Biology subjects

O'Neill, N.

Publications and source records attributed to O'Neill, N..

4 recordsLinked to original sources

bioRxiv2023

Reusable, flexible, and lightweight chronic implants for Neuropixels probes

Electrophysiology has proven invaluable to record neural activity, and the development of Neuropixels probes dramatically increased the number of recorded neurons. These probes are often implanted acutely, but acute recordings cannot be performed in freely moving animals and the recorded neurons cannot be tracked across days. To study key behaviors such as navigation, learning, and memory formation, the probes must be implanted chronically. An ideal chronic implant should (1) allow stable recordings of neurons for weeks; (2) allow reuse of the probes after explantation; (3) be light enough for use in mice. Here, we present the "Apollo Implant", an open-source and editable device that meets these criteria and accommodates up to two Neuropixels 1.0 or 2.0 probes. The implant comprises a "payload" module which is attached to the probe and is recoverable, and a "docking" module which is cemented to the skull. The design is adjustable, making it easy to change the distance between probes, the angle of insertion, and the depth of insertion. We tested the implant across eight labs in head-fixed mice, freely moving mice, and freely moving rats. The number of neurons recorded across days was stable, even after repeated implantations of the same probe. The Apollo implant provides an inexpensive, lightweight, and flexible solution for reusable chronic Neuropixels recordings.

neuroscience↗

bioRxiv2022

Developmental instability of CA1 pyramidal cells in Dravet Syndrome

Dravet Syndrome (DS) is mostly caused by heterozygous loss-of-function mutations in the voltage-gated sodium channel SCN1A (Nav1.1), thought to result in severe epilepsy and neurodevelopmental impairment due to reduced interneuron excitability. Recent studies in mouse models suggest that an "interneuronopathy" alone does not completely explain all the cellular and network impairments seen in DS. Here, we investigated the development of the intrinsic, synaptic, and network properties of CA1 pyramidal cells in a DS model prior to the appearance of overt seizures. We report that CA1 pyramidal cell development is disrupted by loss of Scn1a, and propose that this is explained by a period of reduced intrinsic excitability in early postnatal life, during which Scn1a is normally expressed in hippocampal pyramidal cells. We also use a novel ex vivo model of homeostatic plasticity to show an instability in homeostatic response during DS epileptogenesis. This study provides evidence for an important role of Scn1a haploinsufficiency in pyramidal cells in the pathophysiology of DS.

neuroscience↗

bioRxiv2020

Extracellular GABA waves regulate coincidence detection in excitatory circuits

Coincidence detection of excitatory inputs by principal neurons underpins the rules of signal integration and Hebbian plasticity in the brain. In the hippocampal circuitry, detection fidelity is thought to depend on the GABAergic synaptic input through a feed-forward inhibitory circuit also involving the hyperpolarization-activated Ih current. However, afferent connections often bypass feed-forward circuitry, suggesting that a different GABAergic mechanism might control coincidence detection in such cases. To test whether fluctuations in the extracellular GABA concentration [GABA] could play a regulatory role here, we use a GABA sniffer patch in acute hippocampal slices of the rat and document strong dependence of [GABA] on network activity. We find that blocking GABAergic signalling strongly reduces the coincidence detection window of direct excitatory inputs to pyramidal cells whereas increasing [GABA] through GABA uptake blockade expands it. The underlying mechanism involves membrane-shunting tonic GABAA receptor current; it does not have to rely on Ih but depends strongly on the neuronal GABA transporter GAT-1. We use dendrite-soma dual patch-clamp recordings to show that the strong effect of membrane shunting on coincidence detection relies on nonlinear amplification of changes in the decay of dendritic synaptic currents when they reach the soma. Our results suggest that, by dynamically regulating extracellular GABA, brain network activity can optimise signal integration rules in local excitatory circuits.

neuroscience↗

bioRxiv2020

Pro-inflammatory cytokines drive deregulation of potassium channel expression in primary synovial fibroblasts

The synovium secretes synovial fluid, but is also richly innervated with nociceptors and acts as a gateway between avascular joint tissues and the circulatory system. Resident fibroblast-like synoviocytes (FLS) calcium-activated potassium channels (KCa) change in activity in arthritis models and this correlates with FLS activation. ObjectiveTo investigate this activation in an in vitro model of inflammatory arthritis; 72hr treatment with cytokines TNF and IL1{beta}. MethodsFLS cells were isolated from rat synovial membranes. We analysed global changes in FLS mRNA by RNA-sequencing and then focused on FLS ion channels genes and corresponding FLS electrophysiological phenotype, finally modelling data with Ingenuity Pathway Analysis (IPA) and MATLAB. ResultsIPA showed significant activation of inflammatory, osteoarthritic and calcium signalling canonical pathways by cytokines, and we identified ~200 channel gene transcripts. The large KCa (BK) channel consists of the pore forming Kcnma1 together with {beta}-subunits. Following cytokine treatment, a significant increase in Kcnma1 RNA abundance was detected by qPCR and changes in several ion channels were detected by RNA-sequencing, including a loss of BK channel {beta}-subunit expression Kcnmb1/2 and increase in Kcnmb3. In electrophysiological experiments, there was a decrease in overall current density at 20mV without change in chord conductance at this potential. ConclusionTNF and IL1{beta} treatment of FLS in vitro recapitulated several common features of inflammatory arthritis at the transcriptomic level, including increase in Kcnma1 and Kcnmb3 gene expression.

bioinformatics↗