Biology subjects

Goulding, M.

Publications and source records attributed to Goulding, M..

6 recordsLinked to original sources

bioRxiv2025

Age-related sensory dysfunction reconfigures the spinal circuitry for touch, itch and pain

Sensory dysfunction during aging results in sharp increases in the incidence of chronic itch and pain, which counterintuitively are associated with reduced sensitivity to light touch. While age-related changes in peripheral mechanosensory transmission have been described, the contribution central mechanisms make to altered itch and pain responses remains largely unknown. Here, we show that signalling from cutaneous touch receptors is essential for maintaining the cellular composition of the central somatosensory circuits that process itch and pain information in adult mice. In particular, the loss of excitatory signalling from Merkel cells during aging causes the degeneration of subsets of molecularly defined inhibitory and excitatory neurons in the dorsal spinal cord, including inhibitory neurons that express the neuropeptide NPY. Our demonstration that the activity-dependent loss of inhibitory NPY neurons drives itch and pain hypersensitivity in old animals reveals the mechanism by which aging reconfigures the central neuronal circuits that sense touch, itch and pain.

neuroscience↗

bioRxiv2025

The spinal premotor network driving scratching flexor and extensor alternation

Rhythmic motor behaviors are generated by neural networks termed central pattern generators (CPGs). Although locomotor CPGs have been extensively characterized, it remains unknown how the neuronal populations composing them interact to generate adaptive rhythms. We explored the non-linear cooperation dynamics among the three main populations of ipsilaterally projecting spinal CPG neurons - V1, V2a, V2b neurons - in scratch reflex rhythmogenesis. Ablation of all three neuronal subtypes reduced the oscillation frequency. Activation of excitatory V2a neurons enhanced the oscillation frequency, while activating inhibitory V1 neurons caused atonia. These findings required the development of a novel neuromechanical model that consists of flexor and extensor modules coupled via inhibition, in which rhythm in each module is generated by self-bursting excitatory populations and accelerated by intra-module inhibition. Inter-module inhibition coordinates the phases of flexor and extensor activity and slows the oscillations, while facilitation mechanisms in excitatory neurons explain the V2a activation-driven increase in frequency.

neuroscience↗

bioRxiv2023

A spinal synergy of excitatory and inhibitory neurons coordinates ipsilateral body movements

Innate and goal-directed movements require a high-degree of trunk and appendicular muscle coordination to preserve body stability while ensuring the correct execution of the motor action. The spinal neural circuits underlying motor execution and postural stability are finely modulated by propriospinal, sensory and descending feedback, yet how distinct spinal neuron populations cooperate to control body stability and limb coordination remains unclear. Here, we identified a spinal microcircuit composed of V2 lineage-derived excitatory (V2a) and inhibitory (V2b) neurons that together coordinate ipsilateral body movements during locomotion. Inactivation of the entire V2 neuron lineage does not impair intralimb coordination but destabilizes body balance and ipsilateral limb coupling, causing mice to adopt a compensatory festinating gait and be unable to execute skilled locomotor tasks. Taken together our data suggest that during locomotion the excitatory V2a and inhibitory V2b neurons act antagonistically to control intralimb coordination, and synergistically to coordinate forelimb and hindlimb movements. Thus, we suggest a new circuit architecture, by which neurons with distinct neurotransmitter identities employ a dual-mode of operation, exerting either synergistic or opposing functions to control different facets of the same motor behavior.

neuroscience↗

bioRxiv2023

Myomatrix arrays for high-definition muscle recording

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous systems actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous systems motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

neuroscience↗

bioRxiv2020

Unified neural pathways that gate affective pain and multisensory innate threat signals to the amygdala

Perception of aversive sensory stimuli such as pain and innate threat cues is essential for animal survival. The amygdala is critical for aversive sensory perception, and it has been suggested that multiple parallel pathways independently relay aversive cues from each sensory modality to the amygdala. However, a convergent pathway that relays multisensory aversive cues to the amygdala has not been identified. Here, we report that neurons expressing calcitonin gene-related peptide (CGRP) in the parvocellular subparafasicular thalamic nucleus (SPFp) are necessary and sufficient for affective-motivational pain perception by forming a spino-thalamo-amygdaloid pain pathway. In addition, we find that this thalamic CGRP pain pathway, together with well-known parabrachio-amygdaloid CGRP pain pathway, is critical for the perception of multisensory innate threat cues. The discovery of unified pathways that collectively gate aversive sensory stimuli from all sensory modalities may provide critical circuit-based insights for developing therapeutic interventions for affective pain- and innate fear-related disorders.

neuroscience↗

bioRxiv2020

Phox2a defines a developmental origin of the anterolateral system in mice and humans

Anterolateral system neurons relay pain, itch and temperature information from the spinal cord to pain-related brain regions, but the differentiation of these neurons and their specific contribution to pain perception remain poorly defined. Here, we show that virtually all mouse spinal neurons that embryonically express the autonomic system-associated Paired-like homeobox 2A (Phox2a) transcription factor innervate nociceptive brain targets, including the parabrachial nucleus and the thalamus. We define Phox2a anterolateral system neuron birth order, migration and differentiation, and uncover an essential role for Phox2a in the development of relay of nociceptive signals from the spinal cord to the brain. Finally, we also demonstrate that the molecular identity of Phox2a neurons is conserved in the human foetal spinal cord. The developmental expression of Phox2a as a uniting feature of anterolateral system neurons suggests a link between nociception and autonomic nervous system function.

neuroscience↗