Biology subjects

Hunt, S.

Publications and source records attributed to Hunt, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Opposing influences of sensory and response history in larval zebrafish

Variability is a prominent feature of animal behavior across species. Despite highly controlled experimental conditions, the same individual often responds differently to repeated identical stimulation. Part of this variability can be explained by the sequence of previous sensory stimuli and decision-making events - the trial history. Most studies about trial history are limited to animals that have a cortex, such as rodents or primates, observed as they perform learned cognitive tasks. It is currently unknown whether trial history can shape the behavior of animals lacking cortical structures during untrained, naturalistic behaviors. Here, we address this question in larval zebrafish, performing the optomotor response, an innate sensorimotor behavior in which animals turn in the direction of whole-field visual motion. We observed that a substantial proportion of variability can be explained by recent stimulation and decision-making events, with influences lasting for tens of minutes. Intriguingly, sensory and response histories bias the current response in opposite directions - repulsive and attractive, respectively - analogous to what has been previously reported in humans and rodents. An integrator model operating across multiple timescales explains a considerable fraction of response variability based on trial history alone. Our findings demonstrate that history dependency in animal behavior is not an exclusive feature of higher-order cortical computation after learning, but that it reflects a fundamental and evolutionarily shared property of vertebrate sensorimotor systems. SIGNIFICANCE STATEMENTBehavioral variability is often attributed to noise in sensory and neural processing. We show instead that much of this variability can arise predictably from an animals recent sensory and response history. In freely swimming larval zebrafish performing an innate visual behavior, previous stimuli and responses exert opposing, long-lasting influences: sensory history biases behavior away from the past, whereas response history promotes repetition. Such trial-to-trial effects are increasingly recognized in cognitive neuroscience but, to our knowledge, have not previously been demonstrated in a nonmammalian vertebrate. Their presence in zebrafish, a model system offering brain-wide neural access and powerful molecular tools, creates new opportunities to identify potentially conserved circuit mechanisms underlying persistent sensorimotor computations. HIGHLIGHTSO_LIVisual motion and response histories have opposing influences on behavior C_LIO_LIStimulus history negatively biases response direction over tens of seconds C_LIO_LIAnimals tend to repeat responses across trials, a positive bias that slowly increases over minutes C_LIO_LIA deterministic model applied to experimental sessions explains considerable fractions of response variability C_LI

animal behavior and cognition↗

bioRxiv2026

Different modes of engagement with the nucleosome acidic patch yield distinct functional outcomes

The nucleosome acidic patch is a hub of coordinated engagement by proteins that regulate genomic function. Here we report that S. cerevisiae Dot5 contains an arginine-rich HMGN-like motif that mediates nucleosome acidic patch binding and is required for the cell growth, DNA repair and heterochromatin defects exhibited when the protein is overexpressed. The heterologous expression of camelid single chain antibodies to the nucleosome acidic patch confers a similar range of phenotypes, with the most severe observed when an arginine-anchor mode of binding analogous to many endogenous factors is employed. This highlights a delicate balance between nucleosome acidic patch interactors critical for normal cellular functions and dysregulated in disease.

molecular biology↗

bioRxiv2025

Discrete interneuron subsets participate in GluN1/GluN3A excitatory glycine receptor (eGlyR)-mediated regulation of hippocampal network activity throughout development and evolution.

Decades of studies implicating GluN3A N-methyl-D-aspartate receptor (NMDAR) subunits in physiological and pathological function have largely been interpreted through direct regulation of conventional glutamatergic NMDARs. However, emerging evidence indicates that GluN3A frequently assembles with GluN1 forming unconventional glutamate-insensitive NMDARs that operate as native excitatory glycine receptors (eGlyRs). Here we demonstrate that hippocampal somatostatin and neurogliaform interneurons (Sst-INs and NGFCs) express functional eGlyRs from early postnatal through adult ages. In the developing hippocampus eGlyR-mediated excitation of NGFCs with ambient glycine dramatically increases GABAergic tone, with consequences for the generation of giant depolarizing potentials (GDPs). In the mature hippocampus, eGlyR- mediated excitation of Sst-INs regulates sharp wave ripples (SWRs). Finally, we reveal evolutionary conservation of hippocampal Sst-IN eGlyRs and eGlyR- mediated SWR regulation in non-human primates confirming functional eGlyR availability for therapeutic potential in higher species. Our findings underscore that eGlyR mediated regulation of cell and circuit excitability through both cell autonomous and cell non-autonomous mechanisms must be considered to understand GluN3A roles in brain development, plasticity, and disease.

neuroscience↗

bioRxiv2025

A novel, evolutionarily conserved inhibitory circuit selectively regulates dentate gyrus mossy cell function.

