Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models

Quentin Barraud, Kay Alexander Bartholdi, Grégoire Courtine, Thomas Haynes Hutson, Claudia Kathe
AMER ASSOC ADVANCEMENT SCIENCE, 2019
Article

Résumé

After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential. This effect was dependent on Creb-binding protein (Cbp)-mediated histone acetylation, which increased the expression of genes associated with the regenerative program. Intraperitoneal delivery of a small-molecule activator of Cbp at clinically relevant times promoted regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury. Our findings showed that the increased regenerative capacity induced by enhancing neuronal activity is mediated by epigenetic reprogramming in rodent models of spinal cord injury. Understanding the mechanisms underlying activity-dependent neuronal plasticity led to the identification of potential molecular targets for improving recovery after spinal cord injury.

Official source

https://infoscience.epfl.ch/record/267313?ln=fr

À propos de ce résultat

Cette page est générée automatiquement et peut contenir des informations qui ne sont pas correctes, complètes, à jour ou pertinentes par rapport à votre recherche. Il en va de même pour toutes les autres pages de ce site. Veillez à vérifier les informations auprès des sources officielles de l'EPFL.

Concepts associés

Chargement

Publications associées

Chargement

Quentin Barraud, Kay Alexander Bartholdi, Grégoire Courtine, Thomas Haynes Hutson, Claudia Kathe
AMER ASSOC ADVANCEMENT SCIENCE, 2019
Article

Résumé

Official source

https://infoscience.epfl.ch/record/267313?ln=fr

À propos de ce résultat

Concepts associés (16)

Concepts associés

Chargement

Publications associées (26)

Publications associées

Chargement

Neuroprosthetic rehabilitation and translational mechanism after severe spinal cord injury

Lucia Florinda Friedli Wittler

Traumatic SCIs have long-term health, economic and social consequences, stressing the urgency to develop interventions to improve recovery after such injuries. Today, the only proven effective interventions to enhance recovery after SCI are activity-based rehabilitation therapies, such as locomotor training. However, locomotor training shows no or very limited efficacy to improve function after a severe SCI that induces paralysis of the limbs. To mimic the outcome of severe but incomplete SCI in rodents, we developed a model of double opposite-side lateral hemisections termed staggered hemisection in adult rats. This model induced permanent paralysis below the level of injury but leaves an intervening gap of intact neural tissue that provides a substrate for recovery. We showed that this SCI leads to degradation of motor functions, which correlates with the formation of aberrant neuronal connections below the lesion. Robotic devices with a rehabilitative purpose should act as propulsive or postural neuroprosthesis allowing training under natural conditions. Our versatile robotic interface provides multidirectional bodyweight support during overground locomotion in rats. We next evaluated the effects of robot-assisted gait training enabled by electrochemical stimulation of spinal circuits to restore locomotion after staggered hemisection SCI. We found that after two months of daily training, paralyzed rats recovered the ability to initiate, sustain and adjust bipedal locomotion while supported in the robot under electrochemical stimulation. This recovery correlated with ubiquitous reorganization of corticospinal, brainstem, and intraspinal fibers. We next evaluated whether this treatment was capable of restoring supraspinal control of locomotion after a clinically relevant SCI. Rats received a severe contusion of the spinal cord that spared less than 10% of intact tissue. Robot-assisted rehabilitation restored weight-bearing locomotion in all the trained rats when stimulated electrochemicallay and in a subset of rats in the absence of any enabling factors which paralelled with the reorganization of axonal projections of reticulospinal fibers below the contusion. Virus-mediated silencing of reticulospinal neurons projecting to lumbar segments demonstrated that these inputs were necessary to initiate and sustain walking after training. When delaying the onset of training by two months, in the chronic stage, all the rats regained voluntary locomotor movements but the extent of the recovery was reduced compared to rats trained early after SCI. The results provide a strong rationale to evaluate the impact of neuroprosthetic training to improve motor functions in human patients with incomplete SCI. Translation of treatment paradigms developed in rodent models into effective clinical applications remains a major challenge in biomedical research. Here, we studied recovery of motor functions in more than 400 quadriplegic patients who presented various degree of spinal cord damage laterality. We found that recovery increases with the asymmetry of early motor deficits. We conclude that emergence of spinal cord decussating corticospinal fibers and bilateral motor cortex projections during mammalian evolution supports greater recovery after lateralized SCI primates compared to rodents. Novel experimental models and dedicated therapeutic strategies are necessary to take advantage of this powerful neuronal substrate for recovery after SCI.

