Dahlem Workshop Reports Life Sciences Research Report 24 Repair and Regeneration of the Nervous System The goal of this Dahlem Workshop is: to define how the nervous system is able to restore function after injury by repairing connections or by compensatory mechanisms Life Sciences Research Reports Editor: Silke Bernhard Held and published on behalf of the Stifterverband fUr die Deutsche Wissenschaft Sponsored by: Heinz Breuninger Stiftung GmbH Hermann und Lilly Schilling-Stiftung fUr Medizinische Forschung im Stifterverband fUr die Deutsche Wissenschaft Repair and Regeneration of the Nervous System J. G. Nicholls, Editor Report of the Dahlem Workshop on Repair and Regeneration of the Nervous System Berlin 1981, November 29 - December 4 Rapporteurs: H. J. Anderson' J. W. Lichtman' M. E. Raichle . C. J. Shatz Program Advisory Committee: J. G. Nicholls, Chairman' W. M. Cowan' W. E. Crill H.-J. Freund' N. N. Herschkowitz . J. K. S. Jansen' D. Purves W.J.Singer Springer-Verlag Berlin Heidelberg New York 1982 Copy Editors: M. Cervantes-Waldmann, K. McWhirter Photographs: E. P. Thonke With 4 photographs, 30 figures, and 3 tables ISBN -13: 987-3-642-68634-4 e-ISBN -13: 987-3-642-68632-0 001: 10.1007/987-3-642-68632-0 CIP-Kurztitelaufnahme der Deutschen Bibliothek: Repair and regeneration of the nervous system: report of the Dahlem Workshop on Repair and Regeneration of the Nervous System, Berlin 1981, November 29 - December 41 J. G. Nicholls, ed. Rapporteurs: H. J. Anderson ... [Dahlem Konferenzen. Held and publ. on behalf of the Stifterverb. for d. Dt. Wiss. Sponsored by: Heinz-Breuninger-Stiftung GmbH; Hermann-u.-Lilly-Schilling Stiftung fUr Med. Forschung im Stifterverb. fUr d. Dt. Wiss.]. - Berlin; Heidelberg; New York: Springer, 1982 (Life sciences research report; 24) (Dahlem Workshop reports) NE: Nicholls, John G. [Hrsg.]; Anderson, Hilary, J. [Mitverf.J; Workshop on Repair and Regeneration of the Nervous System <1981, Berlin, West>; Dahlem Konferenzen; 1. GT This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data-banks. Under § 54 of the German Copyright Law, where copies are made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", MUnchen. © Dr. S. Bernhard, Dahlem Konferenzen, Berlin 1982. Sottcover reprint of the hardcover 1st edition 1982 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. 2131/3014 - 5 4 3 2 1 0 Table of Contents The Dahlem Konferenzen .................................... vii Introduction J.G. Nicholls ............................................ . A Synoptic View of the Development of the Vertebrate Central Nervous System W.M. Cowan................................................ 7 Normal and Abnormal Development of the Human Nervous System N.N. Herschkowitz and G.M. McKhann ........................ 25 Factors That Influence Neural Development in Nematodes H.R. Horvitz.............................................. 41 Acute Neural Reaction to Injury G. W. Kreutzberg........................................... 57 Molecular Events in Axonal Regeneration M. Willard and J.H.P. Skene............................... 71 Transplantation of Neurons and Sheath Cells - A Tool for the Study of Regeneration A.J. Aguayo, P.M. Richardson, S. David, and M. Benfey ..... 91 Guidance ofAxons During Development and After Nerve Injury D. Purves .........................•....................... 107 Regeneration of Synapses J.R. Sanes ...................................•............ 127 Cell Recognition and Specific Synapse Formation K.J. Muller ............................................... 155 Factors Involved in the Regulation of the Survival and Differentiation of Neurons H. Thoenen, Y.-A. Barde, and D. Edgar ..................... 173 Regeneration and Repair of the Nervous System: Clinical Aspects H.-J. Freund and H.J. Bauer ............................... 187 vi Table of Contents Recovery Mechanisms in the Mammalian Brain W. Singer................................................. 203 Clinical Evaluation of Injury and Recovery W.E. Crill and M.E. Raichle ............................... 227 Adaptive and Maladaptive Regeneration in the Spinal Cord E. Frank .................................................. 