Publications using TDT

Cognitive dysfunction in conditions such as schizophrenia involves disrupted communication between the prefrontal cortex (PFC) and the mediodorsal thalamus (MD). Parvalbumin interneurons (PVIs) are known to regulate PFC microcircuits and generate synchronized gamma-frequency (∼40 Hz) neural oscillations that are recruited during many executive functions, necessary for cognitive flexibility, and deficient in schizophrenia. While targeting PVI-mediated gamma oscillations holds great therapeutic promise, their nature and specific functions, e.g., for regulating PFC→MD communication, remain elusive. Using dual-color voltage indicators and optogenetics in mice, we reveal that PVIs dynamically synchronize with MD-projecting PFC neurons both locally and contralaterally, creating multiple distinct circuit-specific patterns of distributed gamma synchronization that are recruited in a behaviorally specific manner to support particular aspects of flexible behavior. Thus, gamma oscillations are not unitary phenomena characterized by one microcircuit-wide pattern of synchrony. Rather, they comprise diverse motifs, defined by specific cell types and phase relationships, that are dynamically recruited for specific functions.

We describe properties and laminar organization of visual and auditory responses sampled with linear electrode arrays in and around the supplementary eye field of four macaque monkeys performing a visually guided task with a tone secondary reinforcer. Of pyramidal neurons in all layers and interneurons in L3 and L5/6, one-quarter were visually responsive, one-quarter, auditory, with 30% bimodal. Visual neurons were less common rostral, lateral, and medial to the supplementary eye field. Facilitated visual and auditory responses were much more common than suppressed. Pyramidal and interneurons responded to the stimulus in either hemifield with a weak bias for contralateral targets. Visual response latencies were comparable to values previously reported and later than auditory responses. Facilitated visual responses of interneurons preceded those of pyramidal neurons. Transient visual responses preceded sustained. Current-source density revealed visually evoked current sinks after auditory sinks that were transient for bright flashes and prolonged for the discrete task target. The earliest sink appeared at the L3 to L5 border and spread superficially and deeper with idiosyncratic variability across monkeys. These findings reveal new details about sensory processing in medial frontal cortex and complement our previous descriptions of the functional properties and laminar organization of neurons supporting cognitive control.

A central goal in neuroscience is to develop cross-species frameworks that reveal conserved principles of movement control. Recent work has suggested a potential species difference in the role of primary motor cortex (M1) during skilled forelimb tasks: in rodents, extensive practice appears to shift control to subcortical circuits, leading to "disengagement" of M1 from task execution. Importantly, there is no evidence of such disengagement in macaques. We hypothesized that these differences instead reflect task demands, particularly the need for fine (i.e., grasping) versus gross motor control. Strikingly, M1 lesions in macaques produced recovery patterns similar to rodents: gross motor control, including an exclusively gross motor task, recovered rapidly, whereas fine motor control exhibited persistent deficits. Detailed kinematic analyses in both macaques and mice performing a single-pellet reach-to-grasp task (RGT) revealed analogous disruptions in the temporal structure of sub-movements. These findings underscore the importance of task design and the translational value of rodent models for understanding motor control and recovery.

Nervous systems generate predictions using internal copies of motor commands, termed corollary discharge (CD). CD modulates sensory neurons to distinguish self-generated sensory inputs (reafference) from external inputs (exafference). As behavior changes throughout development and evolution, these predictions must update as reafference changes. However, mechanisms that synchronize CD to reafferent input remain unknown. Mormyrid fish communicate using electric organ discharges (EODs). To distinguish reafferent and exafferent EODs, a CD inhibits sensory neurons whenever a reafferent EOD is produced. EOD duration varies across and within species, and a yet-unknown mechanism precisely time-locks inhibition with reafference. Likewise, seasonal increases in testosterone reversibly elongate male EODs in some species, and testosterone shifts CD timing to match changing reafference. To identify the neural substrates of hormonal CD shifts, we treated Brienomyrus brachyistius with testosterone and recorded field potentials from six nuclei linking electromotor, CD, and electrosensory pathways. Testosterone delayed and elongated field potentials in the mesencephalic command-associated nucleus (MCA) of the CD pathway, which shifted downstream activity. We identified substrates of evolutionary and age-related shifts in two species of Campylomormyrus with dramatically different EODs: one with short-duration EODs and one with long EODs that can elongate as individuals age. Both inter- and intraspecies EOD variation was associated with the onset and duration of MCA field potentials. We find distinct processes-hormonal plasticity over days, age-related changes over years, and evolutionary divergence-converge on a common substrate to synchronize CD with reafference. This suggests that sensorimotor systems can evolve a shared solution for temporal coordination across timescales.

