Biology subjects

Hindges, R.

Publications and source records attributed to Hindges, R..

7 recordsLinked to original sources

bioRxiv2026

Lateralized Tenm4 expression biases visual performance and modulates axonal growth and pre-synapse size in retinal ganglion cells

The precise wiring of neuronal connections is a striking feature of the central nervous system and is critical for correct brain function. During vertebrate visual development, retinal ganglion cells (RGCs) establish synaptic connections with postsynaptic cells in the optic tectum, a process that is in part conferred by cell adhesion molecules. However, a complete understanding of the retinotectal wiring mechanism is lacking. Here, we show that the synaptic adhesion molecule Teneurin-4 (Tenm4) is expressed by RGCs and their postsynaptic tectal cell targets in a left-right side-specific manner in zebrafish. Loss of tenm4 leads to defects in presynaptic structures in RGCs and further affects their axonal growth and arbor complexity. Functional assessment of RGC responses to visual stimuli showed a general increase in response amplitude in mutant animals. Visual behavioral analysis revealed a deficit with a strong left-right asymmetrical component in mutant larvae. Our findings demonstrate that tenm4 plays an important role in sensorimotor circuit assembly, extending to neural activities and visual acuity.

neuroscience↗

bioRxiv2026

Deficiency of the membrane androgen receptor ZIP9 alters brain zinc distribution, reproductive endocrinology, and female fertility

Zinc is an essential trace element involved in numerous biological processes, including cellular signalling, development, and reproduction. Zinc homeostasis is regulated by zinc transporters, yet the physiological roles of many transporters remain poorly understood in vivo. Here, we investigated the function of the zinc transporter ZIP9 (SLC39A9) using a zebrafish (Danio rerio) knockout model. Elemental imaging using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) revealed altered zinc distribution in zip9-deficient larvae. Synchrotron-based X-ray fluorescence (XRF) imaging further showed reduced zinc levels in the brain region of mutant zebrafish. Consistent with these observations, loss of zip9 was associated with altered expression of key neuroendocrine genes within the hypothalamic-pituitary-gonadal (HPG) axis. Zip9 mutant females exhibited disrupted ovarian follicle development, reduced spawning rates, and decreased egg production. In addition, embryos derived from zip9 mutant parents displayed reduced size, impaired early development, and decreased survival. Together, these findings identify ZIP9 as a regulator of zinc distribution in vivo and suggest that ZIP9-mediated zinc signalling contributes to reproductive regulation in zebrafish.

physiology↗

bioRxiv2026

Virtual reality exposes fine-scale alterations in behaviour following loss of the ADHD-linked gene adgrl3.1 in zebrafish

Zebrafish have been used a prominent model for high-throughput phenotypic screens of candidate risk gene mutations for several disorders. This also includes models for attention deficit/hyperactivity disorder (ADHD). Traditional behavioural tests, such as the forced light/dark assay, concentrate on basic locomotion measures. However, recently developed visually-driven locomotion assays, for example closed-loop systems using virtual reality, have allowed extraction of richer data on animal locomotion and decision-making under different sensory stimuli. Here, we have used such a system to assess the behaviour in adgrl3.1 mutant fish, an established model for ADHD. Our results show that mutants exhibit a higher baseline excitability and a lower threshold for initiating motor events, demonstrating that collecting behavioural responses in an interactive environment enables a more precise characterisation of ADHD-relevant phenotypes associated with adgrl3.1 disruption. More generally, we establish a scalable translational platform to screen gene-function relationships and possible therapeutic interventions, not only for ADHD but multiple neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Early visual experience elicits cellular and functional plasticity in the retina and alters behaviour

Our interaction with the surrounding environment shapes how our brain processes sensory information and drives adaptive behaviour. This plasticity allows the brain to rewire in response to specific sensory experiences. For instance, early manipulation of visual inputs profoundly impacts brain plasticity, which is crucial for functions like size perception, object recognition, and visuospatial processing. While neuronal plasticity has been detected in visual target structures such as the colliculus, thalamus, and cortex, it remains unclear if the retina, the primary sensory organ, undergoes significant plasticity. Here, we show that the zebrafish retina demonstrates pronounced plastic transformations in response to alterations of the visual environment during development, which ultimately modifies the detection of oriented visual stimuli. We demonstrate that orientation-selective amacrine cells undergo profound morphological changes in animals exposed to distinct visual environments during development. We further find that the functional orientation-selective output from the retina is altered in a manner consistent with the visual environment in which the animals are raised and that these changes are persistent. Finally, animals tested in a virtual reality system show that early exposure to different visual environments changes their innate preference for specifically oriented patterns. Our findings unveil a unique developmental form of sensory organ plasticity with continuing structural and functional consequences.

neuroscience↗

bioRxiv2024

Excitatory and inhibitory synapses form a tight subcellular balance along dendrites that decorrelates over development

A balance between excitation and inhibition is crucial for neurotypical brain function. Indeed, disruptions in this relationship are frequently associated with the pathophysiology of neurodevelopmental disorders. Nevertheless, how this balance is established during the dynamic period of neurodevelopment remains unexplored. Using multiple techniques, including in utero electroporation, electron microscopy and electrophysiology, we reveal a tight correlation in the distribution of excitatory and inhibitory synapses along dendrites of developing CA1 hippocampal neurons. This balance was present within short dendritic stretches (<20{micro}m), and surprisingly, was most pronounced during early development, sharply declining with maturity. The tight matching between excitation and inhibition was unexpected, as inhibitory synapses lacked an active zone when formed and exhibited compromised evoked release. We propose that inhibitory synapses form as a stabilising scaffold, to counterbalance growing excitation levels. This relationship diminishes over time, suggesting a critical role for a subcellular balance in early neuronal function and circuit formation.

neuroscience↗

bioRxiv2023

Alternative splicing controls teneurin-3 compact dimer formation for neuronalrecognition

Neuronal network formation is facilitated by recognition between synaptic cell adhesion molecules (CAMs) at the cell surface. Alternative splicing of CAMs provides additional specificity in forming neuronal connections. For the teneurin family of CAMs, alternative splicing of the EGF-repeats and NHL domain controls protein-protein interactions at the synapse. Here we present a 3.2 [A] cryo-EM structure of the compact dimeric ectodomain of teneurin-3 harbouring both splice inserts. This dimer is stabilised by an EGF8-ABD contact between subunits. Cryo-EM reconstructions of all four splice variants, together with SAXS and negative stain EM, reveal compacted dimers for each, with variant-specific dimeric arrangements. This results in specific trans-cellular interactions, as tested in cell clustering and stripe assays. The compact conformations provide a structural basis for teneurin homo- and heterophilic interactions. Altogether, our findings demonstrate how alternative splicing results in rearrangements of the dimeric subunits, influencing neuronal recognition and circuit wiring.

biochemistry↗

bioRxiv2023

A locomotion-based assay to measure prepulse inhibition in zebrafish larvae

Sensory gating, assessed using a prepulse inhibition assay (PPI), is a promising endophenotype of neuropsychiatric disorders that can be measured in larval zebrafish models. However, current PPI assays require high-speed cameras to capture rapid c-bend startle behaviours. In this study, we designed and employed a PPI paradigm that uses locomotion as read-out of startle responses. PPI percentage was measured at a maximum of 86% and this was reduced to 42% upon administration of an NMDA receptor antagonist, MK-801. This work provides the foundation for simpler and more accessible PPI assays using larval zebrafish to model key endophenotypes of neurodevelopmental disorders.

animal behavior and cognition↗