| Head: Julita CZARKOWSKA-BAUCH, Ph.D., D.Sc. E-mail: julita@nencki.gov.pl Staff: Małgorzata SKUP, Ph.D. Dorota SULEJCZAK, M.Sc. Maciej WIATER, M.Sc. Ph.D. Students: Anna DWORNIK, M.D. Matylda MACIAS, M.Sc. Marta KAROLKOWSKA, M.Sc. Graduate students: Elżbieta GÓRNICKA Piotr OCHNIEWICZ

Injury of the central nervous system (CNS) causes alterations in the transcriptional programs that determine neuronal fate: survival and recovery or death. These alterations are initiated by the extrinsic factors released as a result of the nervous tissue damage and by intrinsic signaling cascade that links the site of injury and the nucleus. Our long-term goal is to understand the mechanisms of interactions between active molecules involved in these processes leading either to neuronal survival or to death programs.

One of the most powerful pro-survival/recovery programs may be triggered by neurotrophins that influence survival and function of many neuronal and glial populations in the CNS. However, these proteins may cause neuronal death instead of survival depending on their processing and on the type of receptor they activate. Thus, exogenous and endogenous stimuli, which modulate neurotrophin receptors, are in our focus. In particular, receptor responses to physiological activation and to posttraumatic alterations of neurotrophin pools and related molecules are studied. We have recently found that moderate, long-lasting locomotor exercise leads to upregulation of brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) in the spinal cord of intact rat. This effect was accompanied by an upregulation of their high affinity TrkBFL receptor but not TrkBTRK- or p75 receptors. These data suggest that physical training activates TrkBFL -mediated signaling indispensable in recovery processes governed by these neurotrophins. Moreover, N-CAM and L1 adhesion molecules that interact with TrkBFL -mediated signaling were also upregulated due to the exercise. We hypothesize that physical exercise following CNS injury may exert beneficial effects on recovery processes by selective upregulation of neurotrophins and their concert action with TrkBFL receptor limiting signaling through pro-apoptotic pathway.

After trauma, early cellular responses, preceding the neurotrophic alterations are studied. Topography and degree factors determine whether pro-or anti survival signaling of expression of Fos, Jun and NFkB transcription factors together with the death regulatory and executory proteins of Bcl family are under investigations. Modulation of these responses by neurotrophic milieu and interactions between these substances might be a key to understanding which

pathway in neurons will be chosen. These problems are tackled in two different experimental

models: spinal cord injury or devascularizing lesion of the sensory-motor cortical areas.

Histochemical (immunocytochemical, DNA/RNA staining, cell labeling and fiber tracing), neurochemical (HPLC) and molecular biology techniques (electrophoresis and Western blotting, RT PCR, in situ hybridization) are in use. In addition behavioral and electrophysiological methods have been employed that allow to monitor functional aspects of recovery following injury of the nervous system.

Selected publications:

1. Skup M., Torzewska D., Zaremba, M.; Devascularizing injury of the rat brain neocortex causes different neurotrophic response in denervated nucleus basalis magnocellularis and thalamic nuclei. In: Neurochemistry, ed. A. W.Teelken and J. Korf, Plenum Press, New York, pp. 513-518 (1997)

2. Gladden M.H., Jankowska E., Czarkowska-Bauch J.; New observations on coupling between group II muscle afferents and feline gamma motoneurones. J. Physiol. (London) 512: 507-520 (1998)

3. Jankowska E., Gladden M.H., Czarkowska-Bauch J.; Modulation of responses of feline gamma motoneurones by noradrenaline, tizanidine and clonidine. J. Physiol. (London) 512: 521-531 (1998)

4. Skup M., Czarkowska-Bauch J., Dwornik A., Macias M., Sulejczak D., Wiater M.; Locomotion induces changes in Trk B receptors in small diameter cells of the spinal cord. Acta Neurobiol. Exp. 60: 371 (2000)

5. Sulejczak D., Skup M.; Axoplasmic localisation of NFkB p65 subunit in the rat brain. Acta Neurobiol. Exp. 60: 217 (2000)

6. Skup M., Dwornik A., Macias M., Sulejczak D., Wiater M., Czarkowska-Bauch J.; Long-term locomotor training up-regulates TrkB FL receptor-like proteins, brain-derived neurotrophic factor, and neurotrophin 4 with different topographies of expression in oligodendroglia and neurons in the spinal cord. Exp. Neurol. 176: 289-307 (2002).

7. Macias M., Fehr S., Dwornik A., Sulejczak D., Wiater M., Czarkowska-Bauch J., Skup M., Schachner M. Exercise incerases mRNA levels for adhesion molecules N-CAM amd L1 correlating with BDNF response. Neuroreport, 13: 2527-2530 (2002).