Optical coherence tomography has allowed in vivo recording of sound-induced vibrations of different regions within the organ of Corti complex (OCC), including the basilar membrane (BM), outer hair cell/Deiters cell (OHC/DC) region, and reticular lamina (RL). In the hook region of the gerbil cochlea, where measurements can be made with a predominantly transverse optical axis, the three regions have different and characteristic motion responses: The OHC/DC region has greater motions than the other two regions at frequencies below the best frequency (sub-BF); the RL region typically has the greatest BF peak and smallest sub-BF motion. The phase of the OHC/DC-region motion increasingly lags BM motion phase as frequency increases; the RL-region motion phase leads BM, but with a relatively small value. All three regions are compressively nonlinear in the BF peak, but only the OHC/DC region shows sub-BF compressive nonlinearity. Here, we describe the strains that arise when the motion transitions between these regions. Large strains (deformations) were observed in the OHC body close to the RL. A region of large strain can be as short as a single 2.7-μm measurement pixel, or it can extend over several pixels, with extensive strains appearing more often at 70 than at 50 dB sound pressure level. Beyond this RL region of large strain, over a distance that can exceed 20 μm, the OHC/DC region displayed nearly spatially unvarying motion; this region vibrated as a relatively rigid body. And beyond this, at sub-BF frequencies, another region of high strain was present, indicating stretching/compressing or bowing/tilting of the DC microtubular stalk.

Stem cell therapy has been widely studied as a promising treatment for spinal cord injury (SCI). However, a lack of functional scaffolds for stem cell therapy to address SCI leads to low therapeutic efficacy due to poor survival of transplanted cells. To address these challenges, this study aims to enhance regenerative potential of spinal cord organoids (SCOs) by employing extracellular matrix (ECM) recapitulating spinal cord-specific microenvironment. Decellularized spinal cord-derived ECM (ScEM) supports 3D culture for development, maturation, and functionality of human induced pluripotent stem cell-derived SCOs, comparable to standard organoid culture matrix such as Matrigel. Transplantation of SCOs using ScEM hydrogel promotes axonal regeneration with neovascularization in lesions, likely because of enhanced engraftment and integration of transplanted SCOs into defective tissues facilitated by ScEM. Accordingly, this approach induces early locomotor recovery of animals with SCI. These findings suggest that functional ECM scaffold capable of providing microenvironmental complexity of spinal cord can potentiate organoid-based therapeutics for SCI treatment.

Hypothalamic AgRP neurons are uniquely responsive to nutritional cues and play an important role in fuel homeostasis. To investigate the temporal relationship between the activity of these neurons and the glycemic response to an oral glucose load, we simultaneously monitored AgRP neuron activity (by fiber photometry in AgRP-IRES-cre mice) and the arterial glucose level, both before and after oral gavage (OG) of either water or glucose (0.5-2.5 g/kg). We report that the AgRP neuron response to an OG glucose load can be subdivided into two functionally distinct phases - one that begins prior to glucose delivery and a second that extends from peak inhibition through the return towards baseline. The 'first phase' appears to be anticipatory in nature and is also predictive of subsequent changes in glycemia, suggesting a role in the handling of an oral glucose load. To analyze the relationship between the second phase response and changes of glycemia, we employed a model that allows residual activity to be removed subsequent to the 'first phase' component. This analysis reveals that unlike the first phase, the degree of residual inhibition - the second phase - tracks the glycemic response. Moreover, this response is temporally aligned with the blood glucose (BG) rate of change (which is predictive of future BG levels), with AgRP neurons lagging BG rate of change by ∼5 min. We conclude that the AgRP neuron response to an oral glucose challenge consists of two distinct phases, each with its own determinants and metabolic implications: an initial anticipatory component that is predictive of the subsequent glycemic response, and a second phase that tracks the rate of BG change.

