Lab Projects

 

Molecular regulation of axonal growth induction

Spinal cord injury (SCI) leads to severe and persistent functional deficits due to the limited repair of severed axonal connections in the central nervous system (CNS). Therapeutic options are insufficient and their further development has been hampered by the lack of reliable tools to quantify axonal regeneration or reorganization in animal models. We have developed a multi-layered approach to evaluate repair in the injured spinal cord based on the use of transgenic animals, simultaneous tracing of multiple axon tracts and in vivo imaging. This combined approach allows us to (1) reliably quantify CNS regeneration, (2) assess axonal reorganization on multiple anatomical levels and (3) image CNS regeneration in vivo. We can now use this combination of techniques to evaluate new therapeutic strategies. The regulation of axonal regeneration depends on numerous growth-promoting and growth-inhibitory signals that converge on common intracellular signaling cascades. Thus directly targeting downstream regulators of such common pathways is a promising strategy. One example of such a common downstream target is the transcription factor STAT 3 (signal transducers and activators of transcription 3). Recent work by us and others indicates that lack of STAT upregulation is correlated with failure to regenerate: Indeed, while injured peripheral neurons express STAT persistently until complete regeneration to their targets, CNS neurons show only transient STAT upregulation and abortive regeneration. Interestingly, our own data further indicates that STAT transcription factors are induced by therapies that stimulate axonal growth in the CNS. To directly assess the contribution of STAT transcription factors we now genetically manipulate STAT expression in peripheral and central projections neurons and image the resulting neuronal growth response in vivo.

Collaborators: Martin Kerschensteiner, (Institute of Clinical Neurolmmunology), Hildegard Büning (Dept. of Internal Medicine, University of Cologne), Thomas Misgeld (Institute of Neuroscience, TU Munich)

 

Regulation of axon guidance and synapse formation after spinal cord injury

The incidence of Spinal Cord Injury (SCI) in Germany is estimated at about 36 cases per million of the population, which translates to about 3000 new spinal cord injured patients per year. Most of these patients are young adults injured at work or during traffic accidents who will have to live the rest of their life disabled due to the limited repair capacity of severed central axons. Recently, therapeutic options have emerged that can promote some level of axonal outgrowth after SCI. However, our work emphasizes that axonal outgrowth is in itself insufficient and that regrowing axons have to be integrated into reorganized intraspinal networks to promote functional recovery. To achieve this aim the following questions need to be addressed: (i) How do regrowing axons find the correct path to their intermediate or final targets? (ii) How do regenerating axons make appropriate synaptic connections? (iii) Which therapeutic strategies can support axons during pathfinding and synapse formation? The answers to these questions in SCI are essentially unknown. However axonal pathfinding and synapse formation have been studied extensively in the developing nervous system and many of the key mechanisms have been identified. Transfer of this knowledge to SCI has, so far, been limited, partly due to the lack of appropriate techniques to follow axonal pathfinding and synapse formation after injury. Over the recent years we have therefore developed novel approaches to (i) observe and modulate the growth and pathfinding of injured spinal axons in vivo, (ii) visualize and regulate synapse formation in intraspinal circuits and (iii) reliably assess therapeutic effects on axonal repair after SCI. In this project we use these powerful new tools to identify the molecular cues that guide regrowing axons, to determine the molecules that modulate the formation of new synaptic contacts and to develop novel therapeutic strategies that improve axonal pathfinding, synaptic reconnection and functional recovery after injury.

Collaborators:  Hisashi Umemori (Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School, USA), Jeroen Pasterkamp (Dept. of Neuroscience and Pharmacology, University of Utrecht, The Netherlands), Yu Yamaguchi (Sandford Burnham Medical Research Institute, La Jolla, USA)

 

Activity-dependent regulation of detour circuit formation after spinal cord injury

The transection of axonal connections leads to motor and sensory deficits in many traumatic, ischemic and inflammatory conditions of the central nervous system (CNS). Despite the fact that axonal regeneration generally fails in the CNS, dramatic functional recovery can be observed in particular after incomplete lesions to brain and spinal cord.

Our recent work indicates that spontaneous recovery of motor function can be mediated by the formation of intraspinal detour circuits. Detour circuits are formed in the following steps: First, a subpopulation of transected projection neurones forms new collaterals that contact intraspinal relay neurones. Initially these collaterals contact relay neurones irrespective of their projection pattern. However over the following weeks only those sprouts which contact neurones that connect to the original target area are maintained while other sprouts are eliminated. Electrophysiological and behavioural experiments confirm that intraspinal detour circuits are key anatomical substrates of functional recovery.

To understand when and where detour circuits can be formed and which regulatory principles guide their formation we now study: (1) whether the formation of detour circuits is also possible in the somatosensory system and is thus a general blueprint for both motor and sensory recovery, (2) if and how neuronal activity guides the stabilization or elimination of newly formed connections and (3) whether we can design training or activity paradigms that enhance the formation of detour circuits and thereby improve functional recovery after CNS injury.

Collaborators: Karl-Klaus Conzelmann (Genzentrum, LMU München), Daniel Kerschensteiner (Dept. of Opthalmology and Visual Sciences, Washington University School of Medicine, USA), part of the Collaborative Research Centre 870.

 
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Director

Prof. Dr.

Reinhard Hohlfeld

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Prof. Dr.

Martin Kerschensteiner

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Group Leader

Dr.

Florence Bareyre

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