Activity dependent processes guide remodeling after traumatic spinal cord injury

Denecke Muhr, Carmen Katharina (2021): Activity dependent processes guide remodeling after traumatic spinal cord injury. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Spinal cord injury causes a complete life change for patients and their social environment with severe economic, societal, and health implications. So far, there is no cure and only very limited treatment for patients suffering from spinal cord injury. Although central axons fail to regrow successfully after injury, incomplete spinal cord injury is accompanied by spontaneous but limited functional recovery. This recovery is attributed to compensatory neuroanatomical plasticity, where fibers remodel distal to the injury to establish new connections, so called neuronal detour circuits. Whilst various detour circuits in rodents are anatomically characterized in detail, the mechanisms of remodeling are not completely understood. Activity dependent processes, such as N-methyl-D-aspartate receptor (NMDAR) signaling, cyclic AMP response element-binding (CREB) transcription, and neuronal activity itself, play a crucial role in the formation of neural circuits during embryogenesis. We analyzed the role of these processes in the cervical spinal cord, where the corticospinal tract has been demonstrated to sprout and contact novel target neurons after traumatic spinal cord injury. More specifically, we perturbed NMDAR signaling, (ii) suppressed CREB transcription, and (iii) silenced neurons with designer receptor exclusively activated by designer drugs (DREADDs). Inhibiting NMDAR and CREB function in the cervical area during detour circuit formation both resulted in anatomically aberrant remodeling of the corticospinal tract. However, cervical circuitry remained unaltered when activity dependent processes were manipulated before spinal cord injury and after a mature detour circuit had already been established. These experiments demonstrate that spinal cord injury transiently opens a critical window of activity dependent plasticity, enabling detour circuit formation. Furthermore, I argue that target selection during detour circuit formation after spinal cord injury is based on the neuron’s relative level of activity. Firstly, this interpretation is based on our observation that global cervical silencing had no measurable effects whilst selective silencing of specific neuronal populations created an anatomically and functionally defective detour circuit. Secondly, within this defective detour circuit, the degree of neuronal silencing negatively correlated with the likelihood of that neuron to be contacted by corticospinal tract collaterals. With the help of a detailed literature analysis, I demonstrate similarities in plasticity between the developing CNS, the adult intact, and injured CNS and propose future experiments. Taken together, this thesis illustrates that activity dependent processes guide spontaneous detour circuit formation after spinal cord injury.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie ; 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 3. Februar 2021
• 1. Bericht­erstatter:in: Bareyre, Florence