Alcohol Use Disorder (AUD) is a significant health concern characterized by cognitive dysfunction and an inability to control alcohol intake, leading to severe social and health consequences. It is crucial to uncover neuroadaptations and cellular mechanisms responsible for poor decisions surrounding alcohol drinking. Although the mediodorsal thalamus (MD) is an essential brain region for cognitive function and reward-guided choices, the effects of alcohol dependence on MD neuroadaptations and how dependence alters MD activity during choice behaviors for alcohol over natural rewards (i.e., sucrose) are not well understood. Genetic and physiological adaptations in the MD were assessed in mice treated with the chronic intermittent ethanol (CIE) exposure model of dependence, which increased alcohol intake and preference during choice sessions for water or sucrose in males and females. Results indicated that CIE exposure induced time-dependent changes in c-Fos and transcript expression and increased excitability of MD neurons during withdrawal. Enrichment analysis of alcohol-sensitive genes revealed dysregulation of genes that control glial function and axonal myelination. Fiber photometry recordings demonstrated that MD activity was elevated at the start of and after licking bouts for alcohol, water, or sucrose, and the signal for alcohol was significantly higher than the signal for other solutions in control and alcohol dependent mice. These findings demonstrate that CIE exposure causes alcohol-biased choice behaviors and genetic and physiological neuroadaptations in the MD, with MD neurons showing a unique response to alcohol over other solutions.

Contextual encoding in the dorsal hippocampus (DHPC) may recruit hypothalamic feeding modules to calibrate eating across environments, but the mechanistic instantiation of cells and circuits that undergird these processes is limited. Single-cell transcriptomics and transsynaptic tracing of the dorsolateral septum (DLS) identified an evolutionarily conserved prodynorphin (Pdyn)-expressing subpopulation of somatostatin (Sst)-expressing inhibitory neurons that receives dense dorsal, but not ventral, hippocampal inputs. Circuit optogenetics, electrophysiology, and in vivo calcium imaging demonstrated that DLS(Pdyn) neurons inhibit GABAergic neurons of the lateral hypothalamic area (LHA), exhibit context-dependent neural responses to food rewards and aversive stimuli, and confer contextual and internal state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS impaired context-dependent food reward consumption, suggesting a role for dynorphin/kappa opioid receptor signaling in these processes. Together, our findings highlight how ancient LHA feeding circuits integrate DHPC input through DLS(Pdyn) inhibitory neurons to link context with regulation of food consumption.

Implantable microelectrode arrays (MEAs) are powerful tools for neurophysiological studies and hold tremendous potential as a key component of clinical neuroprostheses. However, their long-term efficacy is hampered by inflammatory responses to implantation. This study examines the impact of MEA substrate rigidity on neural recording quality and inflammatory tissue responses. We implanted stiff silicon-based and flexible polyimide-based MEAs with similar geometries in the deep brain region of the mouse striatum and performed weekly impedance and electrophysiological measurements over 4 weeks. The flexible MEAs demonstrated more reliable recording quality in terms of stable signal-to-noise ratio, single-unit yield, peak-to-peak amplitude, noise, and impedance, compared to the stiff probes, whose performance deteriorated over time. Endpoint histological analyses were performed to assess the glial scarring (Iba-1, GFAP), blood-brain barrier integrity (IgG), mechanosensitive ion channel expression (Piezo1), and neuronal population (NeuN and NF200) around the implant site. We found reduced microglial activation and IgG fouling within a 50-μm radius around the flexible MEAs compared to the stiff group. Additionally, a higher expression of Piezo1 was observed localized around the stiff MEA, correlating positively with increased Iba-1 and GFAP intensity. Our results show that flexible MEAs have improved device-tissue integration, indicated by lower inflammation levels and better recording stability. This research underscores the critical role of MEA substrate rigidity in influencing adverse tissue reactions, especially for deep brain regions. This understanding will improve our ability to design stable and reliable devices for chronic neural interface devices and beyond.

Objectives. This study aimed to explore the role of the Pcdh15 gene in hearing maintenance and to examine the effects of its deficiency on cochlear structure, cochlear function, and hearing loss in mice.Methods. CRISPR/Cas9 technology was used to generate Pcdh15 knockout (KO) mice. Auditory function was evaluated using hearing tests, while histological approaches were employed to assess morphological changes in cochlear hair cells and spiral ganglion neurons (SGNs). RNA sequencing (RNA-seq) was performed on cochlear tissue from postnatal day 18 (P18) wild-type (WT) and Pcdh15 KO mice to identify differentially expressed genes (DEGs). These DEGs were subjected to functional annotation and pathway analysis, with particular emphasis on oxidative phosphorylation (OXPHOS). Reactive oxygen species (ROS) levels were quantified using flow cytometry and DCFH-DA assays.Results. Pcdh15 KO mice exhibited progressive sensorineural hearing loss, which worsened to profound deafness by P18. Notably, cochlear hair cells and SGNs showed substantial loss and pronounced morphological abnormalities, particularly within the basal high-frequency region. RNA-seq analysis identified 1,359 DEGs, including 1,024 downregulated and 335 upregulated genes. Pathway analysis indicated that Pcdh15 deficiency was associated with inhibition of the OXPHOS pathway, potentially disrupting mitochondrial respiratory chain complexes I, III, IV, and V and thereby impairing energy production and ATP metabolism. In addition, early-stage cochleae from KO mice demonstrated elevated ROS levels and increased oxidative stress, suggesting that redox imbalance may contribute to hearing damage.Conclusion. Pcdh15 plays a critical role in hearing maintenance. Its deficiency is associated with severe hearing loss and marked cochlear abnormalities, which are linked to inhibition of OXPHOS, disruption of energy metabolism, and exacerbation of oxidative stress. Together, these findings provide new insights into the mechanisms underlying hearing loss and suggest potential targets for therapeutic intervention.

