Biology subjects

Danner, S. M.

Publications and source records attributed to Danner, S. M..

12 recordsLinked to original sources

bioRxiv2026

Defective synapto-nuclear signaling contributes to motoneuron vulnerability in SOD1-ALS

Glutamatergic excitatory synapses not only shape spiking activity and neuronal communication but also initiate activity-dependent signaling pathways that trigger transcriptional programs. Since glutamatergic excitatory synapses onto spinal motoneurons (MNs) are impaired presymptomatically in Amyotrophic Lateral Sclerosis, we investigated whether synapto-nuclear coupling is disrupted in MNs from mSOD1 mice and whether restoring it mitigates pathology. We developed an in vivo approach to selectively investigate the coupling between synaptic excitation and nuclear CREB phosphorylation in spinal MNs. Specific activation of Ia-MN synapses induces CREB phosphorylation in wild-type MNs but not in mSOD1 MNs at P50, indicating presymptomatic synapto-nuclear uncoupling. Enhancing cAMP/PKA signaling by pharmacological inhibition of cAMP degradation restored synapto-nuclear coupling, reduced misfolded SOD1, and slowed neuromuscular-junction denervation. Thus, activity-dependent synapto-nuclear signaling is impaired yet pharmacologically rescuable in mSOD1 MNs, supporting synapto-nuclear signaling as a determinant of MN resilience.

neuroscience↗

bioRxiv2025

Mechanisms of adaptive interlimb coordination to sudden ground loss: a neuromusculoskeletal modeling study

Mammals exhibit robust walking across diverse environments, a capability largely attributed to central pattern generators (CPGs) in the spinal cord. Afferent feedback modulates CPG output and plays a critical role in adaptive locomotion, yet its specific contributions remain poorly understood. To investigate this, we used a neuromusculoskeletal model to simulate hindlimb locomotion in spinalized cats encountering a hole and experiencing a sudden loss of ground support, as described in prior experimental studies. The model couples a trunk-andhindlimb musculoskeletal system to a pair of two-level, half-center CPGs--one for each hindlimb. The model reproduced the observed adaptive interlimb coordination that allows cats to maintain walking after the sudden loss of ground support. Notably, the adaptive response emerged without re-optimizing parameters, which were tuned for steady walking in an environment without holes. Nullcline analysis based on dynamical systems theory revealed that afferent feedback mechanisms controlling the transitions between fast and slow neuronal dynamics facilitated adaptive interlimb coordination. These findings provide mechanistic insight into how spinal feedback circuits support robust locomotion through dynamic interactions between the nervous system, the musculoskeletal system, and the environment.

neuroscience↗

bioRxiv2025

Reorganization of spinal neural connectivity following recovery after thoracic spinal cord injury: insights from computational modelling

Rats exhibit significant recovery of locomotor function following incomplete spinal cord injuries, albeit with altered gait expression and reduced speed and stepping frequency. These changes likely result from and give insight into the reorganization within spared and injured spinal circuitry. Previously, we developed computational models of the mouse spinal locomotor circuitry controlling speed-dependent gait expression (Danner et al. 2017; Zhang et al. 2022). Here, we adapted these models to the rat and used the adapted model to explore potential circuit-level changes underlying altered gait expression observed after recovery from two different thoracic spinal cord injuries (lateral hemisection and contusion) that have roughly comparable levels of locomotor recovery (Danner et al., 2023). The model reproduced experimentally observed gait expression before injury and after recovery from lateral hemisection and contusion, and suggests two distinct, injury-specific routes to restored function. First, recovery after lateral hemisection required substantial functional restoration of damaged descending drive and long propriospinal connections, suggesting compensatory plasticity through formation of detour pathways. Second, recovery after a moderate midline contusion predominantly relied on reorganization of spared sublesional networks and altered control of supralesional cervical circuits, compensating for weakened propriospinal and descending pathways. Despite these differences, sensitivity analysis revealed that restored activation of sublesional lumbar rhythm-generating circuits and appropriately balanced lumbar commissural connectivity are the key determinants of post-injury gait expression, suggesting that injury symmetry shapes how the cord reorganizes, but effective recovery in both cases depends on re-engaging these lumbar networks, which makes them prime targets for therapeutic intervention.

