Auditory Research publications

Everyday decisions depend on associations between sensory stimuli, actions, and outcomes. The striatum supports these sensorimotor associations through dopamine-dependent plasticity. Recent work has characterized a local striatal microcircuit in which cholinergic interneurons (CINs) modulate dopamine release via activation of nicotinic receptors on dopamine axons. Here, we show that visual stimuli evoke dopamine in the dorsomedial striatum partly through this cholinergic mechanism. Using anatomical and functional methods to identify the pathways involved, we found that visual and auditory cortices lack connectivity with CINs and were unable to drive cholinergic-dependent dopamine release. Frontal regions, which were activated by visual stimuli, strongly recruited CINs, producing robust dopamine release both ex vivo and in vivo. These findings reveal a fundamental distinction between sensory and frontal corticostriatal inputs, demonstrating that only the latter can evoke cholinergic-dependent dopamine signals. This work establishes a framework for understanding how cortical circuits shape striatal dopamine to support reinforcement learning.

Objectives. Spatial mapping of sound frequencies along the auditory pathway is refined through sound-evoked activity during early development. However, how neonatal auditory deprivation alters this organization remains unclear. This study examined frequency-specific spatial representations in the inferior colliculus (IC) using targeted low-frequency (apical) and high-frequency (basal) cochlear stimulation, enabling direct evaluation of low-frequency pathway integrity after neonatal deafness.Methods. Sixteen Sprague-Dawley rats (8 normal-hearing [NH] and 8 neonatally deafened [ND]) were studied. Neonatal deafness was induced by daily kanamycin injections from postnatal days 4 to 17. At 8–10 weeks of age, all animals underwent unilateral cochlear implantation with bipolar electrode pairs positioned in apical and basal cochlear regions to activate low- and high-frequency pathways. Multiunit responses were recorded from the contralateral IC using a multichannel linear electrode array. Spatial tuning curves (STCs) based on cumulative discriminability were used to assess thresholds, spread of excitation, and tonotopic precision. Spiral ganglion neuron (SGN) density was quantified histologically.Results. Despite 48%–67% SGN loss across cochlear turns, electrically evoked auditory brainstem response thresholds and IC thresholds were comparable between groups, indicating preserved peripheral excitability. However, ND rats exhibited significantly broader STCs (P=0.002) and reduced dorsoventral separation of apical and basal best sites (1.18± 0.67 mm vs. 1.80±0.40 mm, P=0.039), reflecting degraded central tonotopic precision. The effects were most pronounced for apical (low-frequency) stimulation, consistent with the selective vulnerability of low-frequency pathways to early auditory deprivation.Conclusion. These findings provide direct physiological evidence that early auditory experience is critical for refining frequency-organized connectivity in the auditory midbrain. The preferential degradation of apical (low-frequency) spatial tuning offers translational insights for optimizing stimulation strategies in early-onset deafness.

Exposure to stress can cause long-lasting enhancement of fear and other defensive responses that extend beyond the cues or contexts associated with the original traumatic event. These nonassociative consequences of stress, referred to as fear sensitization, are thought to underlie some symptoms of trauma-related disorders. Fear sensitization has been predominantly studied using the stress-enhanced fear learning (SEFL) paradigm, which models the stress-induced amplification of fear learning. Less is known about the mechanisms through which unlearned fear responses are sensitized by stress. Here, we investigated the neural mechanisms for sensitization of unlearned fear responses using a paradigm we termed stress-enhanced fear responding (SEFR). In this model, mice exposed to a single session of footshock stress exhibit enhanced freezing to a novel tone stimulus. To investigate brain regions that might mediate SEFR, we first used c-Fos mapping to identify neural activity changes associated with stress-induced enhancement of unlearned fear. Our c-Fos screen identified the posterior paraventricular thalamus (pPVT) as a region that was persistently hyperactive after footshock stress and whose activity correlated with behavioral expression of SEFR. Using fiber photometry, we observed that SEFR, but not SEFL, was associated with increased activity in the pPVT. Next, we found that chemogenetic inhibition of the pPVT blocked both the induction of SEFR during stress and its later expression, while artificial stimulation of pPVT in stress-naive mice was sufficient to recapitulate SEFR. Interestingly, pPVT inhibition or stimulation did not affect acquisition or expression of SEFL. In conclusion, our results indicate that sensitization of fear learning (SEFL) and sensitization of unlearned fear (SEFR) have distinct neural mechanisms. Our results identify pPVT hyperactivity as a mechanism for stress-induced sensitization of unlearned fear and highlight pPVT as a potential target for treating arousal and reactivity symptoms of trauma- and stressor-related disorders.

