Biology subjects

Duguid, I.

Publications and source records attributed to Duguid, I..

9 recordsLinked to original sources

bioRxiv2026

Corticospinal neuron subpopulations with opposing dynamics converge to shape spinal interneuron computations

Corticospinal neuron (CSN) activation plays a crucial role in orchestrating goal-directed actions, but the functional role of reduced CSN output, a feature conserved across species, remains unknown. By combining population imaging, projection mapping, and modelling in mice performing a Go/NoGo lever push task, we reveal that distinct corticospinal neuron subpopulations with opposing dynamics (i.e. increased or decreased activity) are selectively associated with skilled movement execution. Both activity profiles are observed throughout CSN somatodendritic compartments and are spatially organized, with increased activity concentrated in upper layer 5B and decreased activity localized to deeper subregions. Notably, single neuron projection mapping revealed that opposing CSN signals converge onto shared spinal interneurons, while modelling showed that reduced CSN output drives subtractive modulation of spinal interneuron input-output transformations, avoiding output saturation and enabling flexible scaling of output firing rates. These findings redefine corticospinal function by demonstrating that reduced output in a subpopulation of CSNs is critical for shaping spinal cord computations during skilled movement execution.

neuroscience↗

bioRxiv2026

Thalamic input drives co-timed excitation and inhibition to suppress cortical neuronal variability during movement initiation

Cortical activity is inherently dynamic, with ongoing fluctuations introducing variability into sensory-to-motor transformations. During movement initiation, neural variability in the motor cortex is sharply reduced, or "quenched," a general phenomenon thought to ensure reliable population responses across cortical areas. However, the synaptic and circuit-level basis for this reduction in neural variability remains unclear. Here, we show that excitatory and inhibitory neurons in layer 5B of mouse motor cortex are co-activated during movement initiation in a cued forelimb push task. Co-timed excitation and inhibition drive pyramidal neuron membrane potential (Vm) trajectories towards the compound synaptic reversal potential, stabilizing the Vm and reducing trial-by-trial variability. Gain- and loss-of-function experiments demonstrate that thalamocortical input is critical for the coordinated recruitment of both excitation and inhibition and variability quenching at the cellular level, while also driving a cortical network state permissive for the expression of reproducible output dynamics. Our findings uncover a simple yet fundamental feedforward mechanism where thalamic input drives neural variability quenching to ensure reliable, structured population dynamics during movement initiation.

neuroscience↗

bioRxiv2025

RatDISCO, a tissue clearing and immunolabelling protocol for large rat brains.

RatDISCO is a simple, cost-effective, and reproducible tissue-clearing protocol optimised for immunolabeling in adult rat brains. It enables robust detection of diverse neuronal subtypes, glial populations, and vasculature, overcoming key limitations in antibody penetration and optical transparency. It is compatible with virally labelled-and transgenic mice, as well as human-derived brain organoids, highlighting its versatility across species and models. Functionally, it enables the detection of activity-dependent markers after behaviour, verified in a rat model of neurodevelopmental disorders, the Fragile X syndrome. These findings highlight RatDISCO as a broadly applicable tool for investigating neuroanatomical and functional alterations in rat models of disorders. HighlightsO_LIOptimised for immunolabeling in adult rat brains C_LIO_LIEnables detection of neurons, glial cells, and vasculature C_LIO_LIAchieves high tissue transparency without requiring specialised equipment. C_LIO_LICompatible with virally labelled mice and human brain organoids C_LIO_LIFacilitates mapping of activity-dependent markers in rat models of neurodevelopmental disorders C_LI

neuroscience↗

bioRxiv2024

Typical development of synaptic and neuronal properties can proceed without microglia

Brain-resident macrophages, microglia, have been proposed to play an active role in synaptic refinement and maturation, influencing plasticity and circuit-level connectivity. Here we show that a variety of neurodevelopmental processes previously attributed to microglia can proceed without them. Using a genetically modified mouse which lacks microglia (Csf1r{Delta}FIRE/{Delta}FIRE) we find that intrinsic properties, synapse number and synaptic maturation are largely normal in the hippocampal CA1 region and somatosensory cortex at stages where microglia have been implicated. Seizure susceptibility and hippocampal-prefrontal cortex coherence in awake behaving animals, processes disrupted in mice deficient in microglia-enriched genes, are also normal. Similarly, eye-specific segregation of inputs into the lateral geniculate nucleus proceeds normally in the absence of microglia. Single cell/nucleus transcriptomic analyses of neurons and astrocytes did not uncover any substantial perturbation due to microglial absence. Thus, the brain possesses remarkable adaptability to execute developmental synaptic refinement, maturation and connectivity in the absence of microglia.

neuroscience↗

bioRxiv2023

A cranial implant for stabilizing whole-cell patch-clamp recordings in behaving rodents

BackgroundIn vivo patch-clamp recording techniques provide access to the sub- and suprathreshold membrane potential dynamics of individual neurons during behavior. However, maintaining recording stability throughout behavior is a significant challenge, and while methods for head restraint are commonly used to enhance stability, behaviorally related brain movement relative to the skull can severely impact the success rate and duration of whole-cell patch-clamp recordings. New methodWe developed a low-cost, biocompatible, and 3D-printable cranial implant capable of locally stabilizing brain movement, while permitting equivalent access to the brain when compared to a conventional craniotomy. ResultsExperiments in head-restrained behaving mice demonstrate that the cranial implant can reliably reduce the amplitude and speed of brain displacements, significantly improving the success rate of recordings across repeated bouts of motor behavior. Comparison with existing methodsOur solution offers an improvement on currently available strategies for brain stabilization. Due to its small size, the implant can be retrofitted to most in vivo electrophysiology recording setups, providing a low cost, easily implementable solution for increasing intracellular recording stability in vivo. ConclusionsBy facilitating stable whole-cell patch-clamp recordings in vivo, biocompatible 3D printed implants should accelerate the investigation of single neuron computations underlying behavior.

