Biology subjects

Whelan, P. J.

Publications and source records attributed to Whelan, P. J..

4 recordsLinked to original sources

bioRxiv2026

The role of Fragile X in the control of vertebrate spinal cord networks

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the leading monogenic cause of autism, resulting from mutations in the Fmr1 gene. While extensive research points to widespread circuit hyperexcitability across cortical and subcortical circuits, the contribution of the spinal cord circuits in the motor phenotypes associated with FXS remains largely unexplored. Given that Fmr1 is expressed in both dorsal and ventral spinal cord, including motoneurons, the possibility exists that loss of its protein product, FMRP, disrupts locomotor circuitry. Here, we investigate whether Fmr1 deletion alters the function of the spinal central pattern generator (CPG) networks and gait-related motor output. Using isolated neonatal spinal cord preparations from Fmr1 knockout (Fmr1 KO) mice, we assessed the ability of spinal circuits to generate coordinated fictive locomotor activity in vitro. In parallel, we quantified the gait parameters and motor performance in freely moving adult mice during unskilled and skill-demanding tasks. Our findings indicate that, despite the absence of FMRP in spinal neurons, neonatal Fmr1 KO spinal cords generated robust and coordinated locomotor rhythms compared to controls. Consistently, adult Fmr1 KO mice exhibited normal gait metrics under baseline conditions. However, these mice displayed hyperactivity and performance deficits during more challenging motor tasks demanding higher coordination. These findings suggest that the fundamental locomotor circuitry is preserved in FXS, likely through compensatory mechanisms. Consequently, motor impairments in FXS may arise primarily from supraspinal or integrative circuit dysfunction, rather than intrinsic deficits in spinal CPG function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/704392v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@19a64cborg.highwire.dtl.DTLVardef@14f8ad2org.highwire.dtl.DTLVardef@1230cbforg.highwire.dtl.DTLVardef@19fd51_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINeonatal Fmr1 KO spinal cords generated robust, coordinated locomotor rhythms similar to controls. C_LIO_LIAdult Fmr1 KO mice exhibited normal gait metrics during baseline, unskilled locomotion. C_LIO_LIFmr1 KO mice displayed hyperactivity and performance deficits during skill-demanding motor tasks. C_LIO_LIFXS motor impairments may arise primarily from supraspinal or integrative circuit dysfunction C_LIO_LISpinal cord circuitry appears to compensate for the fundamental loss of Fmr1 function. C_LI

neuroscience↗

bioRxiv2024

Episodic rhythmicity is generated by a distributed neural network in the developing mammalian spinal cord

Spinal circuits produce diverse motor outputs that coordinate the rhythm and pattern of locomotor movements. Despite the episodic nature of these behaviours, the neural mechanisms encoding these episodes are not well understood. This study investigated mechanisms producing episodic rhythms evoked by dopamine in isolated neonatal mouse spinal cords. Dopamine-induced rhythms were primarily synchronous and propagated rostro-caudally across spinal segments, with occasional asynchronous episodes. Electrical stimulation of the L5 dorsal root could entrain episodes across segments, indicating afferent control of the rhythm generator and a distributed rostro-caudal network. Episodic activity was observed in isolated thoracic or sacral segments after full spinal transection or bilateral ventrolateral funiculus (VLF) lesions, suggesting a distributed network coupled via VLF projections. Rhythmicity was recorded from axons projecting through the VLF and dorsal roots, but not from cholinergic recurrent excitation via motoneurons or isolated dorsal inhibitory circuits. The data suggest episodic rhythmicity is generated by a flexibly coupled network of spinal interneurons distributed throughout the spinal cord.

neuroscience↗

bioRxiv2020

Dynamics of episodic and continuous rhythmic activities from a developing central pattern generator

Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and their transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-centre oscillator (HCO). Following predictions of our computational model, we tested the contributions of key properties to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model recapitulates the diverse state-dependent rhythms evoked by dopamine. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with Na+/K+ ATPase pump (IPump) and hyperpolarization-activated currents (Ih) playing key roles. Modulation of either IPumpMax or Ih produced transitions between episodic and continuous rhythms and silence. As IPump increased, the episode duration and period increased along with a reduction in interepisode interval. Increasing Ih increased the episode period along with an increase in episode duration. Pharmacological manipulations of Ih with ZD7288 and IPump with ouabain or monensin in isolated spinal cords produced findings consistent with the model. Our modelling and experimental results highlight key roles of Ih and IPump in producing episodic rhythms and provide insight into mechanisms that permit a single CPG to produce multiple patterns of rhythmicity. Significance statementThe ability of a single CPG to produce and transition between multiple rhythmic patterns of activity is poorly understood. We deployed a complementary computational half-centre oscillator model and an isolated spinal cord experimental preparation to identify key currents whose interaction produced episodic and continuous rhythmic activity. Together, our experimental and modelling approaches suggest mechanisms in spinal networks that govern diverse rhythms and transitions between them. This work sheds light on the ability of a single CPG to produce episodic bouts observed in behavioural and pathological contexts.

neuroscience↗

bioRxiv2020

A point mutation in Ttc26 causes lumbar spinal cord fusion and synchronous hind-limb locomotion in hop mice

Identifying the spinal circuits controlling locomotion is critical for unravelling the mechanisms controlling the production of gaits. Development of the circuits governing left-right coordination relies on axon guidance molecules such as ephrins and netrins. To date, no other class of proteins have been shown to play a role during this process. Here we have analyzed hop mice, which walk with a characteristic hopping gait using their hind legs in synchrony. Fictive locomotion experiments suggest that a local defect in the ventral spinal cord contributes to the aberrant locomotor phenotype. Hop mutant spinal cords had severe morphological defects, including the absence of the ventral midline and a poorly defined border between white and grey matter. The hop mice represent the first model where the left and right central pattern generators (CPGs) are fused to form one central CPG, with a synchronous gait as a functional consequence. These defects were exclusively found in the lumbar domain and were associated with abnormal developmental processes, including a misplaced notochord and reduced induction of ventral progenitor domains. While the underlying mutation in hop mice has been suggested to lie within Ttc26, other genes in close vicinity have been associated with gait defects. By replicating the point mutation within Ttc26, employing CRISPR technology, we observed mice with an identical phenotype, thereby verifying the hop mutation. Thus, we show that the assembly of the lumbar CPG network is dependent on a fully functional TTC26 protein.

neuroscience↗