CLN3 disease, the most common form of the Neuronal Ceroid Lipofuscinoses (NCLs), causes progressive cognitive decline and language impairment in humans. A pathological hallmark is the accumulation of storage material within neuronal lysosomes resulting from mutations in the CLN3 gene. We previously identified parallel deficits in auditory duration mismatch negativity (MMN), an electroencephalography (EEG)-based marker of auditory change detection, in individuals with CLN3 disease and in Cln3 -/- mice. MMN-dependent auditory change detection relies on sensory-memory comparison mechanisms. However, the anatomical and neurophysiological substrates underlying this response in CLN3 disease remain unclear. Here, we investigated central auditory dysfunction in Cln3 -/- mice by integrating immunohistochemical mapping of lysosomal storage pathology, using the canonical marker Subunit C of Mitochondrial ATP Synthase (SCMAS), with EEG analysis of auditory evoked potentials (AEPs). Neuropathological analyses revealed age-dependent and sex-divergent SCMAS accumulation across the auditory thalamocortical circuit, including the excitatory auditory thalamus, the inhibitory thalamic reticular nucleus, and the primary auditory cortex. In parallel, Cln3 -/- mice exhibited age- and sex-dependent alterations in AEPs relative to wild-type controls. Importantly, an integrated measure of auditory thalamocortical SCMAS accumulation accounted for a substantial portion of age- and sex-matched variation in AEP responses, with stronger associations for the early N1 component than the later MMN component. Together, these findings link age-dependent and sex-divergent auditory neurophysiological deficits to region-specific lysosomal storage pathology within the auditory thalamocortical circuit in the Cln3 -/- mouse model. This integrated functional-anatomical framework provides insight into circuit vulnerability and supports the development of translational neurophysiological biomarkers for CLN3 disease. Graphical Abstract Highlights SCMAS accumulates across the auditory thalamocortical circuit in Cln3 -/- mice Accumulation shows distinct age- and sex-dependent regional trajectories Cln3 -/- mice exhibit progressive alterations in auditory evoked potentials Thalamic pathology is strongly associated with the early auditory N1 response Histology–EEG integration links circuit pathology to auditory dysfunction

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.

Context modulates neural processing of sensory stimuli. Neural responses are suppressed to stimuli that are typical in their context and augmented to stimuli that deviate from their context. The latter has been conceptualized as a “prediction error”, which can serve to enhance the salience, direct attention, or support learning about behaviorally relevant events. Predictive coding theories posit that prediction errors act to signal the difference between internal predictions and actual sensory input, yet most paradigms simultaneously alter both predictions and input, so cannot test for a true difference signal. Increased neural responses to deviants could, instead, encode generalized surprise or augmented bottom-up signaling. Here we compare neural responses to auditory stimuli across oddball paradigm variants. We found that responses of putative excitatory neurons in primary auditory cortex (A1) to auditory deviants contain frequency change information and a memory trace of contextual information. Interestingly, in a fixed-deviant oddball paradigm where predictions are altered but deviant input remains constant, neural response patterns encoded standard-to-deviant frequency difference. These results support the interpretation that A1 deviance detection can be interpreted as a sensory prediction error that represents the difference between prediction and sensory input, a corollary of the predictive coding framework.

Objective: The purpose of this paper is to present a chronic, preclinical, pilot study of a multi-electrode auditory nerve implant. To date, the most successful auditory neuroprosthesis is the cochlear implant, but these devices have known limitations. Intraneural stimulation of the auditory nerve is a promising alternative, but preclinical investigations of multi-electrode devices have been limited to acute or semi-chronic studies. Methods: Six cats were chronically implanted in the right auditory nerve with a 15-channel Utah Slant ArrayTM. The array's position in the internal auditory canal was confirmed using computed tomography. Electrode impedance and evoked responses were recorded regularly during the indwelling period to evaluate performance. Results: Two of the six implants met endpoint criteria at 6 months, with stable electrode impedances and robust evoked responses on at least 50% of their channels. Another two implants exhibited stable electrode impedances, but activation thresholds increased over three months. Two implants failed within the first two weeks due to device migration caused by connector-related issues. Conclusion: This study reports the first successful chronic deployment of an multi-electrode auditory nerve implant in a preclinical model. Two implanted cats exhibited stable chronic performance, marked by a consistent set of electrodes capable of eliciting evoked responses. The failure modes of the remaining four cats are discussed and recommendations are made to stabilize implant placement. The study lays a solid foundation for future chronic safety and efficacy investigations as part of an effort to translate this new neuroprosthetic technology into the clinic.