The mammalian dentate gyrus contributes to mnemonic function by parsing similar events and places. The disparate activity patterns of mossy cells and granule cells is believed to enable this function yet the mechanisms that drive this circuit dynamic remain elusive. We identified a novel inhibitory interneuron subtype, characterized by VGluT3 expression, with overwhelming target selectivity for mossy cells while also revealing that CCK, PV, SOM and VIP interneurons preferentially innervate granule cells. Leveraging pharmacology and novel enhancer viruses, we find that this target-specific inhibitory innervation pattern is evolutionarily conserved in non-human primates and humans. In addition, in vivo chemogenetic manipulation of VGluT3+ interneurons selectively alters the activity and functional properties of mossy cells. These findings establish that mossy cells and granule cells have unique, evolutionarily conserved inhibitory innervation patterns and suggest selective inhibitory circuits may be necessary to maintain DG circuit dynamics and enable pattern separation across species.

neuroscience↗

bioRxiv2024

Control of odor sensation by light and cryptochrome in the Drosophila antenna

Olfaction is a sense employed by insects to differentiate safe from harmful food options, evaluate potential mates, and identify oviposition sites. Here, we found that the fruit fly, Drosophila melanogaster, responds differently to a set of repulsive odors depending on ambient light conditions. Ultraviolet (UV) or blue light reduces the behavioral aversion and electrophysiological responses of olfactory receptor neurons (ORNs) to certain repellent odors, such as benzaldehyde. We found that cryptochrome (cry) is strongly expressed in the antennal support cells that lie adjacent to ORNs, and mutation of cry eliminates the light-dependent reduction in aversion. Thus, these data demonstrate that support cells in an olfactory organ serve a sensory function as light receptor cells. It has been shown that light activation of Cry creates reactive oxygen species (ROS), and ROS activates the TRPA1 channel. We demonstrate that the TRPA1-C isoform is expressed and required in ORNs for benzaldehyde repulsion, and that TRPA1-C is activated in vitro by benzaldehyde. Overexpression of dual oxygenase, which generates hydrogen peroxide, reduced the aversion under dark conditions. Our data support the model that light-dependent creation of hydrogen peroxide persistently activates TRPA1-C. Consequently, the channel is no longer effectively activated by benzaldehyde. Since flies sleep much more at night, and begin feeding at dawn, we propose that the light-induced reduction in aversion to certain odors provides a mechanism to lower the barrier to feeding following the transition from night to day.

neuroscience↗

bioRxiv2024

Complex opioid driven modulation of glutamatergic and cholinergic neurotransmission in a GABAergic brain nucleus associated with emotion, reward and addiction.

The medial habenula (mHb)/interpeduncular nucleus (IPN) circuitry is resident to divergent molecular, neurochemical and cellular components which, in concert, perform computations to drive emotion, reward and addiction behaviors. Although housing one of the most prominent mu opioid receptor (mOR) expression levels in the brain, remarkably little is known as to how they impact mHb/IPN circuit function at the granular level. In this study, our systematic functional and pharmacogenetic analyses demonstrate that mOR activation attenuates glutamatergic signaling whilst producing an opposing potentiation of glutamatergic/cholinergic co-transmission mediated by mHb substance P and cholinergic neurons, respectively. Intriguingly, this latter non-canonical augmentation is developmentally regulated only emerging during later postnatal stages. In addition, we reveal that specific potassium channels act as a molecular brake on nicotinic receptor signaling in the IPN with the opioid mediated potentiation of this arm of neurotransmission being operational only following attenuation of Kv1 function. Thus, mORs play a complex role in shaping the salience of distinct afferent inputs and transmitter modalities that ultimately influences synaptic recruitment of downstream GABAergic IPN neurons. Together, these observations provide a framework for future investigations aimed at identifying the neural underpinnings of maladaptive behaviors that can emerge when opioids, including potent synthetic analogs such as fentanyl, modulate or hijack this circuitry during the vulnerable stages of adolescence and in adulthood.

