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Myotypic Respecification of Regenerated Nerve-fibres in Cichlid Fishes
Abstract
In man and other mammals normal motor co-ordination is not restored, as a rule, after regeneration of a severed peripheral nerve-trunk (Sperry, 1945). The random misdirection of regenerating fibres into foreign muscles tends to prevent normal dissociated action within the re-innervated musculature. In contrast, larval amphibians have been found to show excellent recovery of motor function in the form of ‘homologous or myotypic response’ (Weiss, 1936, 1941) following the cutting and regeneration of limb-nerves, limb transplantation, and the crossconnecting of limb nerves to foreign muscles. Similarly, good restoration of muscle co-ordination has been observed in the pectoral fin of adult teleost fishes (Sperry, 1950, 1956).
It has been suggested (Sperry, 1941, 1951) that such recovery is most easily explained in terms of a central readjustment of synaptic connexions to suit the altered pattern of peripheral innervation. Morphological or other direct evidence for such synaptic changes, however, has not been found.
... Instead, it emerged from the random activation of the musculoskeletal anatomy, but only when that included co-innervation of both intrafusal and extrafusal muscle fibers, as provided by bMNs (as opposed to independent a and cMNs). These results are in line with studies into myotonic specificity where recovery of functional behavior occurred after cross connection of peripheral nerve fibers (70). Indeed, bMNs are known to be widely present in mammals (71), whereas mature cMNs are present only in adult mammals and only gradually develop from perinatal stages and onwards (21,72). ...
Recent spinal cord literature abounds with descriptions of genetic preprogramming and the molecular control of circuit formation. In this paper we explore to what extent circuit formation based on learning rather than preprogramming could explain some prominent aspects of the spinal cord connectivity patterns observed in animals. To test this we developed an artificial organism with a basic musculoskeletal system and proprioceptive sensors, connected to a neural network. We adjusted the initially randomized gains in the neural network according to a Hebbian plasticity rule while exercising the model system with spontaneous muscle activity patterns similar to those observed during early fetal development. The resulting connection matrices support functional self-organization of the mature pattern of Ia to motoneuron connectivity in the spinal circuitry. More coordinated muscle activity patterns such as observed later during neonatal locomotion impaired projection selectivity. These findings imply a generic functionality of a musculoskeletal system to imprint important aspects of its mechanical dynamics onto a neural network, without specific preprogramming other than setting a critical period for the formation and maturation of this general pattern of connectivity. Such functionality would facilitate the successful evolution of new species with altered musculoskeletal anatomy and it may help to explain patterns of connectivity and associated reflexes that appear during abnormal development.
... Instead, it emerged from the random activation of the musculoskeletal anatomy, but only when that included co-innervation of both intrafusal and extrafusal muscle fibers, as provided by bMNs (as opposed to independent α and γMNs). These results are in line with studies into myotonic specificity where recovery of functional behavior occurred after cross-connection of peripheral nerve fibers (Arora and Sperry, 1957). Indeed, bMNs are known to be widely present in mammals (Illert, 1996), whereas mature γMNs are present only in adult mammals and only gradually develop from perinatal stages and onwards (Ashrafi et al., 2012;Shneider et al., 2009). ...
Recent spinal cord literature abounds with descriptions of genetic preprogramming and the molecular control of circuit formation. In this paper we explore to what extent circuit formation based on learning rather than preprogramming could explain some prominent aspects of the spinal cord connectivity patterns observed in animals. To test this we developed an artificial organism with a basic musculoskeletal system and proprioceptive sensors, connected to a neural network. We adjusted the initially randomized gains in the neural network according to a Hebbian plasticity rule while exercising the model system with spontaneous muscle activity patterns similar to those observed during early fetal development. The resulting connection matrices support functional self-organization of the mature pattern of Ia to motoneuron connectivity in the spinal circuitry. More coordinated muscle activity patterns such as observed later during neonatal locomotion impaired projection selectivity. These findings imply a generic functionality of a musculoskeletal system to imprint important aspects of its mechanical dynamics onto a neural network, without specific preprogramming other than setting a critical period for the formation and maturation of this general pattern of connectivity. Such functionality would facilitate the successful evolution of new species with altered musculoskeletal anatomy and it may help to explain patterns of connectivity and associated reflexes that appear during abnormal development.
