Being able to replicate real experiments with computational simulations is a unique opportunity to refine and validate models with experimental data and redesign the experiments based on simulations. However, since it is technically demanding to model all components of an experiment, traditional approaches to modeling reduce the experimental setups as much as possible. In this study, our goal is to replicate all the relevant features of an experiment on motor control and motor rehabilitation after stroke. To this aim, we propose an approach that allows continuous integration of new experimental data into a computational modeling framework. First, results show that we could reproduce experimental object displacement with high accuracy via the simulated embodiment in the virtual world by feeding a spinal cord model with experimental registration of the cortical activity. Second, by using computational models of multiple granularities, our preliminary results show the possibility of simulating several features of the brain after stroke, from the local alteration in neuronal activity to long-range connectivity remodeling. Finally, strategies are proposed to merge the two pipelines. We further suggest that additional models could be integrated into the framework thanks to the versatility of the proposed approach, thus allowing many researchers to achieve continuously improved experimental design.

Rodent models are decisive for translational research in healthy and pathological conditions of motor function thanks to specific similarities with humans. Here, we present an upgraded version of the M-Platform, a robotic device previously designed to train mice during forelimb retraction tasks. This new version significantly extends its possibilities for murine experiments during motor tasks: 1) an actuation system for friction adjustment allows to automatically adapt pulling difficulty; 2) the device can be used both for training, with a retraction task, and for assessment, with an isometric task; and 3) the platform can be integrated with a neurophysiology systems to record simultaneous cortical neural activity. Results of the validation experiments with healthy mice confirmed that the M-Platform permits precise adjustments of friction during the task, thus allowing to change its difficulty and that these variations induce a different improvement in motor performance, after specific training sessions. Moreover, simultaneous and high quality (high signal-to-noise ratio) neural signals can be recorded from the rostral forelimb area (RFA) during task execution. With the novel features presented herein, the M-Platform may allow to investigate the outcome of a customized motor rehabilitation protocol after neural injury, to analyze task-related signals from brain regions interested by neuroplastic events and to perform optogenetic silencing or stimulation during experiments in transgenic mice.

Genetically encoded calcium indicators (GECIs) can be used to monitor the intracellular concentration of free calcium in populations of neurons. GECIs with long emission wavelengths are particularly attractive for deep tissue microscopy in vivo, and have the additional advantage of avoiding spectral overlap with commonly used neuronal actuators such as channelrhodopsin.The aim of this work is to evaluate the performances of four red-shifted GECIs (jRCaMP1a, jRCaMP1b, jRGECO1a, jRGECO1b) using both ex vivo and in vivo experimental techniques.Cortical neurons were infected with adeno-associated virus (AAV) expressing one of the red GECI variants. First we characterized the transfection ex vivo in terms of extension and intensity of the indicator. Next, we monitored the neuronal activity over the right cortical hemisphere of a jRCaMP1a-transfected mouse during a goal-directed motor task. To this aim, we combined wide-field fluorescence microscopy with a robotic device for simultaneous recording of cortical neuronal activity, force applied and forelimb position during task execution.Our results show that jRCaMP1a has sufficient sensitivity to monitor in vivo neuronal activity simultaneously over multiple functional areas, and can be successfully used to perform longitudinal imaging sessions in awake mice.

Background. An ischemic stroke is followed by the remapping of motor representation and extensive changes in cortical excitability involving both hemispheres. Although stimulation of the ipsilesional motor cortex, especially when paired with motor training, facilitates plasticity and functional restoration, the remapping of motor representation of the single and combined treatments is largely unexplored. Objective. We investigated if spatio-temporal features of motor-related cortical activity and the new motor representations are related to the rehabilitative treatment or if they can be specifically associated to functional recovery. Methods. We designed a novel rehabilitative treatment that combines neuro-plasticizing intervention with motor training. In detail, optogenetic stimulation of peri-infarct excitatory neurons expressing Channelrhodopsin 2 was associated with daily motor training on a robotic device. The effectiveness of the combined therapy was compared with spontaneous recovery and with the single treatments (ie optogenetic stimulation or motor training). Results. We found that the extension and localization of the new motor representations are specific to the treatment, where most treatments promote segregation of the motor representation to the peri-infarct region. Interestingly, only the combined therapy promotes both the recovery of forelimb functionality and the rescue of spatio-temporal features of motor-related activity. Functional recovery results from a new excitatory/inhibitory balance between hemispheres as revealed by the augmented motor response flanked by the increased expression of parvalbumin positive neurons in the peri-infarct area. Conclusions. Our findings highlight that functional recovery and restoration of motor-related neuronal activity are not necessarily coupled during post-stroke recovery. Indeed the reestablishment of cortical activation features of calcium transient is distinctive of the most effective therapeutic approach, the combined therapy.

Numerous neurorehabilitative, neuroprosthetic, and repair interventions aim to address the consequences of upper limb impairments after neurological disorders. Although these therapies target widely different mechanisms, they share the common need for a preclinical platform that supports the development, assessment, and understanding of the therapy. Here, we introduce a neurorobotic platform for rats that meets these requirements. A four-degree-of-freedom end effector is interfaced with the rat’s wrist, enabling unassisted to fully assisted execution of natural reaching and retrieval movements covering the entire body workspace. Multimodal recording capabilities permit precise quantification of upper limb movement recovery after spinal cord injury (SCI), which allowed us to uncover adaptations in corticospinal tract neuron dynamics underlying this recovery. Personalized movement assistance supported early neurorehabilitation that improved recovery after SCI. Last, the platform provided a well-controlled and practical environment to develop an implantable spinal cord neuroprosthesis that improved upper limb function after SCI.