Publications using the ED1

DNA repair mechanisms are essential for cellular development and function. This is particularly true in post-mitotic neurons, where deficiencies in DNA damage response proteins can result in severe neurodegenerative and neurodevelopmental disorders. One highly conserved factor involved in DNA repair is Mut-S Homolog 2 ( Msh2 ), which is responsible for correcting base-base mismatches and insertion/deletion loops during cell proliferation. However, its role in mature neuronal function remains poorly understood. This study investigates the impact of Msh2 loss on sensory processing in a mouse model. Using electrophysiological and molecular assays, we identified significant deficits in cortical and thalamic sound processing in Msh2 -/- mice. These deficits were linked to dysfunction of the thalamic reticular nucleus (TRN), a brain region that critically regulates corticothalamic and thalamocortical activity. Our findings revealed increased oxidative damage, aberrant neuronal activity, and elevated parvalbumin (PV) expression in PV + interneurons in the TRN of Msh2 -/- mice. Additionally, we observed the presence of connexin plaques, indicating that disrupted gap junction formation may contribute to impaired TRN function. These results underscore the critical role of Msh2 in supporting the functionality of PV + interneurons in the TRN, thereby profoundly influencing sensory processing pathways. This study provides new insights into the importance of DNA repair mechanisms in neuronal development and function, potentially contributing to our understanding of their role in neurological disorders.

Transgenic mice provide unprecedented access to manipulate and visualize neural circuits; however, those on a C57BL/6 background develop progressive hearing loss, significantly confounding systems-level and behavioral analysis. While outbreeding can limit hearing loss, it introduces strain variability and complicates the generation of complex genotypes. Here, we propose an approach to preserve hearing by crossing transgenic mice with congenic B6.CAST- Cdh23 Ahl + mice, which maintain low-threshold hearing into adulthood. Widefield and two-photon imaging of the auditory cortex revealed that 2.5-month-old C57BL/6 mice exhibit elevated thresholds to high-frequency tones and widespread cortical reorganization, with most neurons responding best to lower frequencies. In contrast, Ahl+ C57BL/6 mice exhibited robust neural responses across tested frequencies and sound levels (4–64 kHz, 30–90 dB SPL) and retained low thresholds into adulthood. Our approach offers a cost-effective solution for generating complex genotypes and facilitates more interpretable systems neuroscience research by eliminating confounding effects from hearing loss.

Sound location coding has been extensively studied at the central nucleus of the mammalian inferior colliculus (CNIC), supporting a population code. However, this population code has not been extensively characterized on the single-trial level with simultaneous recordings or at other anatomical regions like the dorsal cortex of inferior colliculus (DCIC), which is relevant for learning-induced experience dependent plasticity. To address these knowledge gaps, here we made in two complementary ways large-scale recordings of DCIC populations from awake mice in response to sounds delivered from 13 different frontal horizontal locations (azimuths): volumetric two-photon calcium imaging with ~700 cells simultaneously recorded at a relatively low temporal resolution, and high-density single-unit extracellular recordings with ~20 cells simultaneously recorded at a high temporal resolution. Independent of the method, the recorded DCIC population responses revealed substantial trial-to-trial variation (neuronal noise) which was significantly correlated across pairs of neurons (noise correlations) in the passively listening condition. Nevertheless, decoding analysis supported that these noisy response patterns encode sound location on the single-trial basis, reaching errors that match the discrimination ability of mice. The detected noise correlations contributed to minimize the error of the DCIC population code of sound azimuth. Altogether these findings point out that DCIC can encode sound location in a similar format to what has been proposed for CNIC, opening exciting questions about how noise correlations could shape this code in the context of cortico-collicular input and experience-dependent plasticity.

Recent studies have shown promising therapeutic potential for psychedelics in treating neuropsychiatric conditions. Musical experience during psilocybin-assisted therapy is predictive of treatment outcome, yet little is known about how psilocybin affects auditory processing. Here, we conducted two-photon imaging experiments in auditory cortex of awake mice that received a dose of psilocybin. Our results suggest that psilocybin modulates the roles of intrinsic neural activity versus stimulus-driven influences on auditory perception.

