Activity-dependent plasticity occurs in the spinal cord throughout life. Driven by input from the periphery and the brain, this plasticity plays an important role in the acquisition and maintenance of motor skills and in the effects of spinal cord injury and other central nervous system disorders. The responses of the isolated spinal cord to sensory input display sensitization, long-term potentiation, and related phenomena that contribute to chronic pain syndromes; they can also be modified by both classical and operant conditioning protocols. In animals with transected spinal cords and in humans with spinal cord injuries, treadmill training gradually modifies the spinal cord so as to improve performance. These adaptations by the isolated spinal cord are specific to the training regimen and underlie new approaches to restoring function after spinal cord injury. Descending inputs from the brain that occur during normal development, as a result of supraspinal trauma, and during skill acquisition change the spinal cord. The early development of adult spinal cord reflex patterns is driven by descending activity; disorders that disrupt descending activity later in life gradually change spinal cord reflexes. Athletic training, such as that undertaken by ballet dancers, is associated with gradual alterations in spinal reflexes that appear to contribute to skill acquisition. Operant conditioning protocols in animals and humans can produce comparable reflex changes and are associated with functional and structural plasticity in the spinal cord, including changes in motoneuron firing threshold and axonal conduction velocity, and in synaptic terminals on motoneurons. The corticospinal tract has a key role in producing this plasticity. Behavioral changes produced by practice or injury reflect the combination of plasticity at multiple spinal cord and supraspinal sites. Plasticity at multiple sites is both necessary-to insure continued performance of previously acquired behaviors-and inevitable-due to the ubiquity of the capacity for activity-dependent plasticity in the central nervous system. Appropriate induction and guidance of activity-dependent plasticity in the spinal cord is an essential component of new therapeutic approaches aimed at maximizing function after spinal cord injury or restoring function to a newly regenerated spinal cord. Because plasticity in the spinal cord contributes to skill acquisition and because the spinal cord is relatively simple and accessible, this plasticity is a logical and practical starting point for studying the acquisition and maintenance of skilled behaviors.

Activity-dependent spinal cord plasticity in health and disease.

It is postulated that there are 2 major systems in the brain that maintain the ongoing behavior of the vertebrate organism. Arousal System 1 is related to the reticular activating system. It maintains the arousal of the organism, and provides the organization for responses. Arousal System II is related to the limbic system, and provides control of responses through incentive-related stimuli. The organization of these 2 mechanisms is postulated to be mutually inhibitory. It is shown how such an organization is of value in understanding reinforcement as part of a reciprocal relation between drive (Arousal System I) and incentive (Arousal System II). Memory is viewed as a consequence of this reciprocity. The present paper grew out of an attempt to understand the relation between two recent major findings in neurobiology. The first was described by Moruzzi and Magoun (1949) and concerned itself with a medial core primarily in midbrain and hindbrain whjch was capable of activating or arousing the cerebral cortex. This system has often been referred to as the Ascending Reticular Activating System (ARAS). The second finding concerned the discovery (Olds & Milner, 1954) of a series of points primarily within the forebrain which when stimulated prpduced effects similar to "normal" reward. The proposal offered here is that these two discoveries represent the description of two major brain mechanisms that are critical to the organism for the execution of appropriate behavior sequences. Because the two systems operate in such an intimate 1 The author wishes to thank Stanley A. Lorens and Benton J. Underwood for reading a preliminary draft of the manuscript, an4 tp acknowledge his debt to P. Milner, S. Glickman, and J. Olds. During the preparation of the manuscript the author was supported by United States Public Health Service contract MH11991. fashion, much confusion has occurred in the analysis of certain data related to these systems. It is the purpose of the paper to show that an analysis of brain function assuming two arousal systems may be of value in the future to help correct this confusion. A second purpose is to organize a sufficient amount of information to point out where empirical facts appear necessary, and to stress certain special issues which have arisen in considering the information relevant to the two-arousal hypothesis.

The two-arousal hypothesis: reticular formation and limbic system.

Brindley proposed that we initially generate movements “consciously”, under higher cerebral control. As the movement is practiced, the cerebellum learns to link within itself the context in which the movement is made to the lower level movement generators. Marr and Albus proposed that the linkage is established by a special input from the inferior olive, which plays upon an input-output element within the cerebellum during the period of the learning. When the linkage is complete, the occurrence of the context (represented by a certain input to the cerebellum) will trigger (through the cerebellum) the appropriate motor response. The “learned” movement is distinguished from the “unlearned” conscious movement by its now being automatic, rapid, and stereotyped. The idea is still controversial, but has been supported by a variety of animal studies and, as reviewed here, is consistent with the results of a number of human PET and ablation studies. I have added to the idea of context-response linkage what I think is another important variable: novel combinations of downstream elements. With regard to the motor system and the muscles, this could explain how varied combinations of muscles may become active in precise time-amplitude specifications so as to produce coordinated movements appropriate to specific contexts. In this target article, I have further extended this idea to the premotor parts of the brain and their role in cognition. These areas receive influences from the cerebellum; they are active both in planning movements that are to be executed and in thinking about movements that are not to be executed. From recent evidence, the cerebellar output extends even to what has been characterized as the ultimate frontal planning area, the “prefrontal” cortex, area 46. The cerebellum thus may be involved in context-response linkage, and response combination even at these higher levels. The implication would be that, through practice, an experiential context would automatically evoke a certain mental action plan. The plan would be in the realm of thought, and could – but need not – lead to execution. The specific cerebellar contribution would be one of the context linkage and the shaping of the response, through trial and error learning. The prefrontal and premotor areas could still plan without the help of the cerebellum, but not so automatically, rapidly, stereotypically, so precisely linked to context, or so free of error. Nor would their activities improve optimally with mental practice.