243 Temporal Changes After Spinal Cord Injury L. Mendell ................................................ 255 Electroneuroprostheses: Usefulness in Rehabilitation B.S. Nashold, Jr .......................................... 269 Neural Development: Implications for Recovery from Injury Group Report C.J. Shatz, Rapporteur M. Bate, F.J. Bonhoeffer, W.M. Cowan, S.S. Easter N.N. Herschkowitz, H.R. Horvitz, G.M. McKhann, F. Rathjen, M. Schachner, T.A. Sears ...................... 289 Early Responses to Neural Injury Group Report H.J. Anderson, Rapporteur A.J. Aguayo, S.E. Blackshaw, D. Bray, R.W. Gilliatt, A.D. Grinnell, G.W. Kreutzberg, I. Parnas, D. Purves, S. Rotshenker, M.E. Schwab, M.B. Willard .................. 315 Factors Involved in the Restoration of Specific Neural Connections Group Report J.W. Lichtman, Rapporteur T.P. Feng, J.K.S. Jansen, B. Katz, J.B. Martin, K.J. Muller, J.G. Nicholls, G. Raisman, J.R. Sanes, J. Schnitzer, E.M. Shooter, H. Thoenen, N. Tsukahara, T.N. Wiesel ....... 343 Restoration of Function Group Report M.E. Raichle, Rapporteur D.Y. von Cramon, W.E. Crill, H. Flohr, E. Frank, H.-J. Freund, K.-A. Hossmann, L.M. Mendell, M. Mishkin, B.S. Nashold, Jr., W. Precht, J. Zihl .•................... 383 List of Participants ..............................•....... 399 Subject Index ............................................• 405 Author Index ...................................•..••...... 411 The Dahlem Konferenzen DIRECTOR: --------- Silke Bernhard, M.D. F-O-U--N-D-A-T-IO--N-: Dahlem Konferenzen was founded in 1974 and is supported by the Stifterverband fUr die Deutsche Wissenschaft*, in cooperation with the Deutsche Forschungsgemeinschaft** and the Senat of the City of Berlin. OBJECTIVES: ----------- The task of Dahlem Konferenzen is: to promote the interdisciplinary exchange of scientific in formation and ideas, - to stimulate international cooperation in research, and - to develop and test different models conducive to more effec- tive scientific meetings. AIM: Each Dahlem Workshop is designed to provide a survey of the present state of the art of the topic at hand as seen by the various disciplines concerned, to review new concepts and tech niques, and to recommend directions for future research. -T-O-P-IC--S-: The workshop topics (in the Life Sciences and the field of Physicoche~istry) should be: - of contemporary international interest, - timely, interdisciplinary in nature, and - problem-oriented. PROCEDURE: Dahlem Konferenzen approachEs internationally recognized scien tists to suggest topics fulfilling these criteria and to pro pose members for a Program Advisory Committee, which is re sponsible for the workshop's scientific program. Once a year, the topic suggestions are submitted to a scientific board for approval. * ThE Donors Association for the Promotion of Sciences and Humanities ** German Science Foundation viii The Dahlem Konferenzen -PA--R-T-I-C-IP-A-N--T-S-: The number of participants is limited to 48 for each workshop. They are selected exclusively by a Program Advisory Committee. Selection is based on international scientific reputation alone and is independent of national considerations, although a bal ance between Europeans and Americans is desirable. Exception is made for younger German scientists for whom 10% of the places are reserved. THE DAHLEM WORKSHOP MODEL: -------------------------- A special workshop model has been developed by Dahlem Konferenzen, the Dahlem Wo~k~hop Model. The main work of the workshop is done in four small, interdisciplinary discussion groups, each with 12 members. Lectures are not given. Some participants are asked to write background papers_providing a review of the field rather than a report on individual work. These are circulated to all participants 4 weeks before the meeting with the request that the papers be read and questions on them formulated be6o~e the workshop, thus providing the basis for discussions. During the workshop, each group prepares a report reflecting the essential points of its discussions, including suggestions for future research needs. These reports are distributed to all participants at the end of the workshop