Cisplatin is an election chemotherapeutic agent used for many cancer treatments. Its cytotoxicity against neoplastic cells is mirrored by that taking place in healthy cells and tissues, resulting in serious adverse events. A very frequent one is ototoxicity, causing hearing loss which may permanently affect quality of life after successful oncologic treatments. Exacerbated oxidative stress is a main cytotoxic mechanism of cisplatin, including ototoxicity. Previous reports have shown antioxidant protection against cisplatin ototoxicity, but there is a lack of comparative studies on the otoprotectant activity and mechanism of antioxidant formulations. Here, we show evidence that a cocktail of vitamins A, C, and E along with Mg++ (ACEMg), previously shown to protect against noise-induced hearing loss, reverses auditory threshold shifts, promotes outer hair cell survival, and attenuates oxidative stress in the cochlea after cisplatin treatment, thus protecting against extreme cisplatin ototoxicity in rats. The addition of 500 mg N-acetylcysteine (NAC), which, administered individually, also shows significant attenuation of cisplatin ototoxicity, to the ACEMg formulation results in functional degradation of ACEMg otoprotection. Mg++ administered alone, as MgSO4, also prevents cisplatin ototoxicity, but in combination with 500 mg NAC, otoprotection is also greatly degraded. Increasing the dose of NAC to 1000 mg also results in dramatic loss of otoprotection activity compared with 500 mg NAC. These findings support that single antioxidants or antioxidant combinations, particularly ACEMg in this experimental series, have significant otoprotection efficacy against cisplatin ototoxicity. However, an excess of combined antioxidants and/or elevated doses, above a yet-to-be-defined “antioxidation threshold”, results in unrecoverable redox imbalance with loss of otoprotectant activity.

The flow of neural activity across the neocortex during active sensory discrimination is constrained by task-specific cognitive demands, movements, and internal states. During behavior, the brain appears to sample from a broad repertoire of activation motifs. Understanding how these patterns of local and global activity are selected in relation to both spontaneous and task-dependent behavior requires in-depth study of densely sampled activity at single neuron resolution across large regions of cortex. In a significant advance toward this goal, we developed procedures to record mesoscale 2-photon Ca 2+ imaging data from two novel in vivo preparations that, between them, allow for simultaneous access to nearly all 0f the mouse dorsal and lateral neocortex. As a proof of principle, we aligned neural activity with both behavioral primitives and high-level motifs to reveal the existence of large populations of neurons that coordinated their activity across cortical areas with spontaneous changes in movement and/or arousal. The methods we detail here facilitate the identification and exploration of widespread, spatially heterogeneous neural ensembles whose activity is related to diverse aspects of behavior.

Salicylate is commonly used to induce tinnitus in animals, but its underlying mechanism of action is still debated. We therefore tested its effects on the firing properties of neurons in the mouse inferior colliculus (IC). Salicylate induced a large decrease in the spontaneous activity and an increase of ∼20 dB SPL in the minimum threshold of single units. In response to sinusoidally modulated noise (SAM noise) single units showed both an increase in phase locking and improved rate coding. Mice also became better at detecting amplitude modulations, and a simple threshold model based on the IC population response could reproduce this improvement. The responses to dynamic random chords (DRCs) suggested that the improved AM encoding was due to a linearization of the cochlear output, resulting in larger contrasts during SAM noise. These effects of salicylate are not consistent with the presence of tinnitus, but should be taken into account when studying hyperacusis.

Changes in sound-evoked responses in the auditory cortex (ACtx) occur during learning, but how learning alters neural responses in different ACtx subregions and changes their interactions is unclear. To address these questions, we developed an automated training and widefield imaging system to longitudinally track the neural activity of all mouse ACtx subregions during a tone discrimination task. We find that responses in primary ACtx are highly informative of learned stimuli and behavioral outcomes throughout training. In contrast, representations of behavioral outcomes in the dorsal posterior auditory field, learned stimuli in the dorsal anterior auditory field, and inter-regional correlations between primary and higher-order areas are enhanced with training. Moreover, ACtx response changes vary between stimuli, and such differences display lag synchronization with the learning rate. These results indicate that learning alters functional connections between ACtx subregions, inducing region-specific modulations by propagating behavioral information from primary to higher-order areas.

Autism spectrum disorder (ASD) is often associated with social communication impairments and specific sound processing deficits, for example, problems in following speech in noisy environments. To investigate underlying neuronal processing defects located in the auditory cortex (AC), we performed two-photon Ca 2+ imaging in FMR1 ( fragile X messenger ribonucleoprotein 1 ) knock-out (KO) mice, a model for fragile X syndrome (FXS), the most common cause of hereditary ASD in humans. For primary AC (A1) and the anterior auditory field (AAF), topographic frequency representation was less ordered compared with control animals. We additionally analyzed ensemble AC activity in response to various sounds and found subfield-specific differences. In A1, ensemble correlations were lower in general, while in secondary AC (A2), correlations were higher in response to complex sounds, but not to pure tones. Furthermore, sound specificity of ensemble activity was decreased in AAF. Repeating these experiments 1 week later revealed no major differences regarding representational drift. Nevertheless, we found subfield- and genotype-specific changes in ensemble correlation values between the two times points, hinting at alterations in network stability in FMR1 KO mice. These detailed insights into AC network activity and topography in FMR1 KO mice add to the understanding of auditory processing defects in FXS.