Background Stem cell therapy offers promise for the neurodegenerative diseases and has been explored for sensorineural hearing loss (SNHL). However, effective cell delivery strategies remain a critical challenge for SNHL treatment. Methods To address this need, we established an ouabain‐induced SGN injured hearing loss model in rat and evaluated a novel transplantation strategy targeting the cochlear nerve surface via posterior occipital approach, designed to minimize cochlear structural damage and facilitate targeted cell delivery to Rosenthal's canal (RC). The temporal changes in glial cell densities within RC revealed a progressively deteriorating neural microenvironment, supporting early‐stage intervention. Accordingly, hair follicle‐derived neural crest stem cell (HFNCSC) transplantation was performed 3 or 4 days after modeling via two approaches: cochlear nerve surface transplantation (CNT) and round window transplantation (RWT). Results CNT resulted in significant improvements in auditory function, as evidenced by reduced auditory brainstem response (ABR) thresholds, shortened wave I latencies, and preserved wave I amplitudes post‐transplantation. Transplanted cells were distributed along the nerve trunk and within RC. In contrast, RWT failed to improve auditory function and caused cochlear structural damage, with widespread cell dispersion in cochlear fluids. Notably, the CNT group exhibited significantly higher densities of TUJ1‐positive neuron‐like cells and glial cells in the RC, accompanied by enhanced myelin basic protein expression suggestive of remyelination. No such improvements were observed in the RWT group. Conclusions These findings suggest that cochlear nerve surface transplantation enhances stem cell survival and auditory function recovery, and represents a promising delivery approach for stem cell‐based therapy of SGN‐related hearing loss.

Perceptual entrainment and temporal prediction aid speech perception in both quiet and noisy environments. Isochronous, periodic auditory rhythmic cues facilitate neural entrainment and temporal expectations which can benefit encoding and perception of target speech. However, most studies using isochronous cues confound periodicity with predictability. To this end, we characterized how systematic changes in the acoustic dimensions of stimulus rate, target phase, periodicity, and predictably of an entraining sound precursor impact the subsequent identification of concurrent speech targets. Target concurrent vowel pairs were preceded by rhythmic woodblock cues which were either periodic-predictable (PP, isochronous rhythm), aperiodic-predictable (AP, accelerating rhythm), or aperiodic-unpredictable (AU, random rhythm). The number of pulses per rhythm was roved to further manipulate predictability. Stimuli also varied in presentation rate (2.5, 4.5, 6.5 Hz) and target speech phase (in-phase, 0°; out-of-phase, –90°, 180°) relative to the preceding entraining rhythm. We also measured participants’ musical pulse continuation and standardized speech-in-noise perception abilities. We did not observe any effects of stimulus rhythm, rate, or target phase on target speech identification accuracy. However, reaction times were slowest at the nominal speech rate (4.5 Hz) and were most disrupted by out-of-phase presentations following the PP rhythm. Double-vowel task performance was associated with stronger musical pulse continuation abilities, but not speech-in-noise perception. Our results support the notion that perceptual entrainment benefits from rhythmic cues rely on top-down processing and thus are relatively muted when stimulus predictability is unknown. Additionally, we find that individual differences in musical pulse perception may underlie benefits of rhythmic cueing on subsequent speech perception.

