Biology subjects

Randlett, O.

Publications and source records attributed to Randlett, O..

4 recordsLinked to original sources

bioRxiv2018

Distributed plasticity drives visual habituation learning in larval zebrafish

Habituation is a simple form of learning, where animals learn to reduce their responses to repeated innocuous stimuli. While habituation is simple in concept, its exact implementation in the vertebrate brain is not clear. It could occur via a single plasticity event at a singular site in the circuit, or alternatively via more complex strategies that combine multiple mechanisms at various processing stages and sites. Here, we use a visual habituation assay in larval zebrafish, where larvae habituate to sudden reductions in illumination (dark flashes). We find that 8 different components of this response habituate, including the probability of executing a response, its latency, and measures of its magnitude. Through behavioural analyses, we find that habituation of these different behavioural components occurs independently of each other and at different locations in the circuit. Further, we use genetic and pharmacological manipulations to show that habituation of different behavioural components are molecularly distinct. These results are consistent with a model by which visual habituation originates from the combination of multiple independent processes, which each act to adapt specific components of behaviour. This may allow animals to more specifically habituate behaviour based on stimulus context or internal state.

neuroscience↗

bioRxiv2018

Phenotypic landscape of schizophrenia-associated genes defines candidates and their shared functions

Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologues of 132 human schizophrenia-associated genes and created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter cnnm2 and the translational repressor gigyf2, and revealed shared anatomical sites of activity differences, including the pallium, hypothalamus or tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor znf536 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.

genetics↗

bioRxiv2018

Brainwide organization of neuronal activity and convergent sensorimotor transformations in larval zebrafish

Simultaneous recordings of large populations of neurons in behaving animals allow detailed observation of high-dimensional, complex brain activity. However, experimental design and analysis approaches have not sufficiently evolved to fully realize the potential of these methods. We recorded whole-brain neuronal activity for larval zebrafish presented with a battery of visual stimuli while recording fictive motor output. These data were used to develop analysis methods including regression techniques that leverage trial-to-trial variations and unsupervised clustering techniques that organize neurons into functional groups. We used these methods to obtain brain-wide maps of concerted activity, which revealed both known and heretofore uncharacterized brain nuclei. We also identified neurons tuned to each stimulus type and motor output, and revealed nuclei in the anterior hindbrain that respond to multiple stimuli that elicit the same behavior. However, these convergent sensorimotor representations were only weakly correlated to instantaneous motor behavior, suggesting that they inform, but do not directly generate, behavioral output. These findings motivate a novel model of sensorimotor transformation spanning distinct behavioral contexts, within which these hindbrain convergence neurons likely constitute a key step.

neuroscience↗

bioRxiv2017

Whole-Brain Serial-Section Electron Microscopy In Larval Zebrafish

Investigating the dense meshwork of wires and synapses that form neuronal circuits is possible with the high resolution of serial-section electron microscopy (ssEM)1. However, the imaging scale required to comprehensively reconstruct axons and dendrites is more than 10 orders of magnitude smaller than the spatial extents occupied by networks of interconnected neurons2--some of which span nearly the entire brain. The difficulties in generating and handling data for relatively large volumes at nanoscale resolution has thus restricted all studies in vertebrates to neuron fragments, thereby hindering investigations of complete circuits. These efforts were transformed by recent advances in computing, sample handling, and imaging techniques1, but examining entire brains at high resolution remains a challenge. Here we present ssEM data for a complete 5.5 days post-fertilisation larval zebrafish brain. Our approach utilizes multiple rounds of targeted imaging at different scales to reduce acquisition time and data management. The resulting dataset can be analysed to reconstruct neuronal processes, allowing us to, for example, survey all the myelinated axons (the projectome). Further, our reconstructions enabled us to investigate the precise projections of neurons and their contralateral counterparts. In particular, we observed that myelinated axons of reticulospinal and lateral line afferent neurons exhibit remarkable bilateral symmetry. Additionally, we found that fasciculated reticulospinal axons maintain the same neighbour relations throughout the extent of their projections. Furthermore, we use the dataset to set the stage for whole-brain comparisons of structure and function by co-registering functional reference atlases and in vivo two-photon fluorescence microscopy data from the same specimen. We provide the complete dataset and reconstructions as an open-access resource for neurobiologists and others interested in the ultrastructure of the larval zebrafish.

neuroscience↗