Biology subjects

Linden, J. F.

Publications and source records attributed to Linden, J. F..

8 recordsLinked to original sources

bioRxiv2026

Cortical consequences of comorbidity: distinct effects of hearing loss and the 22q11.2 deletion on temporal processing in the auditory cortex

BackgroundPeripheral hearing loss is associated with auditory hallucinations and increased risk for psychotic disorder, particularly in genetically vulnerable individuals. Moreover, both hearing loss and schizophrenia disrupt auditory temporal acuity, a sensitive measure of auditory brain function. Here, we used mouse models of hearing loss and schizophrenia to reveal how neural mechanisms of auditory cortical temporal acuity depend on sensory and genetic risk factors for psychosis. MethodsWe quantified auditory cortical temporal acuity in mice with or without hearing loss and with or without the 22q11.2 deletion -- one of the strongest known genetic risk factors for schizophrenia. Cortical single-unit and population activity were recorded in awake mice (N = 23) during presentations of loudness-adjusted gap-in-noise stimuli with varying durations of silent gap, which are commonly used to assess auditory temporal acuity in humans. ResultsBoth hearing loss and the 22q11.2 deletion disrupted auditory cortical temporal acuity, but through distinct mechanisms. Hearing loss broadly degraded temporal acuity at the level of single-unit responses and neural population activity. In contrast, the 22q11.2 deletion selectively impaired gap duration thresholds in regular-spiking (putative excitatory) but not fast-spiking (putative inhibitory) neurons. Mice with comorbid hearing loss and 22q11.2 deletion exhibited both abnormalities in auditory cortical temporal acuity. ConclusionsSensory and genetic risk factors for psychosis can disrupt auditory cortical temporal acuity via distinct mechanisms that remain partially dissociable even under comorbid conditions. These findings underscore the importance of accounting for hearing loss comorbidity when interpreting auditory cortical dysfunction in psychotic disorder.

neuroscience↗

bioRxiv2026

An adaptive gain model for predicting auditory brain activity in mice outperforms standard methods for predicting cortical speech tracking in human EEG

Human brain activity tracks slow fluctuations in continuous sound, including speech, and modelling this relationship provides insight into how the brain encodes naturalistic auditory input. Traditional approaches to modelling brain tracking of speech with linear regression often use the amplitude envelope of the stimulus as a regressor, implicitly assuming that neural responses scale linearly with sound intensity. However, previous studies of central auditory processing in both animals and humans have shown that adaptive mechanisms adjust auditory responses based on recent sound history. Here, we find that a simple nonlinear transformation of the stimulus envelope, derived from studies of mouse auditory thalamic responses to temporally varying sounds, significantly improves modelling of human cortical speech tracking. This Adaptive Gain transformation essentially normalizes sound level by its recent context. Improvements in modelling of cortical speech tracking using the Adaptive Gain stimulus representation are robust across experiments, participant groups, and languages, indicating that short-timescale adaptation to recent sound level is a general feature of auditory processing. We further show that the optimal adaptation time constant for human cortical responses to continuous speech is approximately 50-100 ms, longer than previously observed for auditory thalamic responses to temporally varying sounds in mice. In summary, the Adaptive Gain transformation is a mathematically simple alternative to the standard envelope representation that captures dynamic adaptation in auditory processing and reliably improves prediction of human cortical EEG signals during listening to continuous speech. Significance StatementStandard models of human brain responses to continuous speech use the raw stimulus envelope as a predictor of EEG responses, implicitly assuming stationary sensitivity to sound intensity. Here, we use instead a simple nonlinear transformation of the stimulus envelope, Adaptive Gain, which normalizes sound level based on recent sound history over tens to hundreds of milliseconds. Originally derived from studies of auditory processing in mice, the Adaptive Gain transformation robustly improves prediction of EEG responses to continuous speech in humans across experiments, participant groups, and languages. Results demonstrate that dynamic adaptation to sound level is a core feature of auditory processing, and can be approximated in a mathematically simple form to improve prediction of cortical speech tracking.

neuroscience↗

bioRxiv2025

Distinctive neurophysiological correlates of sound onset and offset perception in humans