neuroscience↗

bioRxiv2022

Visiomode: an open-source platform for building rodent touchscreen-based behavioral assays

BackgroundTouchscreen-based behavioral assays provide a robust method for assessing cognitive behavior in rodents, offering great flexibility and translational potential. The development of touchscreen assays presents a significant programming and mechanical engineering challenge, where commercial solutions can be prohibitively expensive and open-source solutions are underdeveloped, with limited adaptability. New methodHere, we present Visiomode (www.visiomode.org), an open-source platform for building rodent touchscreen-based behavioral tasks. Visiomode leverages the inherent flexibility of touchscreens to offer a simple yet adaptable software and hardware platform. The platform is built on the Raspberry Pi computer combining a web-based interface and powerful plug-in system with an operant chamber that can be adapted to generate a wide range of behavioral tasks. ResultsAs a proof of concept, we use Visiomode to build both simple stimulus-response and more complex visual discrimination tasks, showing that mice display rapid sensorimotor learning including switching between different motor responses (i.e., nose poke versus reaching). Comparison with existing methodsCommercial solutions are the go to for rodent touchscreen behaviors, but the associated costs can be prohibitive, limiting their uptake by the wider neuroscience community. While several open-source solutions have been developed, efforts so far have focused on reducing the cost, rather than promoting ease of use and adaptability. Visiomode addresses these unmet needs providing a low-cost, extensible platform for creating touchscreen tasks. ConclusionsDeveloping an open-source, rapidly scalable and low-cost platform for building touchscreen-based behavioral assays should increase uptake across the science community and accelerate the investigation of cognition, decision-making and sensorimotor behaviors both in health and disease.

neuroscience↗

bioRxiv2022

Multiscale model of primary motor cortex circuits reproduces in vivo cell type-specific dynamics associated with behavior

Understanding cortical function requires studying multiple scales: molecular, cellular, circuit and behavior. We developed a biophysically detailed multiscale model of mouse primary motor cortex (M1) with over 10,000 neurons and 30 million synapses. Neuron types, densities, spatial distributions, morphologies, biophysics, connectivity and dendritic synapse locations were tightly constrained by experimental data. The model includes long-range inputs from 7 thalamic and cortical regions, as well as noradrenergic inputs from locus coeruleus. Connectivity depended on cell class and cortical depth at sublaminar resolution. The model accurately predicted in vivo layer- and cell type-specific responses (firing rates and LFP) associated with behavioral states (quiet wakefulness and movement) and experimental manipulations (noradrenaline receptor blocking and thalamus inactivation). It also enabled evaluation of multiple mechanistic hypotheses underlying the observed activity. This quantitative theoretical framework can be used to integrate and interpret M1 experimental data and sheds light on the cell type-specific multiscale dynamics associated with a range of experimental conditions and behaviors.

neuroscience↗

bioRxiv2020

Dense movement with embedded sparse action-type representations in the output layer of motor cortex

Motor cortex generates descending output necessary for executing a wide range of limb movements. Although movement-related activity has been described throughout motor cortex, the spatiotemporal organization of movement-specific signaling in deep layers remains largely unknown. Here, we recorded layer 5B population dynamics in the caudal forelimb area of motor cortex while mice performed a forelimb push/pull task and found that most neurons show movement-invariant responses, with a minority displaying movement specificity. Cell-type-specific imaging identified that movement-invariant responses dominated pyramidal tract (PT) neuron activity, with a small subpopulation representing movement type, whereas a larger proportion of intratelencephalic (IT) neurons displayed movement-specific signaling. The proportion of IT neurons decoding movement-type peaked prior to movement initiation, while for PT neurons this occurred during movement execution. Our data suggest that layer 5B population dynamics largely reflect movement-invariant signaling, with information related to movement-type being differentially routed through relatively small, distributed subpopulations of projection neurons.

neuroscience↗

bioRxiv2019

Cerebellar-recipient motor thalamus drives behavioral context-specific movement initiation

To initiate goal-directed behavior, animals must transform sensory cues into motor commands that generate appropriately timed actions. Sensorimotor transformations along the cerebellar-thalamocortical pathway are thought to shape motor cortical output and movement timing, but whether this pathway initiates goal-directed movement remains poorly understood. Here, we recorded and perturbed activity in cerebellar-recipient regions of motor thalamus (dentate / interpositus nucleus-recipient regions, MThDN/IPN) and primary motor cortex (M1) in mice trained to execute a cued forelimb lever push task for reward. MThDN/IPN population responses were dominated by a time-locked increase in activity immediately prior to movement that was temporally uncoupled from cue presentation, providing a fixed latency feedforward motor timing signal to M1FL. Blocking MThDN/IPN output suppressed cued movement initiation. Stimulating the MThDN/IPN thalamocortical pathway in the absence of the cue recapitulated cue-evoked M1 membrane potential dynamics and forelimb behavior in the learned behavioral context, but generated semi-random movements in an altered behavioral context. Thus, cerebellar-recipient motor thalamocortical input to M1 is indispensable for the generation of motor commands that initiate goal-directed movement, refining our understanding of how the cerebellar-thalamocortical pathway contributes to movement timing.

neuroscience↗