposure to food-derived odor (FO) suppresses feeding. However, the mechanisms by which olfaction induces hypophagia remain elusive. In this study, we show that prolonged FO exposure significantly suppresses food intake in male mice. We identified a subset of neurons in the ventral subiculum (vSub) that are specifically activated by FO. We further discovered that these FO-activated neurons in the vSub receive excitatory inputs from the olfactory bulb (OB) and send glutamatergic projections to the ventromedial hypothalamus (VMH). Inhibition of the OB → vSub → VMH circuit abolished the FO-induced reduction in food intake, while activation of this circuit suppressed feeding and reduced body weight. Together, these findings reveal a neurobiological circuitry that mediates the influence of olfactory signals on food intake regulation.

Niemann-Pick disease type C (NPC) is a life-threatening neurodegenerative disease caused by impaired intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for treating NPC, but its ototoxicity remains problematic. We previously reported that β- and γ-forms of cyclodextrin (CD) derivatives with various substituents capable of accommodating/solubilizing unesterified cholesterol (UC) exerted more pronounced therapeutic and ototoxic effects when administered intracerebroventricularly than subcutaneously for NPC treatment. However, the impact of substituent variations on these effects is unconfirmed for cyclic hexasaccharides, α-CD derivatives. Here, we investigated these effects for α-CD derivatives with various replaced substituents from the perspective of their interaction with UC. Even when administered intracerebroventricularly, a representative α-CD derivative had no impact on survival in NPC model mice. The normalization of intracellular cholesterol trafficking in NPC model cells and the auditory dysfunction in wild-type mice, both caused by HP-β-CD, were not seen for the α-CD derivatives, regardless of their substituent variations. Solubility and molecular simulation analyses showed negligible UC-solubilizing ability of α-CD derivatives because of their insufficient capacity to accommodate the UC molecule, rather than their substituent variations. These results underscore the importance of UC accommodation by CD for both efficacy and ototoxicity in NPC treatment.

There is ample evidence from cognitive sciences and neurosciences studies that multisensory stimuli are detected better and faster than their unisensory counterparts. Yet, most of this work has been conducted in settings and with protocols within which participants had the sole detection task to perform. In realistic and complex environments, such as military ones, detection of critical information has to be performed while the operator is concurrently managing several others tasks and processing a vast amount of sensory inputs. To date, it remains to determine whether multisensory benefits for detection hold true in complex multitasking situations. In the present study, we compared the detection performance of healthy participants when the target was only auditory, only tactile, or both auditory and tactile. Detection performance was measured in a simple detection task condition and in a multitasking condition. In the latter, participants had to detect the targets while concurrently performing the subtasks of the MATB-II environment, designed in the 90s by NASA to simulate piloting tasks. Multisensory acceleration of reaction times was larger during multitasking compared to single-task conditions. Crucially, participants detected auditory–tactile targets faster than their unisensory counterparts. While previous studies have reported such facilitation effects in single-task contexts, our results show that multisensory facilitation of detection speed does occur in a realistic multitasking environment and is larger than in simple task conditions. Auditory-tactile displays seem to have the potential to enhance information presentation and could be used in applied settings like military aviation.