Accurate detection of sound onsets and offsets is vital for speech perception. Sound-onset event-related potentials (ERPs) have been well-characterised in electroencephalography (EEG) studies, but the characteristics of sound-offset ERPs have often been obscured by temporal confounds in experimental design. Here, two EEG studies were conducted in human listeners performing an interval duration discrimination task with (i) noise intervals in silence or (ii) silent intervals (gaps) in noise. Stimuli used in the active task were also presented under passive listening conditions. This design enabled us to investigate whether features of the offset ERP could be masked by task demands, and whether the usual temporal precedence of the onset cue in a sound influences the relative magnitude and shape of onset and offset ERPs. The morphology of the offset ERP was distinct from that of the onset ERP in both noise and silent interval duration discrimination tasks, even though the roles of onset and offset cues as initial versus final markers of interval duration were reversed. This observation corroborates evidence from animal studies that there are fundamental differences in brain mechanisms of onset and offset perception. In all experimental conditions, the amplitude of the offset ERP was one-third to one-half that of the onset ERP. Differences between active and passive listening conditions were largely explained by enhancement of ERPs for whichever cue (onset or offset) marked the end of the intervals compared in the duration discrimination task. However, this context dependence emerged in earlier ERP waves for offset than onset responses. Key points summaryO_LIOnset and offset event-related potentials (ERPs) differ in morphology and amplitude C_LIO_LIFor both onset and offset ERPs, P200 and later waves depend on behavioural context C_LIO_LIFor offset ERPs only, P100/N100 waves also depend on behavioural context C_LIO_LIEngagement in duration discrimination alters ERPs primarily for end-interval cues C_LI

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bioRxiv2023

Auditory evoked-potential abnormalities in a mouse model of 22q11.2 Deletion Syndrome and their interactions with hearing impairment

The 22q11.2 deletion is a risk factor for multiple psychiatric disorders including schizophrenia and also increases vulnerability to middle-ear problems that can cause hearing impairment. Up to 60% of deletion carriers experience hearing impairment and [~]30% develop schizophrenia in adulthood. It is not known if these risks interact. Here we used the Df1/+ mouse model of the 22q11.2 deletion to investigate how hearing impairment might interact with increased genetic vulnerability to psychiatric disease to affect brain function. We measured brain function using cortical auditory evoked potentials (AEPs), which are commonly measured non-invasively in humans. After identifying one of the simplest and best-validated methods for AEP measurement in mice from the diversity of previous approaches, we measured peripheral hearing sensitivity and cortical AEPs in Df1/+ mice and their WT littermates. We exploited large inter-individual variation in hearing ability among Df1/+ mice to distinguish effects of genetic background from effects of hearing impairment. Central auditory gain and adaptation were quantified by comparing brainstem activity and cortical AEPs and by analyzing the growth of cortical AEPs with increasing sound level or inter-tone interval duration. We found distinctive measures of central auditory gain or adaptation that were abnormal in Df1/+ mice regardless of hearing impairment, and other measures that were abnormal only in Df1/+ mice with or without hearing impairment. Our data identify potential biomarkers for auditory brain dysfunction in psychiatric disease and illustrate that central auditory abnormalities in 22q11.2DS are a function of both genotype and hearing phenotype.

neuroscience↗

bioRxiv2023

Contextual modulation is a stable feature of the neural code in auditory cortex of awake mice

The perceptual salience of a sound depends on the acoustic context in which it appears, and can vary on a timescale of milliseconds. At the level of single neurons in the auditory cortex, spectrotemporal tuning for particular sounds is shaped by a similarly fast and systematic nonlinear sensitivity to acoustic context. Does this neuronal context sensitivity "drift" over time in awake animals, or is it a stable feature of sound representation in the auditory cortex? We used chronically implanted tetrode arrays in awake mice to measure the electrophysiological responses of auditory cortical neurons to spectrotemporally complex, rapidly varying sounds across many days. For each neuron in each recording session, we applied the nonlinear-linear "context model" to estimate both a principal (spectrotemporal) receptive [fi]eld and a "contextual gain [fi]eld" describing the neurons nonlinear sensitivity to acoustic context. We then quanti[fi]ed the stability of these [fi]elds within and across days, using spike waveforms to match neurons recorded in multiple sessions. Contextual gain [fi]elds of auditory cortical neurons in awake mice were remarkably stable across many days of recording, and comparable in stability to principal receptive [fi]elds. Interestingly, there were small but signi[fi]cant effects of changes in locomotion or pupil size on the ability of the context model to [fi]t temporal fluctuations in the neuronal response. We conclude that both spectrotemporal tuning and nonlinear sensitivity to acoustic context are stable features of neuronal sound representation in the awake auditory cortex, which can be modulated by behavioral state.