neuroscience↗

bioRxiv2024

Non-canonical adrenergic neuromodulation of motoneuron intrinsic excitability through beta-receptors in wild-type and ALS mice

Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loops might hyper- or hypo-excite motoneurons (MNs) and contribute to the pathogenesis. Here, we investigated how the neuromodulation of MN intrinsic properties is homeostatically controlled in presymptomatic adult SOD1(G93A) mice and in the age-matched control WT mice. First, we determined that {beta}2 and {beta}3-adrenergic receptors, which are Gs-coupled receptors and subject to tight and robust feedback loops, are specifically expressed in spinal MNs of both SOD1 and WT mice at P45. We then demonstrated that these receptors elicit a so-far overlooked neuromodulation of the firing and excitability properties of MNs. These electrical properties are homeostatically regulated following receptor engagement, which triggers ion channel transcriptional changes and downregulates those receptors. These homeostatic feedbacks are not dysregulated in presymptomatic SOD1 mice, and they set the MN excitability upon {beta}-adrenergic neuromodulation.

neuroscience↗

bioRxiv2023

Sensory Feedback and Central Neuronal Interactions in Mouse Locomotion

Locomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyze a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behavior to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.

systems biology↗

bioRxiv2023

KCC2 Enhancers Normalize Reflex Responses and Improve Locomotor Function after Chronic Spinal Cord Injury

Within a year after a spinal cord injury (SCI), 75% of individuals develop spasticity. While normal movement relies on the ability to adjust reflexes appropriately, and on reciprocal inhibition of antagonistic muscles, spastic individuals display hyperactive spinal reflexes and involuntary muscle co-contractions. Current anti-spastic medications can suppress uncontrolled movements, but by acting on GABAergic signalling, these medications lead to severe side-effects and weakened muscle force, making them incompatible with activity-based therapies. We have previously shown that pharmacologically enhancing activity of KCC2, a chloride cotransporter, reduces signs of spasticity in anesthetized chronic SCI rats. Here, we examine the effect of enhancing KCC2 in awake animals, using a battery of tests to assess multiple reflex pathways required for normal movement as well as locomotor function. Sprague-Dawley rats were implanted with chronic EMG electrodes bilaterally in ankle flexor and ankle extensor muscles and received a complete spinal transection at T12. Four weeks following SCI, the stretch reflex, the non-nociceptive cutaneous reflex pathway, the flexor withdrawal reflex, and the crossed-extensor reflex pathway as well as locomotor function were evaluated before and after receiving the KCC2 enhancer, CLP290. Our results show that enhancing KCC2 activity normalizes reflex responses in multiple pathways and reduces muscle co-contraction without weakening motor output, thereby improving stepping ability. This work reveals the substantial potential for KCC2 enhancers as a novel antispastic treatment.

neuroscience↗

bioRxiv2023

Spinal control of locomotion before and after spinal cord injury

Thoracic spinal cord injury affects long propriospinal neurons that interconnect the cervical and lumbar enlargements. These neurons are crucial for coordinating forelimb and hindlimb locomotor movements in a speed-dependent manner. However, recovery from spinal cord injury is usually studied over a very limited range of speeds that may not fully expose circuitry dysfunction. To overcome this limitation, we investigated overground locomotion in rats trained to move over an extended distance with a wide range of speeds both pre-injury and after recovery from thoracic hemisection or contusion injuries. In this experimental context, intact rats expressed a speed-dependent continuum of alternating (walk and trot) and non-alternating (canter, gallop, half-bound gallop, and bound) gaits. After a lateral hemisection injury, rats recovered the ability to locomote over a wide range of speeds but lost the ability to use the highest-speed gaits (half-bound gallop and bound) and predominantly used the limb contralateral to the injury as lead during canter and gallop. A moderate contusion injury caused a greater reduction in maximal speed, loss of all non-alternating gaits, and emergence of novel alternating gaits. These changes resulted from weak fore-hind coupling together with appropriate control of left-right alternation. After hemisection, animals expressed a subset of intact gaits with appropriate interlimb coordination even on the side of the injury, where the long propriospinal connections were severed. These observations highlight how investigating locomotion over the full range of speeds can reveal otherwise hidden aspects of spinal locomotor control and post-injury recovery.

