In search of the rules for nerve connections.

S. H. Chung National Institute for Medical Research London NW7 1 AA, England Experimental studies on the formation of nerve con- nections properly began on April 25, 1903, when Sir Henry Head, the celebrated neurologist, had two nerves in his own arm cut so that he could experi- ence the return of skin sensitivity as the nerves re- generated (Head, Rivers, and Sherren, 1905). Since that time, more prosaic but equally productive ex- periments have been carried out, mainly on am- phibia and goldfish, to unravel the rules governing the formation of correct connections between nerves and their target cells. One particularly useful system has been the regenerating optic nerve fibers, which reconnect cells in the retina to those in the brain. In this review, I shall highlight some of the ideas and results which have been .mqst ger- mane in this field-but throughout, experimental paradigms and findings have been intentionally sim- plified, and terminology which is particular to neurophysiology is avoided. For scholarly reviews devoted to a fuller account of established facts, the reader is referred to Gaze (1970), Jacobson (1970), and Szekely (1966). Historical Background By the 1930s there were two prevailing ideas as to how regenerating nerves might reestablish func- tion. The first idea was that regenerating nerves connect with target cells more or less haphazardly, and the appropriate connections are ultimately es- tablished through adaptive processes involving their use and disuse (Holt, 1931). An alternative no- tion, advanced by Weiss (1936), was that, although the initial connections formed by regenerating fibers are indeed haphazard, orderly functional rela- tions are established by a biochemical “signalling” mechanism between the incoming and target cells; the latter would influence the incoming nerves in such a way that they would readjust or “modulate” their central connections so that only appropriate messages are transmitted. Against this background, Sperry (1943, 1944) conducted a series of experiments in which the eyes of frogs (or newts) were rotated after cutting their optic nerves. After a few weeks, optic nerve fibers grew back and made connections with neurons in the tectum (the part of the brain con- cerned with coordinating sensory and motor activi- ty). When a lure was presented within the visual field of the rotated eye, the animals snapped in the air in a direction away from the visual stimulus, and normal vision was never relearned. From these ob- servations, Sperry argued that the connections be- tween the retinal and tectal cells were restored in a rigid and orderly way to give the pattern found in the original animal (see Figure 1). Sperry (1944) postulated a possible mechanism by which the regenerating nerve fibers might find