During sensory-guided behavior, an animal's decision-making dynamics unfold through sequences of distinct performance states, even while stimulus-reward contingencies remain static. Little is known about the factors that underlie these changes in task performance. We hypothesize that these decision-making dynamics can be predicted by externally observable measures, such as uninstructed movements and changes in arousal. Here, using computational modeling of visual and auditory task performance data from mice, we uncovered lawful relationships between transitions in strategic task performance states and an animal's arousal and uninstructed movements. Using hidden Markov models applied to behavioral choices during sensory discrimination tasks, we find that animals fluctuate between minutes-long optimal, sub-optimal, and disengaged performance states. Optimal state epochs are predicted by intermediate levels, and reduced variability, of pupil diameter and movement. Our results demonstrate that externally observable uninstructed behaviors can predict optimal performance states and suggest that mice regulate their arousal during optimal performance.

Striatal dopamine drives associative learning by acting as a teaching signal. Much work has focused on simple learning paradigms, including Pavlovian and instrumental learning. However, higher cognition requires that animals generate internal concepts of their environment, where sensory stimuli, actions and outcomes become flexibly associated. Here, we performed fiber photometry dopamine measurements across the striatum of male mice as they learned cue–action–outcome associations based on implicit and changing task rules. Reinforcement learning models of the behavioral and dopamine data showed that rule changes lead to adjustments of learned cue–action–outcome associations. After rule changes, mice discarded learned associations and reset outcome expectations. Cue- and outcome-triggered dopamine signals became uncoupled and dependent on the adopted behavioral strategy. As mice learned the new association, coupling between cue- and outcome-triggered dopamine signals and task performance re-emerged. Our results suggest that dopaminergic reward prediction errors reflect an agent’s perceived locus of control.

Psilocybin is a serotonergic psychedelic believed to have therapeutic potential for neuropsychiatric conditions. Despite well-documented prevalence of perceptual alterations, hallucinations, and synesthesia associated with psychedelic experiences, little is known about how psilocybin affects sensory cortex or alters the activity of neurons in awake animals. To investigate, we conducted 2-photon imaging experiments in auditory cortex of awake mice and video analysis of mouse behavior, both at baseline and during psilocybin treatment. We found biphasic effects of psilocybin on behavioral and cortical activity. A 2 mg/kg dose of psilocybin initially increased behavioral activity and neural responses to sound. 30 minutes post-dose, mice became behaviorally hypoactive and cortical responses to sound decreased, while neural response variance and noise correlations increased. In contrast, neuronal selectivity for auditory stimuli remained stable during psilocybin treatment. Our results suggest that psilocybin modulates the role of intrinsic versus stimulus-driven activity in sensory cortex, while preserving fundamental sensory processing. Graphical Abstract. Summary of psilocybin’s effect on auditory cortical responses to sound in mice. 30 minutes after injecting the inert vehicle saline, typical auditory responses occur within a relatively narrow range of possible amplitudes, i.e., each neuron’s response variance is weakly correlated with a neighboring neuron’s response variance. In contrast, 30 minutes after injecting 2 mg/kg of psilocybin, population response variance becomes more correlated between individual neurons, and the range of response amplitudes increases. These findings suggest that psilocybin modulates the role of intrinsic versus stimulus-driven neural activity in sensory perception, which may serve as a basis for auditory hallucination at the level of neuronal micro-circuits.

Despite the significance of lateralized auditory processing in human cognition, there are limited studies in animal models exploring the developmental mechanisms of this cortical specialization. Here, we find that cellular and network signs of maturity in the Auditory Cortex (ACx) appear earlier in the right hemisphere in male mice. We further demonstrate that persistent, experience dependent map reorganization is confined to the hemisphere that is actively maturing and can be differentially engaged by temporally limited manipulations of the sensory environment. Our data suggests that differential timing in hemisphere development could lead to lateralized auditory functioning.