The hippocampus is classically linked to memory, yet increasing evidence points to a broader role in perceptual inference and deviance detection. Predictive coding theories propose that perception minimizes mismatches between expected and actual sensory input, expressed in neural signatures such as mismatch negativity (MMN) and P300. Although MMN arises mainly from sensory and prefrontal cortices, the hippocampus is anatomically interconnected with both and may also contribute to prediction error processing. We recorded single- and multi-unit activity and local field potentials (LFPs) from DG and CA1 in urethane-anesthetized rats during an auditory oddball paradigm and a no-repetition control sequence to dissociate prediction error from repetition suppression. Approximately 20% of hippocampal neurons were sound responsive, and a subset showed deviant selectivity. Spiking activity predominantly reflected prediction errors, while LFPs revealed complementary contributions from repetition suppression and prediction error. Early LFP components were enhanced for randomly presented deviants, whereas later components within the P300 latency range were stronger for predictable deviants, indicating temporally distinct phases of error signaling and top-down modulation. These findings identify the hippocampus as an active contributor to auditory deviance detection and support a hierarchical model in which hippocampal circuits participate in predictive sensory processing beyond memory.

The lateral habenula (LHb) integrates cortical and basal forebrain (BF) input to control monoaminergic outflow and is implicated in depression, anxiety, impulsivity, and aversion. Although cannabis withdrawal is associated with negative affect and heightened anxiety, LHb involvement is not established. Here, effects of withdrawal from the psychoactive cannabis constituent Δ 9 -tetrahydrocannabinol (Δ 9 -THC) on LHb neurons were assessed with photometric calcium measurement during fear conditioning and in vitro electrophysiology. LHb calcium signals were larger during footshock, and presentation of a tone paired with footshock in Δ 9 -THC withdrawn rats. Fear-induced freezing to the tone was also larger during Δ 9 -THC withdrawal. Electrophysiology revealed larger LHb excitatory-inhibitory (E-I) ratios during Δ 9 -THC withdrawal, resulting from impaired synaptic GABA release. Moreover, GABA release via optogenetic activation of BF-LHb inputs was impaired during Δ 9 -THC withdrawal, whereas no changes occurred at ventral tegmental area-LHb inputs. Recovery of BF-LHb GABA release and cannabinoid CB1 receptor desensitization were incomplete at 30 days of Δ 9 -THC withdrawal. The data show that LHb responsivity to primary aversive and conditioned stimuli are increased during Δ 9 -THC withdrawal, and that this is likely mediated by altered E-I balance. We propose negative affect experienced during cannabis withdrawal is related to LHb hypersensitivity to aversive stimuli and this facilitates encoding of associated environmental cues.

Context‐dependent sensory processing within the predictive coding framework relies on detecting mismatches between incoming stimuli and internal predictive models. Sensory deviants elicit prediction errors, seen as enhanced neural responses, that update these models and influence attention and behaviour. Although prediction errors have been widely observed across brain regions, the downstream processes remain poorly understood. In this study, we recorded electrocorticography in five urethane‐anaesthetised rats and identified cortical slow oscillations, characterised by spontaneous transitions between ‘Up’ and ‘Down’ states. Deviant stimuli in an auditory oddball paradigm evoked an initial positive prediction error, followed by a prolonged, all‐or‐nothing response which spread in a travelling wave across the cortex. Identified as putative evoked cortical Up states, these responses were not evoked by standards, omissions or a many‐standards control. Up states following deviants occurred more recently after a previous Up state when compared to spontaneous Up states. In preliminary data from an awake rat, long‐latency Up states were not present spontaneously or evoked. In a different rat, anaesthetic depth was key to spontaneous and evoked Up states, with more robust Up/Down states and more reliable triggering of Up states under deeper anaesthesia. These results suggest that sensory deviants may cause shifts in cortical state under anaesthesia, explaining the long‐latency mismatch response under anaesthesia and sleep.

