Traumatic brain injury

Chahin, Maryam (2025): Traumatic brain injury: a binding condition in search of solutions. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Traumatic brain injury (TBI) is a current economical and societal burden affecting around 70 million individuals worldwide. Traumatic brain injury is categorised in different severity level, being mild, moderate and severe, mild traumatic brain injury (mild TBI) representing 80% of all TBI cases. The heterogeneity displayed by patient undergoing a TBI has made it difficult for the clinician as well as for the scientist to give the appropriate diagnosis and care and develop the adequate therapy and treatment to alleviate the impact of such a trauma. Moderate and severe TBI, which are invasive injury, are rather straightforward in the display of their repercussion as compared to mild TBI (or concussion) which have displayed no macroscopic changes but rather specific microscopic alterations. Behavioural impairments have also been detected and the extent of the impairments is dependent on the injury severity level. In this thesis, we will tackle different aspects of TBI and investigate the consequences and mechanisms of TBI. In the first study of this thesis, I introduce an innovative automated analysis tool named Automated Limb Motion Analysis (ALMA), tailored for evaluating locomotion and paw placement in mice afflicted with various neurological disorders. ALMA uses pose estimation derived from DeepLabCut with a user-friendly graphical interface to automate the computation of kinematic parameters, footfall detection, kinematic data analysis, and visualization of gait kinematics. Interestingly, in this study, we used ALMA to analyze, among others, motor dysfunction following TBI. While motor dysfunction is always difficult to quantify following TBI, ALMA allows an in-depth access to gait parameters and can capture small but important impairments and recovery following trauma to the brain. The second study of my thesis delves into the intricate structural and functional changes occurring in the contralesional cortex following TBI. Despite initial neuronal cell loss and circuit disruption leading to behavioural and cognitive deficits, both clinical observations and animal models indicate a potential for spontaneous recovery, implicating neuronal circuit plasticity. In order to clarify the circuit rearrangements occurring in the contralesional cortex after traumatic brain injury (TBI), the study uses a comprehensive methodology that combines selective labelling of neuronal subpopulations, structural and functional in vivo imaging techniques, and mono-synaptic circuit tracing approaches. Results highlight specific adaptations of callosal neurons and their input circuits, shedding light on the mechanisms underlying cortical plasticity and recovery following TBI. This investigation not only advances our understanding of cortical plasticity but also provides crucial insights into potential therapeutic targets for enhancing recovery mechanisms in TBI patients. Concussive injuries represent the majority of TBI and pose a significant health risk to the victims. While symptoms often dissipate shortly after a single impact, repetitive concussions, particularly prevalent in sports, lead to enduring acute and chronic deficits. This third and last study aimed to establish a mouse model of concussive head injury to examine differences in behaviour and anatomy between single and repetitive injuries. Our results demonstrate that the consequences of a single concussion in term of synaptic changes or microglial structure and function are less severe than following repetitive injury. In particular, I showed that repetitive concussions result in a specific cortical and hippocampal loss of excitatory synapses, below the concussion site, associated to a chronic heightened microglial activation and increased engulfment of presynaptic excitatory synapses. These alterations coincide with a temporary deterioration in spatial memory followed by changes in fear and anxiety-related behaviours. This study underscores the significance of concussion repetition in initiating pathological processes affecting excitatory synapses, attributed to enhanced microglial engulfment function. By integrating the findings from these three studies, my thesis offers a comprehensive understanding of behavioral deficits, cortical plasticity, mechanisms initiating the impairments following different severity of TBIs.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Traumatic brain injury, Mild TBI, Microglia, Synapse engulfment, Repetitive concussion, Behavioural analysis
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 14. Februar 2025
• 1. Bericht­erstatter:in: Bareyre, Florence