... In parallel paper, we reported caspase-3 dependent apoptosis and downreguration of insulin-like growth factor-I in rat retinal ganglion cells (RGCs) after optic nerve (ON) injury. On the other hand, RGCs of lower vertebrates such as fish can successfully regenerate their axons after ON injury (Arora and Sperry, 1957). ...
Goldfish retinal ganglion cells (RGCs) can regrow their axons after optic nerve injury. However, the reason why goldfish RGCs can regenerate after nerve injury is largely unknown at the molecular level. To investigate regenerative properties of goldfish RGCs, we divided the RGC regeneration process into two components: (1) RGC survival, and (2) axonal elongation processes. To characterize the RGC survival signaling pathway after optic nerve injury, we investigated cell survival/death signals such as Bcl-2 family members in the goldfish retina. Amounts of phospho-Akt (p-Akt) and phospho-Bad (p-Bad) in the goldfish retina rapidly increased four- to five-fold at the protein level by 3-5 days after nerve injury. Subsequently, Bcl-2 levels increased 1.7-fold, accompanied by a slight reduction in caspase-3 activity 10-20 days after injury. Furthermore, level of insulin-like growth factor-I (IGF-I), which activates the phosphatidyl inositol-3-kinase (PI3K)/Akt system, increased 2-3 days earlier than that of p-Akt in the goldfish retina. The cellular localization of these molecular changes was limited to RGCs. IGF-I treatment significantly induced phosphorylation of Akt, and strikingly induced neurite outgrowth in the goldfish retina in vitro. On the contrary, addition of the PI3K inhibitor wortmannin, and IGF-I antibody inhibited Akt phosphorylation and neurite outgrowth in an explant culture. Thus, we demonstrated, for the first time, the signal cascade for early upregulation of IGF-I, leading to RGC survival and axonal regeneration in adult goldfish retinas through PI3K/Akt system after optic nerve injury. The present data strongly indicate that IGF-I is one of the most important molecules for controlling regeneration of RGCs after optic nerve injury.
Fish were trained to jump at the correct (rewarded) one of two differently colored feeders and to avoid feeders of other colors and different shades of gray. It was found that the fish could discriminate the colors red, blue, yellow, and green both in the normal state and after complete section and regeneration of the optic nerve.When the color preferences were trained prior to optic nerve section, regeneration of the nerve resulted in reinstatement of the same color preferences, no relearning being necessary. Some of the implications regarding specificity of the optic fibers and factors governing their central synapsis in the optic tectum are discussed.
Nerves supplying forearm flexor muscles were exchanged (crossed) with those supplying forearm extensors. After complete recovery, the movements of the forelimb were the same as those of normal limbs. Dissections showed that the nerves remained crossed, and electrical stimulation of the crossed nerves close to the muscles they supplied showed that the nerves were functionally connected to the foreign muscles. On the basis of these criteria, it appeared that axolotl nerves could respecify themselves.
Stimulation of the crossed nerves further from the muscles they innervated, however, yielded contractions in the muscles that the nerves had originally supplied. Therefore, one of the two crossed nerves was severed at the shoulder and allowed to degenerate so that any movements elicited by subsequent electrical stimulation could be ascribed unambiguously to the remaining, non‐degenerated nerve. Electrical stimulation now showed clearly that the nerve which had originally innervated forearm flexors continued to produce flexion responses after it was crossed, and the nerve which had formerly innervated extensors continued to produce extension. Thus the fibers had somehow recrossed to reinnervate their original muscles.
It therefore appears from the present investigation that axolotl nerves do not respecify themselves. Instead, a few fibers find their way back to their original muscles, and this is enough to produce normal movement.
It has long been considered a general rule for nerve regeneration that the reinnervation of skeletal muscle is nonselective. Regenerating nerve fibers are supposed to reconnect with one skeletal muscle as readily as another according to studies covering a wide range of vertebrates (Weiss, 1937; Weiss & Taylor, 1944; Weiss & Hoag, 1946; Bernstein & Guth, 1961; Guth, 1961, 1962, 1963). Similarly, in embryogenesis proper functional connexions between nerve centers and particular muscles are supposedly attained, not by selective nerve outgrowth but rather through a process of ‘myotypic modulation’ (Weiss, 1955) that presupposes nonselective peripheral innervation.
Doubt about the general validity of this rule and the concepts behind it has come from a series of studies on regeneration of the oculomotor nerve in teleosts, urodeles, and anurans and of spinal fin nerves in teleosts (Sperry, 1946, 1947, 1950, 1965; Sperry & Deupree, 1956; Arora & Sperry, 1957a, 1964).