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bioRxiv2019

Sustained Activation of PV+ Interneurons in Auditory Cortex Enables Robust Divisive Gain Control for Complex and Naturalistic Stimuli

Sensory cortices must flexibly adapt their operations to internal states and external requirements. Modulation of specific inhibitory interneurons may provide a network-level mechanism for adjustments on behaviourally relevant timescales. Understanding of the computational roles of such modulation has mostly been restricted to phasic optogenetic activation and short, transient stimuli. Here, we aimed to extend the understanding of modulation of cortical inhibition by using sustained, network-wide optogenetic activation of parvalbumin-positive interneurons in core auditory cortex to study modulation of responses to transient, sustained, and naturalistic stimuli. We found highly conserved spectral and temporal tuning, despite profoundly reduced overall network activity. This reduction was predominantly divisive, and consistent across simple, complex, and naturalistic stimuli. A recurrent network model with power-law input-output functions replicated our results. We conclude that modulation of parvalbumin-positive interneurons on timescales typical of more sustained neuromodulation may provide a means for robust divisive gain control conserving stimulus representations.

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bioRxiv2019

Hearing loss promotes schizophrenia-relevant brain and behavioral abnormalities in a mouse model of human 22q11.2 Deletion Syndrome

Hearing loss has been implicated as a risk factor for schizophrenia, but it is not known whether this association arises from common etiology, top-down influences (e.g., social isolation), bottom-up neurobiological mechanisms, or combinations of these factors. Patients with 22q11.2 Deletion Syndrome (22q11.2DS) have a 25-30% risk of developing schizophrenia, and also suffer frequent hearing loss. Here, we used the Df1/+ mouse model of 22q11.2DS to investigate the relationship between hearing loss and susceptibility to schizophrenia-relevant brain and behavioral abnormalities. Df1/+ mice have a multi-gene deletion analogous to the chromosomal microdeletion that causes human 22q11.2DS, and like human 22q11.2DS patients exhibit high rates of hearing loss arising primarily from susceptibility to middle ear inflammation. We found that hearing loss in Df1/+ mice affected schizophrenia-relevant endophenotypes, including electrophysiological measures of central auditory gain and behavioral measures of auditory sensorimotor gating. Moreover, PV+ inhibitory interneurons, another marker for schizophrenia pathology, were significantly reduced in density in auditory cortex but not secondary motor cortex of Df1/+ mice with hearing loss. These results reveal bottom-up neurobiological mechanisms through which peripheral hearing loss arising from the 22q11.2 deletion may promote the emergence of schizophrenia-relevant auditory brain and behavioral abnormalities, and also suggest a link between conductive hearing loss and reduced PV+ interneuron density in the auditory cortex. SIGNIFICANCE STATEMENTHearing loss is a known risk factor for schizophrenia. Deletion of chromosomal locus 22q11.2 is associated with both schizophrenia and hearing loss in humans. In the Df1/+ mouse model of human 22q11.2 Deletion Syndrome, we find that hearing loss shapes measures that are considered schizophrenia-relevant endophenotypes, such as central auditory gain and auditory sensorimotor gating. Moreover, we report a reduction in density of PV+ inhibitory interneurons in the auditory cortex, but not secondary motor cortex, of Df1/+ mice with hearing loss. These results suggest mechanisms through which hearing loss associated with the 22q11.2 deletion may promote emergence of schizophrenia-relevant auditory brain and behavioral abnormalities and indicate that conductive hearing loss may influence PV+ interneuron density in the auditory cortex.

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bioRxiv2018

An ultralight head-mounted camera system integrates detailed behavioral monitoring with multichannel electrophysiology in freely moving mice

Breakthroughs in understanding the neural basis of natural behavior require neural recording and intervention to be paired with high-fidelity multimodal behavioral monitoring. An extensive genetic toolkit for neural circuit dissection, and well-developed neural recording technology, make the mouse a powerful model organism for systems neuroscience. However, methods for high-bandwidth acquisition of behavioral signals in mice remain limited to fixed-position cameras and other off-animal devices, complicating the monitoring of animals freely engaged in natural behaviors. Here, we report the development of an ultralight head-mounted camera system combined with head-movement sensors to simultaneously monitor eye position, pupil dilation, whisking, and pinna movements along with head motion in unrestrained, freely behaving mice. The power of the combined technology is demonstrated by observations linking eye position to head orientation; whisking to non-tactile stimulation; and, in electrophysiological experiments, visual cortical activity to volitional head movements.

neuroscience↗