Blast-induced hearing loss (BIHL) is a prevalent form of sensory neurotrauma resulting from military and occupational blast exposure. However, effective post-injury interventions remain limited, and progress is hindered by challenges in delivering therapeutics to the injured cochlea. In this study, we developed a reproducible compressed-air blast mouse model with quantified output characteristics and evaluated a localized post-blast TrkB activation strategy using 7,8-dihydroxyflavone (7,8-DHF) delivered to the cochlea via poly(lactide-co-glycolide)-graft-polyethylenimine (PgP) nanoparticles. Device characterization demonstrated a monotonic relationship between regulator-setting pressure (100–250 psi) and acoustic output (72–124 dB). In addition, device modification increased acoustic output while reducing peak pressure relative to the prior configuration, thereby enabling reproducible, pressure-dependent injury. A single unilateral blast exposure produced robust elevations in auditory brainstem response (ABR) thresholds that partially recovered at intermediate regulator settings; however, these thresholds remained elevated over time at higher regulator settings. Since the modified blast paradigm frequently produced tympanic membrane perforation, we leveraged this transient access route to deliver 7,8-DHF-loaded nanoparticles through the ear canal immediately after blast. Compared with vehicle treatment, local 7,8-DHF delivery accelerated functional recovery and yielded significantly improved ABR thresholds, whereas vehicle-treated mice remained persistently impaired at 1 month. Histological analyses revealed preserved inner hair cell density, but significant outer hair cell loss and reduced inner hair cell ribbon synapses in mice exposed to blast. 7,8-DHF-loaded PgP attenuated outer hair cell loss and partially preserved ribbon synapses, with the strongest protection in basal cochlear regions. Together, these findings provide an accessible BIHL platform and support nanoparticle-enabled local TrkB activation as a feasible post-blast strategy that improves both functional and structural endpoints relevant to sensory neurotrauma.

The neural response of the brainstem to brief sounds, known as the auditory brainstem response (ABR), is widely employed in the laboratory and the clinic to diagnose hearing loss. Current ABR approaches are limited to analyzing the average ABR to hundreds of stimulus trials. Historically, trial-by-trial ABR analysis has not been possible owing to each trial's small signal-to-noise ratio. Here we overcome this limitation and show how to score individual ABR trials. We use the distribution of individual-trial ABR scores to define thresholds, which we call auditory brainstem detection (ABD) thresholds, and to assess suprathreshold hearing. Scores based on individual-trial amplitude and similarity produce lower ABD thresholds than scores based on individual-trial amplitude alone. Our method enables us to rank the suprathreshold hearing of individual subjects. Despite having normal ABR thresholds, some subjects appear to have suprathreshold hearing deficits.

Many substances and drugs are administered intranasally. These include opioid overdose reversal drugs, anti-epileptic medications, migraine medications, hormone treatments and medicines to treat/prevent allergies, colds and flus, including nasally administered vaccines, corticosteroids, antihistamines and decongestants. In addition, intranasal (IN) administration is the preferred route of entry by users of illicit drugs. Despite the widespread use of the IN route of administration, there is no established paradigm to access this route of administration preclinically to yield precise and reliable control over delivery. This poses major gaps in therapeutic discovery/testing, establishing pharmacokinetic/pharmacodynamic relationships of therapeutics and understanding the mechanisms of actions of therapeutics. Here we developed an in-dwelling microfluidic device that, when implanted upon the nasal bone in mice, accesses the nasal cavity to allow reliable and precise IN fluid delivery during freely moving behavior. We validated this device, called the nasal access port (NAP), to confirm it allows rapid and precise control of fluids. We further exemplified the application of the NAP for studying outcomes of IN cocaine in mice, including its pharmacokinetic profile, and both the rapid release of dopamine and behavioral effects upon IN cocaine. By achieving precise and reliable access to the IN route of administration, the NAP represents a substantial methodological advance with broad applicability in the biomedical and life sciences, especially in the neuroscience, pharmacology, medicinal chemistry and physiology domains.

The ventral pallidum (VP) is a key basal ganglia structure involved in integrating reward-related signals to guide motivated behavior and feeding. VP neuronal activity is strongly tuned to reward-predictive cues and palatable rewards, tracking changes in value and motivational state. Recent studies have established important and opposing roles for GABAergic and glutamatergic VP neurons in reward- and avoidance-related behaviors. However, much less is known about the role of VP cholinergic neurons (VP-CNs), which comprise only ∼10% of VP neurons in mice, but maintain extensive connectivity with reward-related circuitry. Here, using cell type-selective in vivo fiber photometry during instrumental reward behavior, we found that VP-CN activity responds to cues, actions, and reward retrieval in a training-independent manner. Phasic VP-CN responses to reward retrieval were reduced by reward dilution, whereas pre-feeding with the reward enhanced these responses. In contrast, non-cholinergic VP neurons exhibited modulation by pre-feeding but not by reward dilution. Together, these findings identify VP-CNs as a distinct and dynamically regulated VP population whose activity is sensitive to both reward palatability and physiological state, extending our current understanding of the VP and its roles in reward processing.

