More Like this

1. Improved Locomotor Recovery in a Rat Model of Spinal Cord Injury by BioLuminescent-OptoGenetic (BL-OG) Stimulation with an Enhanced Luminopsin

   https://doi.org/10.3390/ijms232112994  

   Ikefuama, Ebenezer C.; Kendziorski, Griffin E.; Anderson, Kevin; Shafau, Lateef; Prakash, Mansi; Hochgeschwender, Ute; Petersen, Eric D. (November 2022, International Journal of Molecular Sciences)

   Irrespective of the many strategies focused on dealing with spinal cord injury (SCI), there is still no way to restore motor function efficiently or an adequate regenerative therapy. One promising method that could potentially prove highly beneficial for rehabilitation in patients is to re-engage specific neuronal populations of the spinal cord following SCI. Targeted activation may maintain and strengthen existing neuronal connections and/or facilitate the reorganization and development of new connections. BioLuminescent-OptoGenetics (BL-OG) presents an avenue to non-invasively and specifically stimulate neurons; genetically targeted neurons express luminopsins (LMOs), light-emitting luciferases tethered to light-sensitive channelrhodopsins that are activated by adding the luciferase substrate coelenterazine (CTZ). This approach employs ion channels for current conduction while activating the channels through treatment with the small molecule CTZ, thus allowing non-invasive stimulation of all targeted neurons. We previously showed the efficacy of this approach for improving locomotor recovery following severe spinal cord contusion injury in rats expressing the excitatory luminopsin 3 (LMO3) under control of a pan-neuronal and motor-neuron-specific promoter with CTZ applied through a lateral ventricle cannula. The goal of the present study was to test a new generation of LMOs based on opsins with higher light sensitivity which will allow for peripheral delivery of the CTZ. In this construct, the slow-burn Gaussia luciferase variant (sbGLuc) is fused to the opsin CheRiff, creating LMO3.2. Taking advantage of the high light sensitivity of this opsin, we stimulated transduced lumbar neurons after thoracic SCI by intraperitoneal application of CTZ, allowing for a less invasive treatment. The efficacy of this non-invasive BioLuminescent-OptoGenetic approach was confirmed by improved locomotor function. This study demonstrates that peripheral delivery of the luciferin CTZ can be used to activate LMOs expressed in spinal cord neurons that employ an opsin with increased light sensitivity. 

   more » « less
2. Ipsilateral and Contralateral Interactions in Spinal Locomotor Circuits Mediated by V1 Neurons: Insights from Computational Modeling

   https://doi.org/10.3390/ijms23105541  

   Shevtsova, Natalia A.; Li, Erik Z.; Singh, Shayna; Dougherty, Kimberly J.; Rybak, Ilya A. (May 2022, International Journal of Molecular Sciences)

   We describe and analyze a computational model of neural circuits in the mammalian spinal cord responsible for generating and shaping locomotor-like oscillations. The model represents interacting populations of spinal neurons, including the neurons that were genetically identified and characterized in a series of previous experimental studies. Here, we specifically focus on the ipsilaterally projecting V1 interneurons, their possible role in the spinal locomotor circuitry, and their involvement in the generation of locomotor oscillations. The proposed connections of these neurons and their involvement in different neuronal pathways in the spinal cord allow the model to reproduce the results of optogenetic manipulations of these neurons under different experimental conditions. We suggest the existence of two distinct populations of V1 interneurons mediating different ipsilateral and contralateral interactions within the spinal cord. The model proposes explanations for multiple experimental data concerning the effects of optogenetic silencing and activation of V1 interneurons on the frequency of locomotor oscillations in the intact cord and hemicord under different experimental conditions. Our simulations provide an important insight into the organization of locomotor circuitry in the mammalian spinal cord. 

   more » « less
3. Effects of transcutaneous spinal stimulation on spatiotemporal cortical activation patterns: a proof-of-concept EEG study

   https://doi.org/10.1088/1741-2552/ac7b4b  

   Steele, Alexander G; Manson, Gerome A; Horner, Philip J; Sayenko, Dimitry G; Contreras-Vidal, Jose L (July 2022, Journal of Neural Engineering)

