Abstract
A traumatic injury to the central nervous system (CNS) is a tragic event that turns life upside down within a matter of seconds. The limited regenerative capacity of in the CNS allows minor spontaneous recovery acutely after the injury, leading to mostly limited functional recovery. However, in a more chronic stage, the restoration of lost functions plateaus, resulting in permanent neurological dysfunction after injuries such as spinal cord injuries (SCI) and traumatic brain injuries (TBI). Currently, acute care, rehabilitative therapy, and palliative care by medication to ease the symptoms are the only available treatment options. While great progress has been made in the understanding of the injury-induced pathophysiological changes, the intrinsic repair mechanisms triggered by an injury, and intrinsic and extrinsic factors impeding with this injury-induced regenerative process in the CNS, we are still lacking therapeutic strategies to promote axon regeneration that were successfully translated into clinics. The knowledge of the pathophysiological mechanisms underlying the failure of CNS regeneration reveals a multitude of potential targets for therapeutic interventions to improve axon regeneration and sprouting, which could augment the functional recovery after CNS injury. This dissertation contributes to this matter and focuses on two different promising therapeutic approaches to improve regeneration and recovery after spinal cord injury and after traumatic brain injury. Part I provides background information about the currently existing knowledge and the two projects, Part II presents our main findings in detail, and Part III concludes the projects and presents possible future directions in an outlook. In Chapter 1 we summarize the current knowledge about the extrinsic and neuronal intrinsic factors regulating CNS regeneration, discuss neuroplasticity and mechanisms for spontaneous recovery after SCI and TBI, and present possible therapeutic approaches to improve CNS regeneration after injury. In Chapter 2 and 3 we outline two of these therapeutic approaches and provide the aims of the two projects. In Chapter 4 we investigated the safety window of the electrical stimulation of the cuneiform nucleus (CnF-DBS) in intact rats, examined the main input structures of the CnF, defined a therapeutic time window for CnF-DBS after severe but incomplete SCI, and investigated the anatomical plasticity of the CnF after injury. We then conducted two cohorts of rats that underwent CnF-DBS-enabled training in either the subchronic or chronic phase after injury to investigate the therapeutic potential of CnF-DBS-enabled high-intensity training to improve locomotor recovery after severe SCI. In Chapter 5 we concluded this project with the assessment of the potential of CnF-DBS to improve locomotion in a clinically relevant translational setting in rats with incomplete SCI comparable to ASIA C severity in human 4 patients. A restriction of the suprathreshold stimulation intensity and reduction in the physically exhausting training in an enriched environment setup as rehabilitation aimed at an overall reduction of the intensity of the therapeutic intervention to improve clinical feasibility. Chapter 6 focuses on the establishment and characterization of a diffuse closed head TBI model, reflecting the most prevalent form of TBI in a clinical setting, and that induces comparable transient and persisting multi-faceted symptoms affecting cognitive, emotional, and learning and memory modalities. This established diffuse closed head TBI model was used to investigate the potential beneficial effects of an anti-Nogo-A antibody treatment on the functional recovery after diffuse TBI. Preliminary data of the first two cohorts of mice are displayed and discussed in Chapter 7. In Chapter 8 we conclude that CnF-DBS qualifies as promising therapeutic intervention to ameliorate locomotion deficits in severe subchronic and chronic incomplete SCI rats after a high-intensity CnF-DBS-enabled rehabilitative training. A similar beneficial effect was also present in rats with smaller SCI lesions that performed a low- to medium-intensity CnF-DBSsupported rehabilitation paradigm, feasible in a clinical setting with human patients. With our work, we hope to contribute to an improved rehabilitation of motor deficits in spinal cord injured patients. In Chapter 9 we conclude that the established diffuse closed head TBI model induces persisting functional deficits in sensorimotor, emotional, anxiety, and cognitive functions and is reliable and reproducible, allowing the investigation of clinically relevant therapeutic interventions. With our work, we hope to lay the foundation to essential pre-clinical research in the field of TBI, hopefully leading to successful clinical translation of promising treatments in the future.
Scheuber, Myriam Ilona