neuroscience↗

bioRxiv2024

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate specific neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the telencephalic interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic interneurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

neuroscience↗

bioRxiv2024

Fiber-based Probes for Electrophysiology, Photometry, Optical and Electrical Stimulation, Drug Delivery, and Fast-Scan Cyclic Voltammetry In Vivo

Recording and modulation of neuronal activity enables the study of brain function in health and disease. While translational neuroscience relies on electrical recording and modulation techniques, mechanistic studies in rodent models leverage genetic precision of optical methods, such as optogenetics and imaging of fluorescent indicators. In addition to electrical signal transduction, neurons produce and receive diverse chemical signals which motivate tools to probe and modulate neurochemistry. Although the past decade has delivered a wealth of technologies for electrophysiology, optogenetics, chemical sensing, and optical recording, combining these modalities within a single platform remains challenging. This work leverages materials selection and convergence fiber drawing to permit neural recording, electrical stimulation, optogenetics, fiber photometry, drug and gene delivery, and voltammetric recording of neurotransmitters within individual fibers. Composed of polymers and non-magnetic carbon-based conductors, these fibers are compatible with magnetic resonance imaging, enabling concurrent stimulation and whole-brain monitoring. Their utility is demonstrated in studies of the mesolimbic reward pathway by simultaneously interfacing with the ventral tegmental area and nucleus accumbens in mice and characterizing the neurophysiological effects of a stimulant drug. This study highlights the potential of these fibers to probe electrical, optical, and chemical signaling across multiple brain regions in both mechanistic and translational studies.

neuroscience↗

bioRxiv2024

Long-read sequencing and structural variant characterization in 1,019 samples from the 1000 Genomes Project

Structural variants (SVs) contribute significantly to human genetic diversity and disease1-4. Previously, SVs have remained incompletely resolved by population genomics, with short-read sequencing facing limitations in capturing the whole spectrum of SVs at nucleotide resolution5-7. Here we leveraged nanopore sequencing8 to construct an intermediate coverage resource of 1,019 long-read genomes sampled within 26 human populations from the 1000 Genomes Project. By integrating linear and graph-based approaches for SV analysis via pangenome graph-augmentation, we uncover 167,291 sequence-resolved SVs in these samples, considerably advancing SV characterization compared to population-wide short-read sequencing studies3,4. Our analysis details diverse SV classes--deletions, duplications, insertions, and inversions--at population-scale. LINE-1 and SVA retrotransposition activities frequently mediate transductions9,10 of unique sequences, with both mobile element classes transducing sequences at either the 3'- or 5'-end, depending on the source element locus. Furthermore, analyses of SV breakpoint junctions suggest a continuum of homology-mediated rearrangement processes are integral to SV formation, and highlight evidence for SV recurrence involving repeat sequences. Our open-access dataset underscores the transformative impact of long-read sequencing in advancing the characterisation of polymorphic genomic architectures, and provides a resource for guiding variant prioritisation in future long-read sequencing-based disease studies.

genomics↗

bioRxiv2024

Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development

Within the adult rodent hippocampus, opioids suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting local micro-circuits. However, it is unknown if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in hippocampus proper but not primary neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when PV-INs and opioids were found to regulate early population activity. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