   Abstract Objective. Transcutaneous spinal cord stimulation (TSS) has been shown to be a promising non-invasive alternative to epidural spinal cord stimulation for improving outcomes of people with spinal cord injury (SCI). However, studies on the effects of TSS on cortical activation are limited. Our objectives were to evaluate the spatiotemporal effects of TSS on brain activity, and determine changes in functional connectivity under several different stimulation conditions. As a control, we also assessed the effects of functional electrical stimulation (FES) on cortical activity. Approach . Non-invasive scalp electroencephalography (EEG) was recorded during TSS or FES while five neurologically intact participants performed one of three lower-limb tasks while in the supine position: (1) A no contraction control task, (2) a rhythmic contraction task, or (3) a tonic contraction task. After EEG denoising and segmentation, independent components (ICs) were clustered across subjects to characterize sensorimotor networks in the time and frequency domains. ICs of the event related potentials (ERPs) were calculated for each cluster and condition. Next, a Generalized Partial Directed Coherence (gPDC) analysis was performed on each cluster to compare the functional connectivity between conditions and tasks. Main results . IC analysis of EEG during TSS resulted in three clusters identified at Brodmann areas (BA) 9, BA 6, and BA 4, which are areas associated with working memory, planning, and movement control. Lastly, we found significant ( p  < 0.05, adjusted for multiple comparisons) increases and decreases in functional connectivity of clusters during TSS, but not during FES when compared to the no stimulation conditions. Significance. The findings from this study provide evidence of how TSS recruits cortical networks during tonic and rhythmic lower limb movements. These results have implications for the development of spinal cord-based computer interfaces, and the design of neural stimulation devices for the treatment of pain and sensorimotor deficit. 

   more » « less
4. Effect of spinal cord injury on neural encoding of spontaneous postural perturbations in the hindlimb sensorimotor cortex

   Jaimie B Dougherty (January 2021, Journal of neurophysiology)

   Capers, Miriam (Ed.)

   Supraspinal signals play a significant role in compensatory responses to postural perturbations after spinal cord injury (SCI). SCI disrupts descending motor control signals as well as ascending somatosensory information to and from below the lesion. In intact animals, While cortical signals are not necessary for basic postural tasks, but neurons in the motor cortex have been shown to respond to periodic postural perturbations in intact animals. However, the role of the cortex in postural control after spinal cord injury in response to unexpected postural perturbations has not been studied. To better understand how spinal lesions impact cortical encoding of information about unexpected postural perturbations, the activity of single neurons in the rat hindlimb sensorimotor cortex (HLSMC) were recorded during unexpected tilts before and after a complete midthoracic spinal transection. In a subset of animals, limb ground reaction forces were collected as well. Results show that responses in the HLSMC were modulated with changes in tilt severity (i.e. tilt velocity). As initial velocity of the tilt increased, more information was conveyed by the HLSMC neurons about the perturbation due to increases in both the number of recruited neurons and the magnitude of their response. After SCI hindlimb ground reaction forces were both attenuated and delayed, and the neural responses were delayed and less likely to respond to slower tilts. This resulted in a moderate decrease inan attenuation of the information conveyed by cortical neurons about the tilts, requiring more cells to convey the same amount of information as before the transection. Given that reorganization of the hindlimb sensorimotor cortex in response to therapy after complete mid-thoracic SCI is necessary for behavioral recovery, this sustained encoding of information after SCI could be a substrate for the reorganization that uses sensory information from above the lesion to control trunk muscles that permit weight-supported stepping and postural control. 

   more » « less
5. Myelin Debris Stimulates NG2/CSPG4 Expression in Bone Marrow-Derived Macrophages in the Injured Spinal Cord

   https://doi.org/10.3389/fncel.2021.651827  

   Liu, Yang; Hammel, Grace; Shi, Minjun; Cheng, Zhijian; Zivkovic, Sandra; Wang, Xiaoqi; Xu, Pingyi; He, Xijing; Guo, Bing; Ren, Yi; et al (March 2021, Frontiers in Cellular Neuroscience)

   null (Ed.)

   Although the increased expression of members of the chondroitin sulfate proteoglycan family, such as neuron-glial antigen 2 (NG2), have been well documented after an injury to the spinal cord, a complete picture as to the cellular origins and function of this NG2 expression has yet to be made. Using a spinal cord injury (SCI) mouse model, we describe that some infiltrated bone marrow-derived macrophages (BMDMΦ) are early contributors to NG2/CSPG4 expression and secretion after SCI. We demonstrate for the first time that a lesion-related form of cellular debris generated from damaged myelin sheaths can increase NG2/CSPG4 expression in BMDMΦ, which then exhibit enhanced proliferation and decreased phagocytic capacity. These results suggest that BMDMΦ may play a much more nuanced role in secondary spinal cord injury than previously thought, including acting as early contributors to the NG2 component of the glial scar. 

   more » « less