Background: Age related hearing loss (ARHL) is a sensorineural hearing disease caused by multiple factors and its pathogenesis is still unclear. This work aims to investigate the precise role of AIMP1 in ARHL. Methods: HEI-OC1 cells were treated with 1 mM H2O2 for 2 h to induce cell damage. CCK-8, flow cytometry and TUNEL staining examined cell viability and apoptosis. DCFH-DA fluorescence probe assessed ROS. The levels of MDA, SOD and copper were detected by kits. The expression of proteins related to mitophagy, cuproptosis were examined by western blotting and immunofluorescence. Finally, D-galactose was administered to mice to establish an ARHL model for verifying the functional role of AIMP1 in ARHL. Results: AIMP1 and SIRT1 were down-regulated in H2O2-treated HEI-OC1 cells. AIMP1 overexpression promoted cell viability, reduced ROS and MDA levels, and increased SOD levels in H2O2-treated HEI-OC1 cells. Moreover, the levels of copper and apoptosis were decreased in H2O2-treated HEI-OC1 cells in the presence of AIMP1 overexpression. AIMP1 overexpression caused a down-regulation of cuproptosis-related proteins FDX1, DLAT, DLST, and an up-regulation of mitophagy-related proteins PINK1, Parkin, Mfn2 and Drp1 in H2O2-treated HEI-OC1 cells. Knockdown PINK1 or SIRT1 reversed the influence of AIMP1 overexpression on H2O2 induced HEI-OC1 cell damage. In vivo, AIMP1 overexpression reduced damage of cochlear tissues and partially restored hearing in ARHL mice. Conclusion: AIMP1 up-regulated SIRT1 to promote PINK1/Parkin-mediated mitophagy and inhibit cuproptosis of cochlear hair cells in ARHL mice. Thus, AIMP1 may be a potential target for ARHL treatment.

Background: Hearing loss is known to cause structural and functional abnormalities in the central auditory pathways. Interventions with hearing aids that amplify acoustic signals have been developed to combat hearing loss. However, little is known about how such devices may affect the brain and mitigate the progression of hearing loss. We hypothesized that timely intervention that amplifies acoustic signals would delay further progression of hearing loss by maintaining central auditory activity and neural structure. Method: To that end, we provided eight weeks of acoustic stimulation tailored to compensate for subject-specific patterns of frequency loss in two mouse models of progressive hearing loss. We evaluated the effects of sound amplification on endbulb of Held anatomy at different ages of intervention in mice with early-onset (DBA/2) and late-onset (C57Bl/6) hearing loss. Results: We observed in both strains that endbulbs undergo rapid and progressive atrophy in untreated control subjects exposed to a baseline, unamplified, sound environment. In contrast, endbulb atrophy was significantly slowed in treated mice (p < 0.05). Conclusions: These data provide a possible explanation for how the brain benefits from sound amplification via hearing aid devices.

The startle response (SR) is a generalized defensive response elicited by the presentation of a sudden intense stimulus. The presentation of a less intense signal (prepulse) before the central stimulus (pulse) affects the amplitude and latency of SR differently depending on the prepulse lead interval. The most studied form of such changes is prepulse inhibition (PPI), i.e. a decrease in SR amplitude at lead intervals of 50-500 ms. Prepulse facilitation, i.e. an increase in SR amplitude, can also be observed at lead intervals of 2000-4500 ms. The PPI deficiency has been found in a variety of psychopathologies and it has been suggested that it is a transdiagnostic phenomenon. However, some data from the literature support the existence of specific different nosologies, such as neurophysiological, neurochemical and molecular mechanisms that cause PPI lowering and affect prepulse facilitation of SR. This review provides a comparative analysis of studies on SR prepulse modification in healthy subjects and different groups of patients with mental or neurological disorders. The results of such an analysis may help to define directions for further research to improve methods of early diagnosis and to improve the validity of translational models.

Autism is a common neurodevelopmental disorder that despite its complex etiology, is marked by deficits in prediction that manifest in a variety of domains including social interactions, communication, and movement. The tendency of individuals with autism to focus on predictable schedules and interests that contain patterns and rules highlights the likely involvement of the cerebellum in this disorder. One candidate-autism gene is contactin-associated protein 2 ( CNTNAP2 ), and variants in this gene are associated with sensory deficits and anatomical differences. It is unknown, however, whether this gene directly impacts the brain’s ability to make and evaluate predictions about future events. The current study was designed to answer this question by training a genetic knockout rat on a rapid speech sound discrimination task. Rats with Cntnap2 knockout (KO) and their littermate wildtype controls (WT) were trained on a validated rapid speech sound discrimination task that contained unpredictable and predictable targets. We found that although both genotype groups learned the task in both unpredictable and predictable conditions, the KO rats responded more often to distractors during training as well as to the target sound during the predictable testing conditions compared to the WT group. There were only minor effects of sex on performance and only in the unpredictable condition. The current results provide preliminary evidence that removal of this candidate-autism gene may interfere with the learning of unpredictable scenarios and enhance reliance on predictability. Future research is needed to probe the neural anatomy and function that drives this effect.