The auditory brainstem response (ABR) to tone burst stimuli of thirteen frequencies ranging from 0.5 to 48 kHz was recorded in the nine-banded armadillo (Dasypus novemcinctus ), the only extant member of the placental mammal superorder Xenarthra in North America. The armadillo ABR consisted of five main peaks that were visible within the first 10 ms when stimuli were presented at high intensities. The latency of peak I of the armadillo ABR increased as stimulus intensity decreased by an average of 20 μs/dB. Estimated frequency-specific thresholds identified by the ABR were used to construct an estimate of the armadillo audiogram describing the mean thresholds of the eight animals tested. The majority of animals tested (six out of eight) exhibited clear responses to stimuli from 0.5 to 38 kHz, and two animals exhibited responses to stimuli of 48 kHz. Across all cases, the lowest thresholds were observed for frequencies from 8 to 12 kHz. Overall, we observed that the armadillo estimated audiogram bears a similar pattern as those observed using ABR in members of other mammalian clades, including marsupials and later-derived placental mammals.

The sensory neocortex has been suggested to be a substrate for long-term memory storage, yet which exact single cells could be specific candidates underlying such long-term memory storage remained neither known nor visible for over a century. Here, using a combination of day-by-day two-photon Ca 2+ imaging and targeted single-cell loose-patch recording in an auditory associative learning paradigm with composite sounds in male mice, we reveal sparsely distributed neurons in layer 2/3 of auditory cortex emerged step-wise from quiescence into bursting mode, which then invariably expressed holistic information of the learned composite sounds, referred to as holistic bursting (HB) cells. Notably, it was not shuffled populations but the same sparse HB cells that embodied the behavioral relevance of the learned composite sounds, pinpointing HB cells as physiologically-defined single-cell candidates of an engram underlying long-term memory storage in auditory cortex.

Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to achieve its biological functions. Defective PG remodeling causes MEGDEL (non-alcohol fatty liver disease and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like) syndrome through poorly defined mechanisms. Here, we identify LPGAT1, an acyltransferase that catalyzes PG remodeling, as a candidate gene for MEGDEL syndrome. We show that PG remodeling by LPGAT1 at the ER is closely coordinated with mitochondrial transport through interaction with the prohibitin/TIMM14 mitochondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl compositions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista structure and respiration. Consequently, genetic deletion of the LPGAT1 in mice leads to cardinal features of MEGDEL syndrome, including 3-methylglutaconic aciduria, deafness, dilated cardiomyopathy, and premature death, which are highly reminiscent of those caused by TIMM14 mutations in humans.

Usher syndrome (USH) is the leading cause of combined deafness and blindness, with USH2A being the most prevalent form. The mechanisms responsible for this debilitating sensory impairment remain unclear. This study focuses on characterizing the auditory phenotype in a mouse model expressing the c.2290delG mutation in usherin equivalent to human frameshift mutation c.2299delG. Previously we described how this model reproduces patient’s retinal phenotypes. Here, we present the cochlear phenotype, showing that the mutant usherin, is expressed during early postnatal stages. The c.2290delG mutation results in a truncated protein that is mislocalized within the cell body of the hair cells. The knock-in model also exhibits congenital hearing loss that remains consistent throughout the animal’s lifespan. Structurally, the stereocilia bundles, particularly in regions associated with functional hearing loss, are disorganized. Our findings shed light on the role of usherin in maintaining structural support, specifically in longer inner hair cell stereocilia, during development, which is crucial for proper bundle organization and hair cell function. Overall, we present a genetic mouse model with cochlear defects associated with the c.2290delG mutation, providing insights into the etiology of hearing loss and offering potential avenues for the development of effective therapeutic treatments for USH2A patients.

Introduction Autism spectrum disorder (ASD) is characterized by deficits in communication and social interaction, restricted interests, repetitive behaviors, and sensory alterations, with auditory hypersensitivity being one of the most commonly reported sensory–perceptual abnormalities. Several candidate genes for involvement in this disorder have emerged from patient studies, including SHANK3 , a gene that encodes a protein (SHANK3) in the postsynaptic density of excitatory synapses. Previous work has shown that mutant mice carrying a human ASD mutation in the Shank3 gene ( InsG3680 ) exhibit repetitive behaviors and social interaction deficits, indicating important construct and face validity for this genotype as an animal model of ASD. Methods To further address whether these mice also present auditory sensory–perceptual alterations, we developed a novel behavioral test in which mice can choose between different soundscapes. Results Our results reveal that, in comparison to wild-type mice, Shank3 mutants display a strong behavioral preference toward silent regions of the arena. Discussion These data suggest that Shank3 - mutant mice might express an auditory hypersensitivity phenotype, further adding to the face validity of this genotype as an animal model of ASD.

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

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