neuroscience↗

bioRxiv2023

Distinct roles of spinal commissural interneurons in transmission of contralateral sensory information

Crossed reflexes (CR) are mediated by commissural pathways transmitting sensory information to the contralateral side of the body, but the underlying network is not fully understood. Commissural pathways coordinating the activities of spinal locomotor circuits during locomotion have been characterized in mice, but their relationship to CR is unknown. We show the involvement of two genetically distinct groups of commissural interneurons (CINs) described in mice, V0 and V3 CINs, in the CR pathways. Our data suggest that the exclusively excitatory V3 CINs are directly involved in the excitatory CR, and show that they are essential for the inhibitory CR. In contrast, the V0 CINs, a population that includes excitatory and inhibitory CINs, are not directly involved in excitatory or inhibitory CRs but down-regulate the inhibitory CR. Our data provide insights into the spinal circuitry underlying CR in mice, describing the roles of V0 and V3 CINs in CR.

neuroscience↗

bioRxiv2023

Investigating the roles of reflexes and central pattern generators in the control and modulation of human locomotion using a physiologically plausible neuromechanical model

Studying the neural components regulating movement in human locomotion is obstructed by the inability to perform invasive experimental recording. Neuromechanical simulations can provide insights by modeling the locomotor circuits. Past neuromechanical models proposed control of locomotion either driven by central pattern generators (CPGs) with simple sensory commands or by a purely reflex-based network regulated by state-machine mechanisms. However, the physiological interpretation of these state-machines remains unclear. Here, we present a physiologically plausible model to investigate spinal control and modulation of human locomotion. We propose a bio-inspired controller composed of two coupled central pattern generators (CPGs) that produce the rhythm and pattern and a reflex-based network simulating low-level reflex pathways and Renshaw cells. This reflex network is based on leaky-integration neurons, and the whole system does not rely on changing reflex gains according to the gait cycle state. The only component of the controller that maintains a state-machine mechanism is the balance controller of the trunk. The musculoskeletal model is composed of a skeletal structure and 9 muscles per leg generating movement in sagittal plane. After optimizing the open parameters, human locomotion replicating kinematics and muscle activation naturally emerged. Furthermore, when CPGs were not activated, no stable and physiologically plausible gaits could be achieved through optimization, suggesting the necessity of this component to generate rhythmic behavior without a state machine mechanism regulating reflex activation. The controller could reproduce a wide range of speeds from 0.3 to 1.9 m/s. The results also showed that the net influence of feedback on motoneurons during perturbed locomotion is predominantly inhibitory and that the CPG network provides the timing of motoneurons activation by exciting or inhibiting muscles in specific gait phases. The proposed bio-inspired controller could contribute to our understanding of locomotor circuits of the intact spinal cord and could be used to study neuromotor disorders.

neuroscience↗

bioRxiv2021

The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice

Speed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. We have previously demonstrated that a subset of spinal V3 neurons contributes to stable locomotion by mediating mutual excitation between left and right lumbar rhythm generators (RGs). Here, we expanded our investigation to the V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotor speed, were unable to move using stable trot, gallop, or bound, and predominantly used lateral-sequence walk. To understand the functional roles of V3 aLPNs, we adapted our previous model of spinal circuitry controlling quadrupedal locomotion (Danner et al., 2017), by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The updated model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left-right interactions within lumbar and cervical cords, promote left-right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.

neuroscience↗

bioRxiv2020

On the organization of the locomotor CPG: insights from split-belt locomotion and mathematical modeling