EPFL2014

Chargement

Spinal cord injury (SCI) leads to permanent deficits in sensory and motor function due to the physical disruption of descending and ascending pathways. As a consequence, spinal circuits below the level of lesion remain in an intact, but inactive state. A number of studies have shown that epidural electrical stimulation (EES) of the lumbar spinal cord can reactivate these spinal circuits after SCI. EES reversed paralysis of lower limbs in rodent and primate models of SCI as well as in a number of clinical case studies. However, although the positive effects of EES have been documented, little is known about the neural circuits through which EES enables motor pattern formation after SCI. In the first part of this thesis, we examined the neural circuits activated by EES. In the past, modeling experiments highlighted a pivotal role for large-diameter, myelinated afferent circuits in mediating the facilitating effects of EES after SCI. Using calcium imaging and chemogenetic inactivation experiments, we confirmed that EES primarily recruits proprioceptive and low-threshold mechanoreceptor feedback circuits. We next sought to exploit this knowledge to specifically enhance the effects of EES. We found that alpha2a receptors are prominently expressed on proprioceptive afferent neurons in DRGs, whereas alpha2c receptors are located on low-threshold mechanoreceptor interneurons in the dorsal spinal horn. Based on this knowledge, we built a computational model that identified beneficial and detrimental interactions between EES and noradrenergic circuits. This understanding guided the design of a circuit-specific, electrochemical neuromodulation that specifically gated the effects of EES towards proprioceptive feedback circuits and re-established locomotion in paralyzed mice and rats. The second part of this thesis uncovers the impact of movement on sensory afferent pathways. For this, mice were exposed to environmental enrichment (EE) or standard housing (SH). We found that EE primed sensory dorsal root ganglia neurons, inducing a lasting increase in their regenerative potential after SCI. This EE-mediated increase in regenerative potential was confined to proprioceptive afferent neurons and characterized through increased calcium signalling and CBP-dependent histone acetylation which is associated with enhanced gene expression. In a next step, we mimicked the exposure to EE using pharmacology. The pharmacological activation of CBP after injury enhanced axonal growth of proprioceptive afferent fibers and enhanced the recovery of sensory and motor functions. Here, we provide direct and conclusive experimental evidence for the mechanistic understanding of EES and EE and how they mediate functional recovery after SCI. Based on this knowledge, we identified specific receptors and epigenetic mechanisms for pharmacological modulation. Our findings demonstrate the importance of large-diameter afferent fibers in mediating functional recovery and will be important in establishing a framework for the design of targeted neuromodulation therapies after SCI in human patients.

EPFL2019

Chargement

Cortico-reticulo-spinal circuits mediate functional recovery after spinal cord contusion

Léonie Asboth

After a spinal cord injury (SCI), only half of affected individuals regain voluntary control of leg movements below the level of the lesion. Anatomical, electrophysiological and imaging data revealed that even the most severe forms of SCI usually spare a small bridge of tissue in the surrounding of the lesion cavity. These bridges contain residual fibers from brain projections that maintain a physical connection with the lumbar spinal cord, where the circuits coordinating leg movements reside. However, without therapeutic interventions, these spared fibers will fail to conduct nervous information from brain centers to the spinal circuits below injury, leading to permanent paralysis. It is accepted that spontaneous regeneration of lesioned fibers is limited in the adult nervous system, but hope for motor recovery lies in the capacity of the spared neural motor network to readapt and find compensational routes. In the past, a neuroprosthetic rehabilitation strategy combining electrochemical neuromodulation of the spinal cord during robot-assisted overground locomotion was developed for rats to restore volitional control of the paralyzed legs. Such rehabilitation platforms was developed for rats, enabling large-scale studies prior to pre-clinical trials in non-human primates. However, most innovative tools for the manipulation of specific populations of neurons are currently designed for mice, and these techniques are essential to establish causality between the anatomical reorganization and the observed functional recovery. In the first part of this thesis, we developed a robotic interface with end-effector modules that can be rapidly exchanged between experiments with rats or mice. The functionalities of the robot are tailored to the size and weight of the animal, to the personalized need of assistance and to the type of performed task. Using this platform, the next part of the thesis uncovers the mechanisms enabling motor recovery after a clinically relevant injury model â a severe spinal cord contusion. Such injury leads to permanent leg motor deficits with very little spontaneous recovery. Similar to humans, the modelled contusion injury induce highly variable white matter damage with undefined neural pathway sparing. For the first time, we show that the rehabilitation strategy enabled rats to regain supraspinal control of leg movements that persisted without any neuromodulation even during unpracticed motor tasks. We then investigated the reorganization of the spared circuitry that mediated this functional recovery after contusion. Despite interruption of direct corticospinal projections, we showed that the motor cortex regained adaptive control over the paralyzed legs during neuromodulation of lumbar circuits. We found that the cortical command was relayed through spared glutamatergic projection neurons in the reticular formation. Indeed, due to the distributed spatial topography of reticulospinal projections, the contusion systematically spares a subset of these projections. Extensive training promoted plasticity of the identified cortico-reticulo-spinal pathway mediating a motor cortex dependent recovery of voluntary leg movements. As the anatomy and function of reticulospinal pathways are well-conserved across mammals, this pathway may be recruited by similar therapeutic interventions to improve recovery in humans.

EPFL2017

Chargement

Neuroprosthetic rehabilitation and translational mechanism after severe spinal cord injury

Lucia Florinda Friedli Wittler

EPFL2014

EPFL2019

Cortico-reticulo-spinal circuits mediate functional recovery after spinal cord contusion

Léonie Asboth

EPFL2017