Maternal defense, a hallmark of motherhood, often involves protecting offspring at personal risk. However, the neural mechanisms underlying the emergence and modulation of this behavior remain not-well understood. Here, we introduce a novel paradigm in which mother mice under threat prioritize offspring protection over self-preservation by approaching, collecting, and retreating pups to safety, a risk-associated behavior that also develops in virgin females following maternal experience. Microendoscopic calcium imaging reveals sequential activation of distinct corticofugal neuronal populations in the medial prefrontal cortex (mPFC) during maternal defense. Specifically, layer (L)6 dopamine receptor D1-expressing (D1) neurons are active during pup approach, while L5 neurons are engaged during pup collection and retreat. Activation of the L6 neurons bidirectionally modulates maternal defense via projections to the medial preoptic area. These findings suggest that mPFC L6 D1 neurons may facilitate the transition to maternal behavior by influencing behavioral selection and initiating maternal defense response under threat.

Sensorineural hearing loss (SNHL) is characterized by cochlear inflammation, macrophage activation, and degeneration of hair cells, synapses, and neurons. Macrophage-mediated inflammation in the damaged cochlea is regulated via CX3CR1-CX3CL1 signaling, where the fractalkine ligand CX3CL1 serves as a chemotactic and calming signal for macrophage activation. Furthermore, disrupted CX3CR1-CX3CL1 signaling in CX3CR1-KO and CX3CL1-KO mice leads to reduced macrophage numbers, exacerbated inflammation, and loss of hair cells, ribbon synapses, and neurons in the damaged cochlea. Notably, ~ 25% of the human population carries single-nucleotide polymorphisms (SNPs) in the CX3CR1 gene, CX3CR1I249/M280, which results in a receptor with lower binding affinity for CX3CL1, while most individuals carry the common wild-type CX3CR1V249/T280 allele. Although these polymorphisms are associated with various CNS neurodegenerative disorders, their impact on SNHL, cochlear degeneration and the macrophage response remains largely unknown. Here, we used a humanized mouse model expressing human CX3CR1 SNPs in lieu of its murine counterpart to investigate the effects of I249/M280 polymorphisms on cochlear function and structure following noise trauma. Young CX3CR1 WT, CX3CR1 KO, and human CX3CR1I249/M280 mice of both sexes were exposed to a noise level of 93 decibel sound pressure for 2 h at an octave band (8-16 kHz). Cochlear function was assessed prior to exposure and at 1 day and 2 weeks postexposure. Also, the densities of inner and outer hair cells, ribbon synapses, and macrophages in Rosenthal's canal were examined after two weeks of exposure and compared among the three genotypes. We found that at 2 weeks postexposure, hearing thresholds were elevated and input‒output function was impaired in hCX3CR1I249/M280 and CX3CR1 KO, whereas mice carrying WT alleles showed functional recovery. A significant synaptic loss (~ 30%) in hCX3CR1I249/M280 and CX3CR1 KO mice was observed relative to that in WT, which exhibited synaptic repair. hCX3CR1I249/M280 resulted in a ~ 17% loss of outer hair cells, which correlated with reduced otoacoustic emissions in the basal cochlear region. Noise led to increased macrophage numbers in the spiral ganglion and lateral wall of the WT; however, this response was attenuated in the CX3CR1 KO and hCX3CR1I249/M280 strains. Additionally, macrophages from CX3CR1 KO and hCX3CR1I249/M280 mice presented altered morphology, increased CD68 expression, and inflammation. Compared with those of mice carrying the CX3CR1 WT or KO allele, young hCX3CR1I249/M280 mice fostered under ambient noise presented early elevations in hearing thresholds at basal frequencies. Together, these findings reveal that human CX3CR1 variant-mediated macrophage dysregulation strongly correlates with worsening of hearing loss and cochlear degeneration after noise trauma. Our work proposes a novel immune-related genetic polymorphism that may aid in the identification of individuals with increased vulnerability to SNHL.