Rhythmic limb movements during locomotion are controlled by a central pattern generator (CPG) circuits located in the spinal cord. It is considered that these circuits are composed of individual rhythm generators (RGs) for each limb interacting with each other through multiple commissural and long propriospinal circuits. The organization and operation of each RG are not fully understood, and different competing theories exist about interactions between its flexor and extensor components, as well as about left-right commissural interactions between the RGs. The central idea of circuit organization proposed in this study is that with an increase of excitatory input to each RGs (or an increase in locomotor speed) the rhythmogenic mechanism within the RGs changes from "flexor-driven" rhythmicity to a "classical half-center" mechanism. We test this hypothesis using our experimental data on changes in duration of stance and swing phases in the intact and spinal cats walking on the ground or tied-belt treadmills (symmetric conditions) or split-belt treadmills with different left and right belt speeds (asymmetric conditions). We compare these experimental data with the results of mathematical modeling, in which simulated CPG circuits operate in similar symmetric and asymmetric conditions with matching or differing control drives to the left and right RGs. The obtained results support the proposed concept of state-dependent changes in RG operation and specific commissural interactions between the RGs. The performed simulations and mathematical analysis of model operation under different conditions provide new insights into CPG network organization and limb coordination during locomotion. Key Point SummaryO_LILimb movements during locomotion are controlled by neural circuits located within the spinal cord. These circuits include rhythm generators (RGs) controlling each limb interacting through multiple commissural pathways. C_LIO_LIThe organization and operation of spinal RGs are not fully understood, and different competing concepts exists. We suggest that the operation of RGs is state-dependent, so that with an increase of external excitation the rhythmogenesis changes from "flexor-driven" oscillations to a "classical half-center" mechanism. C_LIO_LIA mathematical model of spinal circuits representing bilaterally-interacting RGs has been developed based on the above suggestion and used to interpret experimental data from intact and spinal cats walking on the ground or tied-belt treadmills (symmetric conditions) as well as on split-belt treadmills with different left and right belt speeds (asymmetric conditions). C_LIO_LIThe performed simulations and mathematical analysis of the model under different conditions provide new insights into operation of spinal circuits and limb coordination during locomotion. C_LI

neuroscience↗

bioRxiv2019

Spinal V3 interneurons and left-right coordination in mammalian locomotion

Commissural interneurons (CINs) mediate interactions between rhythm-generating locomotor circuits located on each side of the spinal cord and are necessary for left-right limb coordination during locomotion. While glutamatergic V3 CINs have been implicated in left-right coordination, their functional connectivity remains elusive. Here, we addressed this issue by combining experimental and modeling approaches. We employed Sim1Cre/+; Ai32 mice, in which light-activated Channelrhodopsin-2 was selectively expressed in V3 interneurons. Fictive locomotor activity was evoked by NMDA and 5-HT in the isolated neonatal lumbar spinal cord. Flexor and extensor activities were recorded from left and right L2 and L5 ventral roots, respectively. Bilateral photoactivation of V3 interneurons increased the duration of extensor bursts resulting in a slowed down on-going rhythm. At high light intensities, extensor activity could become sustained. When light stimulation was shifted toward one side of the cord, the duration of extensor bursts still increased on both sides, but these changes were more pronounced on the contralateral side than on the ipsilateral side. Additional bursts appeared on the ipsilateral side not seen on the contralateral side. Further increase of the stimulation could suppress the contralateral oscillations by switching to a sustained extensor activity, while the ipsilateral rhythmic activity remained. To delineate the function of V3 interneurons and their connectivity, we developed a computational model of the spinal circuits consisting of two (left and right) rhythm generators (RGs) interacting via V0V, V0D and V3 CINs. Both types of V0 CINs provided mutual inhibition between the left and right flexor RG centers and promoted left-right alternation. V3 CINs mediated mutual excitation between the left and right extensor RG centers. These interactions allowed the model to reproduce our current experimental data, while being consistent with previous data concerning the role of V0V and V0D CINs in securing left-right alternation and the changes in left-right coordination following their selective removal. We suggest that V3 CINs provide mutual excitation between the spinal neurons involved in the control of left and right extensor activity, which may promote left-right synchronization during locomotion.

neuroscience↗