and are discussed in plenum. PUBLICATION: ------------ The Dahlem Workshop Reports contain: - the Chairperson's introduction, - the Background Papers, and - the Group Reports. The Dahlem "']orkshop Reports are available in two series: 1) Life Sciences Research Reports (LS) and 2) Physical and Chemical Sciences Research Reports (PC). DAHLEM KONFERENZEN, Wallotstrasse 19, D-1000 Berlin 33, Federal Republic of Germany Repair and Regeneration of the Nervous System, ed. J.G. Nicholls, pp. 1-5. Dahlem Konferenzen 1982. Berl in, Heidelberg, New York: Springer-Verlag. Introduction J. G. Nicholls Dept. of Neurobiology, Stanford University School of Medicine Stanford, CA 94305, USA This volume deals with a key problem in modern biology and clini cal neurology, namely, the way in which the nervous system is able to repair itself, to restore function, and to regenerate synaptic connections. Faced with patients suffering from a stroke, a severed peripheral nerve, or an injury to the spinal cord, the clinician has to assess the extent of the lesion and the possibility of recovery, and, if recovery does occur, the mechanism by which it has been brought about. To what extent can the restoration of function in a patient be attributed to collateral sprouting, to some neurons taking over the function of others, or to regeneration? At the same time, the mechanisms involved in the responses to injury of neurons and glial cells, in growth and in recovery, represent tantalizing problems for the cell biologist and neurobiologist interested in the develop ment and function of the nervous system. Accordingly, it seemed particularly appropriate for there to be a Dahlem Workshop deal ing with regeneration and restoration of function in the nervous system, with its main focus being on the interactions not only between basic scientists from widely different disciplines, but also with clinicians who everyday see patients suffering from damage to the nervous system that results from trauma or disease. 2 J.G. Nicholls What is striking is how much the field has advanced over the past few years, and how different this dialogue is now compared to what was possible just a few years ago. In the past, there was a great deal of information available about regeneration in the peripheral nervous system, particularly with respect to the re-innervation of skeletal muscles in frogs and mammals. How ever, little was known about the biochemistry of acetylcholine receptors, the role of activity in regulating supersensitivity, or the properties of the basal lamina. Similarly, for the cen tral nervous system, it was taken for granted that the mamma lian brain had little or no power of regeneration following an injury, apart from limited sprouting with no obvious functional consequence. The only definite examples of central nervous sys tem regeneration were obtained in invertebrates and lower ver tebrates, and there the most intensively studied systems were the connections from retina to tectum in frogs, fishes, and salamanders. The phenomena revealed an extraordinary degree of plasticity in the eNS. Thus, in a frog, if the optic nerve was cut, fibers could be shown to grow back from the retina to the tectum, where they became reconnected to their original targets with sufficient accuracy for function to be restored, enabling the frog to see once again. This type of experiment poses a range of questions that still need to be considered today and that serve as a focus for the organization of this volume. 1) What are the effects of sectioning axons on the cell body, and how is sprouting induced? What are the mechanisms by which a neuron is made to extend its processes? 2) Once neurons are growing, what determines the direction that the axons will take, and what interactions occur between the neurons and the glial cells or Schwann cells that surround them? 3) When neurons reach their destination, what signals pass from the targets or from associated structures to terminate growth and to induce the specialization of terminals? 4) What determines whether a cell will make connections with another cell or will fail to do so? If errors are made, are they corrected?