Biology subjects

Heller, C. R.

Publications and source records attributed to Heller, C. R..

6 recordsLinked to original sources

bioRxiv2026

Usherin in the pineal gland: altered sleep in zebrafish models of Usher syndrome type 2a

Usher syndrome type 2A (USH2a), the most common form of hereditary deaf-blindness, is frequently accompanied by fatigue and poor sleep quality. As these sleep problems occur independently of visual decline, it is hypothesized that the USH2A-encoded protein usherin regulates sleep and circadian rhythmicity via an extra-retinal mechanism. Ush2a knockout zebrafish models were utilized to investigate this hypothesis. Immunohistochemical analysis demonstrated usherin localisation in pineal gland photoreceptor cells in wild-type larvae, alongside the USH2 complex proteins Adgrv1 and Whrna. Cross-species transcriptomic and proteomic analyses confirmed USH2A expression in all mammalian pineal gland tissues studied. Circadian clock gene expression was measured over 24 h and showed preserved oscillatory patterns in wild-type and mutant zebrafish. Ex vivo superfusion of pineal glands revealed sustained circadian melatonin release with comparable phase and period to controls, although potential differences in absolute melatonin levels could not be excluded. Despite intact clock gene expression and melatonin release in ush2a mutants, behavioural classification over 24-h recordings revealed altered sleep-wake behaviour: ush2a mutants displayed elevated daytime sleep and significantly prolonged and more variable sleep latency. The dissociation between intact molecular rhythms and abnormal sleep behaviour likely implicates that usherin plays a role in sleep-wake regulation independent of the circadian pacemaker and melatonin synthesis. These findings suggest a novel role of usherin in the pineal gland and establish a mechanistic link between usherin dysfunction and sleep disturbances, providing a biological basis for the fatigue and sleep problems reported in USH2a patients.

animal behavior and cognition↗

bioRxiv2023

Neural and behavioral organization of rapid eye movement sleep in zebrafish

Sleep is ubiquitous across the animal kingdom. However, the definition for sleep varies significantly across species. In organisms such as C. elegans, Drosophila, and zebrafish, sleep is classically defined as periods of locomotor quiescence with an increased arousal threshold1-6. In mammals, sleep is further subdivided into rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, but the evolutionary origin of these two sleep states remains unclear7-12. Using longitudinal, high-resolution imaging of naturalistic sleep-wake behavior, we find that the classical definition of larval zebrafish sleep encompasses two clearly distinct quiescent states, one with rapid eye movements (qREM) and one without rapid eye movements (qNREM). Remarkably, qREM states are maintained in congenitally blind larval zebrafish, suggesting that qREM emerged during vertebrate evolution not as a response to internally generated visual imagery (i.e., the "scanning hypothesis")13, but potentially as a strategy to maintain oculomotor stimulation during rest14. Lastly, using brain-wide imaging in freely swimming animals, we find that, in contrast to fixed point attractor models of sleep developed in invertebrates15, population-level activity during zebrafish qREM unfolds along smooth committed trajectories through state-space. This work suggests a significant rethinking of the behavioral and neural organization of sleep in early vertebrates and the emergence of REM during vertebrate evolution.

neuroscience↗

bioRxiv2023

Task-specific invariant representation in auditory cortex

Categorical sensory representations are critical for many behaviors, including speech perception. In the auditory system, categorical information is thought to arise hierarchically, becoming increasingly prominent in higher order cortical regions. The neural mechanisms that support this robust and flexible computation remain poorly understood. Here, we studied sound representations in primary and non-primary auditory cortex while animals engaged in a challenging sound discrimination task. Population-level decoding of simultaneously recorded single neurons revealed that task engagement caused categorical sound representations to emerge in non-primary auditory cortex. In primary auditory cortex, task engagement caused a general enhancement of sound decoding that was not specific to task-relevant categories. These findings are consistent with mixed selectivity models of neural disentanglement, in which early sensory regions build an overcomplete representation of the world and allow neurons in downstream brain regions to flexibly and selectively read out behaviorally relevant, categorical information.

neuroscience↗

bioRxiv2021

Dimensionality reduction for neural population decoding

Rapidly developing technology for large scale neural recordings has allowed researchers to measure the activity of hundreds to thousands of neurons at single cell resolution in vivo. Neural decoding analyses are a widely used tool used for investigating what information is represented in this complex, high-dimensional neural population activity. Most population decoding methods assume that correlated activity between neurons has been estimated accurately. In practice, this requires large amounts of data, both across observations and across neurons. Unfortunately, most experiments are fundamentally constrained by practical variables that limit the number of times the neural population can be observed under a single stimulus and/or behavior condition. Therefore, new analytical tools are required to study neural population coding while taking into account these limitations. Here, we present a simple and interpretable method for dimensionality reduction that allows neural decoding metrics to be calculated reliably, even when experimental trial numbers are limited. We illustrate the method using simulations and compare its performance to standard approaches for dimensionality reduction and decoding by applying it to single-unit electrophysiological data collected from auditory cortex.

neuroscience↗

bioRxiv2020

Selective effects of arousal on population coding of natural sounds in primary auditory cortex

The ability to discriminate between complex natural sounds is critical for survival. Changes in arousal and other aspects of behavioral state can impact the accuracy of sensory coding, affecting both the reliability of single neuron responses and the degree of correlated noise between neurons. However, it is unclear how these effects interact to influence coding of diverse natural stimuli. We recorded the spiking activity of neural populations in primary auditory cortex (A1) evoked by a large library of natural sounds while monitoring changes in pupil size as an index of arousal. Heightened arousal increased response magnitude and reduced noise correlations between neurons, improving coding accuracy on average. Rather than suppressing shared noise along all dimensions of neural activity, the change in noise correlations occurred via coherent, low-dimensional modulation of response variability in A1. The modulation targeted a different group of neurons from those undergoing changes in response magnitude. Thus, changes in response magnitude and correlation are mediated by distinct mechanisms. The degree to which these low-dimensional changes were aligned with the high-dimensional natural sound-evoked activity was variable, resulting in stimulus-dependent improvements in coding accuracy.

neuroscience↗

bioRxiv2020

Dissociation of task engagement and arousal effects in auditory cortex and midbrain

Both generalized arousal and engagement in a specific task influence sensory neural processing. To isolate effects of these state variables in the auditory system, we recorded single-unit activity from primary auditory cortex (A1) and inferior colliculus (IC) of ferrets during a tone detection task, while monitoring arousal via changes in pupil size. We used a generalized linear model to assess the influence of task engagement and pupil size on sound-evoked activity. In both areas, these two variables affected independent neural populations. Pupil size effects were more prominent in IC, while pupil and task engagement effects were equally likely in A1. Task engagement was correlated with larger pupil; thus, some apparent effects of task engagement should in fact be attributed to fluctuations in pupil size. These results indicate a hierarchy of auditory processing, where generalized arousal enhances activity in midbrain, and effects specific to task engagement become more prominent in cortex.

neuroscience↗