Anxiety disorders are highly prevalent and often refractory to existing treatments, motivating the development of alternative neuromodulatory strategies. Peripheral bioelectronic approaches targeting the gut–brain axis such as vagus nerve stimulation (VNS) demonstrate that modulation of visceral afferent pathways can influence central emotional circuits. Gastric electrical stimulation (GES) is a clinically established therapy for gastrointestinal motility disorders. While the stomach is densely innervated by vagal afferents, the effect of GES on anxiety-related behavior has not been systematically examined. We sought to identify neural pathways engaged by GES and effects of continuous chronic GES on behavior. To do this, we developed a gastric stimulation platform for rodents, a fully implantable, untethered system enabling chronic neuromodulation in freely moving rats. We combined this with cross-species whole-brain activity mapping in mice to interrogate circuit-level mechanisms. Using open field and elevated plus mazes, together with machine-learning-based behavioral tracking and multivariate modeling, we show that acute GES induces a robust, context-dependent anxiogenic phenotype characterized by reduced exploration and increased freezing, particularly in novel open-field environments. In contrast, chronic GES produces a divergent post-stimulation behavioral profile marked by enhanced exploratory behavior relative to acutely stimulated animals, indicating temporally dynamic reorganization of anxiety-related behavior. Principal component analysis and hierarchical clustering further revealed that stimulation reshapes the multivariate structure of behavioral features rather than shifting animals along a single anxiety continuum. Whole-brain c-Fos mapping revealed anatomically distributed modulation of limbic–cortical networks following gastric stimulation, including suppression of ventral medial entorhinal cortex, excitation of nucleus tractus solitarii and heterogeneous recruitment of amygdalar and hippocampal subregions. These circuit-level patterns align with the behavioral dissociation between contextual exploration and explicit threat avoidance, providing convergent cross-species evidence that gastric stimulation engages distributed anxiety-related networks. Together, these findings establish the first freely moving behavioral model of chronic gastric neuromodulation, demonstrate temporally dynamic and context-sensitive effects on anxiety-like behavior, and provide systems-level validation that the stomach can serve as a viable peripheral access point for modulating central emotional circuits.

Background: Prolonged exposure to moderate and loud noise is known to impair hearing; however, the safety of long-duration exposure to low-level sound, such as that encountered during everyday conversation, remains unclear. This study aimed to determine the effect of continuous exposure to sound at a 65 dB sound pressure level (SPL) on auditory processing. Methods: Auditory brainstem responses (ABRs) were recorded in C57BL/6 mice before and after a 1 h exposure to a continuous pure tone at 65 dB SPL. Changes in ABR thresholds, wave amplitudes, and latencies were analyzed across frequencies and time points. Correlations between amplitude and latency changes across ABR waves were also assessed. Results: Tone exposure induced a significant, frequency-specific increase in ABR thresholds, with a mean elevation of approximately 6 dB and a maximum shift of 15 dB. Significant reductions in amplitudes and prolongations of latencies were observed in Waves I–III, while Wave V amplitude remained relatively stable. A strong negative correlation between amplitude reduction and latency increase was found in Wave I, which progressively weakened from Wave II to Wave V. These functional changes persisted for up to three hours following exposure before gradually returning to baseline. Conclusions: Prolonged exposure to low-level sound at intensities typical of conversational speech can transiently impair auditory function and alter early neural processing in the auditory pathway. These findings suggest that sound levels commonly considered safe may still pose a risk when exposure is sustained, with implications for understanding hidden hearing loss and improving early diagnostic approaches.

Through learning and memory, the cortex dynamically forms sensory associations to guide our behavior in an ever-changing environment. How memory-related brain regions, such as the medial-temporal lobe, influence sensory cortex to support this process remains unclear. Here, we used two-photon calcium imaging of axonal projections from the perirhinal (PRh) cortex to the auditory cortex during learning and generalization of an auditory discrimination task. PRh input in the auditory cortex increased during learning and influenced performance in a categorization task. Chemogenetically silencing PRh input selectively disrupted the activity of auditory cortex layer 2/3 pyramidal neurons, and PRh photoactivation drove behavior toward overgeneralization. These findings highlight PRh input as a key modulatory pathway that shapes cortical dynamics underlying auditory learning and memory-guided sensory perception.