The thalamocortical pathways exhibit neuroplasticity not only during the critical period but also in adulthood. In this study, we investigated how cholecystokinin (CCK) modulates age-dependent thalamocortical plasticity. Our findings demonstrated that CCK is expressed in thalamocortical neurons and that high-frequency stimulation (HFS) of the thalamocortical pathway triggers the release of CCK in auditory cortex (ACx), as detected by a CCK sensor. HFS of the medial geniculate body (MGB) induced thalamocortical long-term potentiation (LTP) in wild-type young adult mice. However, knockdown of CCK expression in MGB neurons or blockade of the CCK-B receptor (CCKBR) in the ACx abolished HFS-induced LTP. Interestingly, this LTP could not be elicited in juvenile (3-week-old) or aged mice (over 18-month-old) due to distinct mechanisms: the absence of CCKBR in juveniles and the inability to release CCK in aged mice. Notably, exogenous administration of CCK into the ACx rescued LTP in aged mice and significantly improved frequency discrimination. These findings highlight the potential of CCK as a therapeutic intervention for ameliorating neuroplasticity deficits associated with thalamocortical connectivity.

Background CLN3 disease, also known as juvenile Batten disease, is a recessively inherited neurodevelopmental disorder caused by mutations in the CLN3 gene. It represents the most common form of Neuronal Ceroid Lipofuscinoses (NCLs), a group of lysosomal storage disorders that impair brain function. Clinical features include progressive vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates the neurological assessment of cognitive dysfunction, while the rarity of CLN3 cases limits the study of sex-specific disease trajectories in humans. Therefore, there is a critical need for objective, translational biomarkers to monitor disease progression and support therapeutic development in preclinical animal models. Methods Building on our recent studies in individuals with CLN3 disease, we developed a parallel experimental paradigm using high-density electroencephalography (EEG) in Cln3 knockout ( Cln3-/-) mice to longitudinally assess auditory neurophysiological changes. We applied a duration-based mismatch negativity (MMN) paradigm, similar to that used in our human studies, to evaluate automatic detection of auditory pattern changes in male and female mice between 3 and 9 months of age. Results Wild-type (WT) mice of both sexes showed robust and stable duration MMN responses across this age range. In contrast, Cln3-/- mice showed marked sex- and age-dependent deficits: female mutants displayed persistent MMN deficits, whereas male mutants exhibited early MMN abnormalities that unexpectedly improved with age. Auditory brainstem responses confirmed intact peripheral hearing in Cln3-/- mice, indicating a central origin for the observed abnormalities. Further analyses revealed that MMN impairments were driven by age- and sex-specific alterations in auditory evoked potentials to both standard and deviant stimuli. Conclusions These findings demonstrate sex- and age-dependent disruptions in central auditory processing in Cln3-/- mice and support auditory duration MMN as a sensitive, translational biomarker of brain dysfunction in CLN3 disease. This approach offers a functional, cross-species measure for tracking disease progression and evaluating therapeutic interventions in Batten disease.

Cross-modal responses are common in primary sensory cortex, yet a recent study showed that signals in primary visual cortex (V1) once labeled multisensory were instead more closely related to face movements. To what extent can multisensory processing in other modalities also be explained by face movements? We measured face movements and neural activity in awake mouse primary auditory cortex (A1) and V1 in response to visual and auditory stimulation as well as during spontaneous activity. We find that visual stimuli rarely evoke face movements, A1 responses to visual input remain robust even in the absence of face movement, and optogenetic silencing of V1 reduces A1 visual responses. Taken together, these results confirm that cross-modal responses in the auditory system are primarily sensory, not state driven, in origin.