Purpose Present-day cochlear implants (CIs) can deliver usable speech reception in quiet surroundings. Most CI users, however, show impaired sensitivity to temporal fine structure, which hampers their use of pitch contours and spatial cues to segregate competing talkers. In previous short-term animal studies, we used intraneural (IN) electrodes to stimulate pathways originating from various cochlear turns. Neurons in the inferior colliculus synchronized to apical stimulation at higher rates than to stimulation of the middle-to-basal pathways that are stimulated primarily by today’s CIs. Here, we use non-invasive recordings to test the safety and efficacy of up to 6 months of IN implantation and stimulation in cats. Methods Deafened cats (ten female, two male) were implanted with IN and/or conventional CI electrodes. The IN electrodes were single activated-iridium shanks that targeted apical-turn fibers. Scalp recordings were made from sedated animals at 2–3-week intervals. Auditory brainstem responses to single electrical pulses (eABR) tracked sensitivity and growth of responses. Frequency following responses to electrical pulse trains (eFFR) assessed brainstem temporal transmission at varying pulse rates. Results Thresholds for eABR were lower for IN than for CI stimulation, dynamic ranges were wider, and (by inference) spread of activation was more restricted. The eFFR evaluated at latencies comparable to those of inferior-colliculus spikes synchronized at maximum pulse rates averaging > 360 pulses/s for IN compared to ~ 240 pulses/s for CI stimulation. The eABR thresholds and eFFR cutoff rates were stable out to 6 months after implantation. Conclusions The results demonstrate the safety and efficacy of chronic IN stimulation in an animal model. In a future clinical device, an IN electrode could augment cochlear-implant performance by enhancing temporal acuity, thereby improving speech reception amid competing sounds.

Objective Cisplatin is a chemotherapeutic agent with the undesirable side effect of ototoxicity. Transtympanic injections of antioxidant formulations may provide local otoprotection. We tested a novel antioxidant‐eluting microparticle for its otoprotective capability from systemic cisplatin as measured by cochlear electrophysiology. Study Design Basic science. Setting Translational research laboratory. Methods Eighteen mice were assigned to three groups. All mice underwent baseline click‐evoked auditory brainstem response (ABR) audiometry and right ear microparticle injections before beginning 42‐day intraperitoneal administration regimens of either saline (healthy control empty microparticle [HCEMP] group) or cisplatin (cisplatin empty microparticle [CEMP] group and cisplatin N ‐acetylcysteine microparticle [CNAC] group). These regimens consisted of three 4‐day cycles of intraperitoneal saline or cisplatin administration followed by 10 rest days. HCEMP and CEMP received right‐sided transtympanic empty microparticles, and CNAC received transtympanic N ‐acetylcysteine eluting microparticles. On day 43, all mice underwent posttreatment ABR. ABR thresholds and threshold shifts were analyzed with mixed‐effects models and Tukey's post hoc tests and were compared across pretreatment/posttreatment ears, treatment groups, and injected and non‐injected ears. Results We found that threshold shifts in the ears that received a transtympanic injection of N ‐acetylcysteine and three cycles of intraperitoneal cisplatin were similar to the paired ears of mice that received no cisplatin. Mice that received a transtympanic injection without N ‐acetylcysteine and intraperitoneal cisplatin had increased thresholds compared to mice that received a transtympanic injection of N ‐acetylcysteine and cisplatin. Conclusion Transtympanic N ‐acetylcysteine microparticle injections provided functional otoprotection in cisplatin‐exposed mice.