neuroscience↗

bioRxiv2023

Vault particles are common contaminants of extracellular vesicle preparations

Extracellular vesicles (EVs) may contain a variety of molecular cargo including proteins and nucleic acids. Vault particle components have been repeatedly reported in the literature as EV cargo. Here, we demonstrated by small RNA sequencing that vault RNA (vtRNA) were highly abundant in EV pellets enriched by differential centrifugation. EVs were prepared by commonly used enrichment methods and biochemical assays used to determine whether vault particle components were bona fide EV cargo. EVs were isolated by differential centrifugation, size exclusion chromatography (SEC) and Dynabead immunocapture. RNase and proteinase treatment of EV preparations demonstrated that most vtRNA and major vault protein (MVP) were not enclosed and protected within the EV membrane. Vault-like particles were visualised in differential centrifugation pellets by cryo-transmission electron microscopy. EVs enriched by size exclusion chromatography and those isolated by immunocapture post-ultracentrifugation showed co-purification of MVP, whereas EVs isolated by direct immunocapture from conditioned medium were MVP-negative. Taken together, commonly used isolation techniques, such as differential centrifugation and SEC, can lead to contamination of EVs with vault particles. The current study highlights the importance of determining the topology of putative EV-associated components to determine if they are EV cargo or contaminants that have been co-purified.

cell biology↗

bioRxiv2023

Mobilisation and analyses of publicly available SARS-CoV-2 data for pandemic responses

The COVID-19 pandemic has seen large-scale pathogen genomic sequencing efforts, becoming part of the toolbox for surveillance and epidemic research. This resulted in an unprecedented level of data sharing to open repositories, which has actively supported the identification of SARS-CoV-2 structure, molecular interactions, mutations and variants, and facilitated vaccine development and drug reuse studies and design. The European COVID-19 Data Platform was launched to support this data sharing, and has resulted in the deposition of several million SARS-CoV-2 raw reads. In this paper we describe (1) open data sharing, (2) tools for submission, analysis, visualisation and data claiming (e.g. ORCiD), (3) the systematic analysis of these datasets, at scale via the SARS-CoV-2 Data Hubs as well as (4) lessons learned. As a component of the Platform, the SARS-CoV-2 Data Hubs enabled the extension and set up of infrastructure that we intend to use more widely in the future for pathogen surveillance and pandemic preparedness.

bioinformatics↗

bioRxiv2021

A distributed dopamine-gated circuit underpins reproductive state-dependent behavior in Drosophila females

Motherhood induces a drastic, sometimes long-lasting, change in internal state and behavior in most female animals. How a change in reproductive state or the discrete event of mating modulates specific female behaviors is still incompletely understood. Using calcium imaging of the whole brain of Drosophila females, we find that mating does not induce a global change in brain activity. Instead, mating modulates the pheromone response of dopaminergic neurons innervating the flys learning and memory center, the mushroom body (MB). Using the mating-induced increased attraction to the odor of important nutrients, polyamines, we show that disruption of the female flys ability to smell, for instance the pheromone cVA, during mating leads to a reduction in polyamine preference for days later indicating that the odor environment at mating lastingly influences female perception and choice behavior. Moreover, dopaminergic neurons including innervation of the {beta}1 compartment are sufficient to replace mating experience in virgin females inducing the lasting behavioral increase in polyamine preference. We further show that MB output neurons (MBON) of the {beta}1 compartment are activated by pheromone odor and their activity during mating bidirectionally modulates preference behavior in mated and virgin females. Their activity is not required, however, for the expression of polyamine attraction. Instead, inhibition of another type of MBON innervating the {beta}2 compartment enables expression of high polyamine attraction. In addition, the response of a lateral horn (LH) neuron, AD1b2, which output is required for the expression of polyamine attraction, shows a modulated polyamine response after mating. Taken together, our data in the fly suggests that mating-related sensory experience regulates female odor perception and expression of choice behavior through a dopamine-gated learning circuit.

neuroscience↗

bioRxiv2021

Expansion of cortical layers 2 and 3 in human left temporal cortex associates with verbal intelligence