Deep Brain Stimulation (DBS) of the superolateral medial forebrain bundle has shown promising long-term anti-depressant effects in treatment-resistant depression patients, although the mechanisms are not clear. The study explored medial forebrain bundle DBS mediated modulation of central noradrenaline transmission in a rodent depression model, the Flinders Sensitive Line (FSL), and in controls, Sprague Dawley (SD) rats. In vivo noradrenergic signaling in the prefrontal cortex (PFC) and nucleus accumbens (NAc) and ultrasonic vocalization were monitored during unilateral mfb-DBS across diverse stimulation parameters. The fiber amount, myelination status, and the activation of ascending projected noradrenergic cell groups (A1, A2, A6) were quantified. Moreover, stimulation induced changes in the parvalbumin-mediated feedforward microcircuitry and neuron activation at PFC and NAc were assessed. FSL rats showed decrease in NA fibers in mfb. Stimulation increased PFC noradrenergic signaling similarly across both groups compared to baseline, but in the NAc, the FSLs had notably higher signaling compared with SDs. FSLs demonstrated more positive affective ultrasonic vocalizations post-DBS than SDs. Brainstem nuclei A1 and A2 had similar noradrenergic neuron density across the experimental groups, and mfb DBS increased neuronal activation in both groups. FSLs had fewer noradrenergic neurons in the A6 nuclei, fewer unmyelinated noradrenergic fibers traversing the mfb, and decreased parvalbumin interneuron activity in both PFC and NAc. DBS normalized parvalbumin interneuron activity in the FSL rats. The study proposes that mfb DBS, via the modulation of the central NA system and the GABAergic inhibitory control of neural excitability, likely contributes to the anti-depressant therapeutic mechanisms reported in both clinical and experimental studies.

The locus coeruleus–norepinephrine (LC-NE) system regulates arousal and awakening; however, it remains unclear whether the LC does this in a global or circuit-specific manner. We hypothesized that sensory-evoked awakenings are predominantly regulated by specific LC-NE efferent pathways. Anatomical, physiological, and functional modularities of LC-NE pathways involving the mouse basal forebrain (BF) and pontine reticular nucleus (PRN) were tested. We found partial anatomical segregation between the LC → PRN and LC → BF circuits. Extracellular NE dynamics in BF and PRN exhibited distinct sound-evoked activation during sleep, including a fast sound-evoked NE peak specific to PRN. Causal optogenetic interrogation of LC efferent pathways, by retro-channelrhodopsin (ChR2) activation or Platynereis dumerilii ciliary opsin (PdCO) silencing of synapses in target regions, revealed a role for early LC → PRN activity in driving arousal and sound-evoked awakenings. Together, our results uncover a role for early LC-NE PRN activity in connecting sensory and arousal pathways and establish LC heterogeneity in regulating arousal.

The activity of neurotransmitter-based cell types in the cuneiform and pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation is not fully understood. Using fiber photometry in mice, we found cell-type specific responses to sensory stimuli. Glutamatergic and GABAergic cells responded to sound, visual looming, and air puffs, except for pedunculopontine GABAergic cells, which did not respond to visual looming. Cholinergic cells responded to air puffs. Air puffs triggered high-speed locomotion, whereas visual looming and sound stimuli evoked low-speed locomotion. During air puff–evoked locomotion, cuneiform glutamatergic neuron activity was higher than in trials without locomotion. In contrast, during locomotion evoked by visual looming or sound, activity in pedunculopontine glutamatergic neurons was higher than when no locomotion occurred. In the open-field arena, mice exhibited spontaneous low-speed locomotion during which activity increased in pedunculopontine glutamatergic cells. Activity also increased in a cell type-specific manner during grooming or rearing. Our study shows cell type-specific activity in the cuneiform or pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation. Sensory responsiveness likely has relevance in Parkinson’s disease, where sensory circuits are increasingly targeted to improve walking.

A crucial aspect of auditory perception is the ability to use sound cues to predict future events and to time actions accordingly. For example, the sound of an approaching vehicle signals when it is safe to cross the street; distinct smartphone notification sounds reflect a call that needs to be answered within a few seconds, or a text that can be read later. Other animals similarly use sounds to plan, time and execute behaviors such as hunting, evading predation and tending to offspring. However, the neural mechanisms that underlie sound-guided prediction of upcoming salient event timing are not well understood. To address this gap, we employed an appetitive sound-triggered reward time prediction behavior in head-fixed mice. We find that mice trained on this task reliably estimate the time from a sound cue to upcoming reward on the scale of a few seconds, as demonstrated by learning-dependent well-timed increases in predictive licking for reward. Moreover, mice showed a dramatic impairment in their ability to use sound to predict delayed reward when the auditory cortex was inactivated, demonstrating its causal involvement. To identify the neurophysiological signatures of auditory cortical reward-timing prediction, we recorded local field potentials during learning and performance of this behavior and found that the magnitude of auditory cortical responses to the sound prospectively encoded the duration of the anticipated sound-reward time interval. Next, we explored how and where these sound-triggered time interval prediction signals propagate from the auditory cortex to time and initiate consequent action. We targeted the monosynaptic projections from the auditory cortex to the posterior striatum and found that chemogenetic inactivation of these projections impaired animals’ ability to predict sound-triggered delayed reward. Simultaneous neural recordings in the auditory cortex and posterior striatum during task performance revealed coordination of neural activity across these regions during the sound cue predicting the time interval to reward. Collectively, our findings identify an auditory cortical-striatal circuit supporting sound-triggered timing-prediction behaviors.

