C6: The impact of traumatic brain injury on neuronal integrity and nerve regeneration: gene expression mechanisms and neuroprotective strategies

PI: B. Knöll

Traumatic brain injury (TBI) caused by an external mechanical impact results in transient or persisting cognitive and physical impairments. Notably, head injuries such as car accidents injuries are the major cause of deaths and disabilities for people aged under 45. This project analyses TBI consequences on neuronal function with particular focus given to those cellular secondary damage processes affecting neuronal morphology and motility. These include processes typically impaired by brain trauma such as axon sprouting, axon growth and regeneration as well as dendrite and synapse morphology and number. From a molecular point of view the central question of this project is whether known neuroprotective gene expression programs exerted by the transcription factors SRF (serum response factor) or ATF3 (activating transcription factor 3) alleviate the impact of traumatic neuronal damage. Towards this end we will experimentally address two hypotheses. First of all, we analyse whether TBI elicits a gene expression response of so-called immediate early genes (IEGs; e.g. c-Fos) or regeneration-associated genes (RAGs; e.g. Gap43). Subsequently, we investigate TBI consequences on neuronal survival, axonal degeneration, axonal transport, growth and sprouting as well as dendrite complexity and spine shape and number.  In addition to neuronal damage we analyse further secondary processes affected by TBI including myelination, metabolism (e.g. glutamate exotoxicity), oedema and haemorrhage formation, blood-brain barrier (BBB) leakage and brain immune responses. Furthermore, we investigate the  neuroprotective function of key transcription factors (Atf3, Srf) in TBI. In the second project summarised under hypothesis 2 (H2) we investigate whether neuronal gene expression programmes protect from traumatic neuronal injury targeted to a specific nerve. Here we use the facial nerve as target. Facial nerve trauma imposes severe motoric as well as psycho-social impairments to humans. These processes include activation of an IEG and RAG transcriptional response (see above), axonal sprouting and regeneration, synaptic denervation and re-innervation of motoric endplates and associated cellular events such as neuroinflammation of e.g. microglia.



Prof. Dr. Bernd Knöll
Institut für Physiologische Chemie
Universität Ulm 
Albert-Einstein-Allee 11
89081 Ulm
Tel.: +49 731 500 33839
Fax: +49 731 500 22892

Hippocampal neurons growing in cell culture were labelled for localization of the actin (red) and microtubule (green) cytoskeleton.
Individual axons of the facial nerve enter motor neurons involved in regulation of facial muscle contraction.