The expansion of supragranular cortical layers is thought to have enabled evolutionary development of human cognition and language. However, whether increased volume of supragranular cortical layers can actually support greater cognitive and language abilities in humans has not been demonstrated. Here, we find that subjects with higher general and verbal intelligence test (VIQ) scores have selectively expanded layers 2 and 3 only in the left temporal cortex, an area associated with language and IQ-test performance. This expansion is accompanied by lower neuron densities and larger cell-body size. Furthermore, individuals with higher VIQ scores had neurons with larger dendritic trees in left temporal cortex, potentially impacting their function. Indeed, neurons of subjects with higher VIQ scores had faster action potential upstroke kinetics, which improves information processing. These data show that expansion of supragranular layer volume, cortical and cellular micro-architecture and function are associated with improved verbal mental ability in human subjects.

neuroscience↗

bioRxiv2021

Neuronal morphology and physiology, functional brain networks and memory in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown. We leverage a unique cross-scale dataset of therapy-resistant TLE patients, who underwent fMRI, MEG and/or neuropsychological testing before neurosurgery. fMRI and MEG underwent atlas-based connectivity analyses. Functional network centrality of the lateral middle temporal gyrus, part of the DMN, was used as a measure of local network integration. Subsequently, non-pathological cortical tissue from this region was used for single cell morphological and electrophysiological patch-clamp analysis, assessing integration in terms of total dendritic length and action potential rise speed. As could be hypothesized, greater network centrality related to better memory performance. Moreover, greater network centrality correlated with more integrative properties at the cellular level across patients. We conclude that individual differences in cognitively relevant functional network integration of a DMN region are mirrored by differences in cellular integrative properties of this region in TLE patients. These findings connect previously separate scales of investigation, increasing translational insight into focal pathology and large-scale network disturbances in TLE.

neuroscience↗

bioRxiv2021

The GA4GH Variation Representation Specification (VRS): a Computational Framework for the Precise Representation and Federated Identification of Molecular Variation

Maximizing the personal, public, research, and clinical value of genomic information will require that clinicians, researchers, and testing laboratories exchange genetic variation data reliably. Developed by a partnership among national information resource providers, public initiatives, and diagnostic testing laboratories under the auspices of the Global Alliance for Genomics and Health (GA4GH), the Variation Representation Specification (VRS, pronounced "verse") is an extensible framework for the semantically precise and computable representation of variation that complements contemporary human-readable and flat file standards for variation representation. VRS objects are designed to be semantically precise representations of variation, and leverage this design to enable unique, federated identification of molecular variation. We describe the components of this framework, including the terminology and information model, schema, data sharing conventions, and a reference implementation, each of which is intended to be broadly useful and freely available for community use. The specification, documentation, examples, and community links are available at https://vrs.ga4gh.org/.

bioinformatics↗

bioRxiv2020

Transarterial embolization modulates the immune response within target and non-target hepatocellular carcinomas.

Recent successes in the field of immuno-oncology have generated considerable interest in the investigation of approaches that combine standard of care treatments with immunotherapies. Transarterial embolization (TAE) represents an attractive candidate for this approach given the potential for immune system stimulation, however little is known about the influence of TAE on the tumor immunoenvironment. The purpose of this study was to perform a cellular analysis of tumor infiltrating lymphocytes (TILs) and PD-L1 expression following TAE in a translational rat model of hepatocellular carcinoma (HCC) and to identify factors that influence this response. We show that TAE causes dynamic changes in immune cell populations, with variable increases in CD3, CD4, and CD8 cells within embolized tumors over time. We also show that TAE alters the immunobiology of distant, non-target tumors as demonstrated by an increased number of CD4, CD8, and Foxp3+ cells within the intratumoral compartment of non-target tumors. We demonstrate that, in response to TAE, tumor cells up-regulate expression of PD-L1. Finally, we demonstrate marked differences in terms of the foreign body reactions induced by two commonly used embolic particles, and show changes in lymphocyte and macrophage recruitment that depend on the type of embolic particles and their propensity to extravasate beyond the vasculature and into the tumor parenchyma. These findings hold important implications for the on-going development of novel therapeutic strategies combining locoregional therapy with immunomodulators, as well as for the development of techniques and materials that can further leverage the unique modulation of the tumor immune microenvironment.

immunology↗

bioRxiv2020

Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance to human circuit function. In this study, we focus on neurogliaform cells, a specialized form of neuron that possess physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms relevant for human cognitive processing and behavior.

neuroscience↗