Introduction Tinnitus is the perception of non-meaningful sound in the absence of external stimuli. Although tinnitus behavior in animal models is associated with altered central nervous system activity, it is not currently possible to identify tinnitus using neuronal activity alone. In the mouse inferior colliculus (IC), a subpopulation of neurons demonstrates a sustained increase in spontaneous activity after a long-duration sound (LDS). Methods Here, we use the “ LDS test ” to reveal tinnitus-specific differences in sound-evoked plasticity through IC extracellular recordings and the auditory brainstem response (ABR LDS ) in CBA/CaJ mice after sound exposure and behavioral tinnitus assessment. Results Sound-exposed mice showed stronger and shorter tone-evoked responses in the IC compared to unexposed controls, but these differences were not strong predictors of tinnitus. In contrast, in the LDS test, non-tinnitus mice had a significantly stronger suppression in tone-evoked spike rate compared to tinnitus and unexposed control mice. ABR peak amplitudes also revealed robust differences between tinnitus and non-tinnitus mice, with ABR peaks from non-tinnitus mice exhibiting significantly stronger suppression in the LDS test compared to tinnitus and control mice. No significant differences were seen between cohorts in ABR amplitude, latency, wave V:I ratio, wave V:III ratio, I-V intra-peak latency, and I-VI intra-peak latency. We found high-frequency tone stimuli better suited to reveal tinnitus-specific differences for both extracellular IC and ABR recordings. Discussion We successfully used the LDS test to demonstrate that tinnitus-specific differences in sound-evoked plasticity can be shown using both multi-unit near-field recordings in the IC and non-invasive far-field recordings, providing a foundation for future electrophysiological research into the causes and treatment of tinnitus.

High-frequency stimulation (HFS)-induced long–term potentiation (LTP) is generally regarded as a homosynaptic Hebbian-type LTP, where synaptic changes are thought to occur at the synapses that project from the stimulation site and terminate onto the neurons at the recording site. In this study, we first investigated HFS-induced LTP on urethane-anesthetized rats and found that cortical HFS enhances neural responses at the recording site through the strengthening of local connectivity with nearby neurons at the stimulation site rather than through synaptic strengthening at the recording site. This enhanced local connectivity at the stimulation site leads to increased output propagation, resulting in signal potentiation at the recording site. Additionally, we discovered that HFS can also nonspecifically strengthen distant afferent synapses at the HFS site, thereby expanding its impact beyond local neural connections. This form of plasticity exhibits a neo-Hebbian characteristic as it exclusively manifests in the presence of cholecystokinin release, induced by HFS. The cortical HFS-induced local LTP was further supported by a behavioral task, providing additional evidence. Our results unveil a previously overlooked mechanism underlying cortical plasticity: synaptic plasticity is more likely to occur around the soma site of strongly activated cortical neurons rather than solely at their projection terminals.

Demyelination is a common pathological feature in a wide range of diseases, characterized by the loss of myelin sheath and myelin-supporting oligodendrocytes. These losses lead to impaired axonal function, increased vulnerability of axons to damage, and result in significant brain atrophy and neuro-axonal degeneration. Multiple pathomolecular processes contribute to neuroinflammation, oligodendrocyte cell death, and progressive neuronal dysfunction. In this study, we use the cuprizone mouse model of demyelination to investigate long-term non-invasive gamma entrainment using sensory stimulation as a potential therapeutic intervention for promoting myelination and reducing neuroinflammation in male mice. Here, we show that multisensory gamma stimulation mitigates demyelination, promotes oligodendrogenesis, preserves functional integrity and synaptic plasticity, attenuates oligodendrocyte ferroptosis-induced cell death, and reduces brain inflammation. Thus, the protective effects of multisensory gamma stimulation on myelin and anti-neuroinflammatory properties support its potential as a therapeutic approach for demyelinating disorders.