On the specific role of the cerebellum in motor learning and cognition: Clues from PET activation and lesion studies in man

The persistence of many contrasting notions of climbing fiber function after years of investigation testifies that the issue of climbing fiber contributions to cerebellar transactions is still unresolved. The proposed capabilities of the climbing fibers cover an impressive spectrum. For many researchers, the climbing fibers signal errors in motor performance, either in the conventional manner of frequency modulation or as a single announcement of an “unexpected event”. More controversial is the effect of these signals on the simple spike modulation of Purkinje cells. In some hands, they lead to a long-term depression of the strength of parallel fiber synapses, while, in other hands, they lead to a short-lasting enhancement of the responsiveness of Purkinje cells to mossy fiber inputs or contribute to the often-seen reciprocal relation between complex and simple spike modulation. For still other investigators, the climbing fibers serve internal timing functions through their capacity for synchronous and rhythmic firing. The above viewpoints are presented in the spirit of trying to reach some consensus about climbing fiber function. Each point of view is introduced by summarizing first the key observations made by the respective proponents; then the issues of short-lasting enhancement, reciprocity between complex and simple spikes, and synchrony and rhythmicity are addressed in the context of the visual climbing fiber system of the vestibulocerebellum.

More on climbing fiber signals and their consequence(s)

SUMMARY

Daily unilateral electrical stimulation of amygdala in forebrain bisected cats provoked the development of the final stage of the kindled convulsion with remarkable rapidity regardless of presence or absence of anterior commissure. The chronological and spatial pattern of propagation of afterdischarge, interictal spike discharge, and clinical manifestations strongly suggest the significant role played by the midbrain reticular formation and possibly other brainstem structures in the progressive electroclinical seizure development. This assumption was supported by the results of a lesion study in which placement of a destructive lesion in the ipsilateral midbrain reticular formation markedly increased the generalized seizure triggering threshold, later-alized the afterdischarge to the stimulated hemisphere when induced with increased intensity stimulation, fragmented clinical seizure manifestations, and failed to produce progression of clinical and electrographic events with prolonged daily stimulation. This is in contrast to the insignificant effect produced by a peduncular lesion. Our findings suggest that vertical (limbic-brainstem), but not horizontal (transhemispheric interlimbic) connection is critically involved in the amygdaloid seizure development while the forebrain commissures may play a role in the development of bisynchronous and bisymmetrical ictal and interictal electrographic and clinical manifestations. Finally, possible differential effect of forebrain bisection depending on developing in contrast with an established (cerebral) hemispheric epileptogenic process is postulated to explain the “facilitatory” effect observed in our series in contrast to the beneficial effects reported on some intractable seizure patients.



RESUME

Une stimulation electrique journaliere de l'amygdale dans l'encephale anterieur bisseque de chats, provoque une evolution de l‘etat final de la convulsion excitee remarquablement rapide, sans considerer la prence ou l'absence de commissure anterieure. Le mode de propagation chronologique et spatial de apres-decharge, “interictal spike decharge” et les manifestations cliniques indiquent clairement le role vital joue par formation reticulaire du mesencephale et peut-etre d'autre structures pedonculaire du cerveau dans le developpement de l'etat final de l'attaque. Cette hypothese est soutenu par les resultats de l'etude d'une lesion, dans laquelle 1'introduction d'une lesion de-structriace dans la formation reticulaire homo-laterale du meencephale augmente remarquablement le seuil de l'attaque, bloque l'apparence d'une attaque generalised, et lateral-ise Papresdecharge dans Phemisphere stimule. Ceci contraste avec l'effet insignificant produit par une lesion pedonulaire. Nos recherches suggerent que le renforcement de 1'attache due pedoncle limbique du cerveau (formation reticulaire du mesencfiphale) est d'une importance decisive pour le phenomene d'excitation pendant que la commissure du “forebrain” joue un role dans le developpement electrographique et clinique des manifestations bisynchronique et bisymetrique, “ictal” et “inter-ictal.” Enfin, un effet differenciel possible de la bissection du prosencephale, celon le development du procede compare a celui hemispherique (cerebral) epileptogene connu, est suggere pour expliquer l'effet de “frayage” (facilitatory) observe dans nos serie d'experiences en contraste avec les effets salutaires relates chez quelques malades critiques intraitables.



RESUMEN

La estimulacidn electrica diaria de la arm'gdala en gatos produce un desarrollo progresivo de ataques electroclinicos que culminan en convulsiones generalizadas (Kindling).



Una lesion electrolftica en la sustancia reticular mesencefalica, homolateral a la amfgdala estimulada, produjo una marcada elevacion del umbral para convulsiones generalizadas y redujo la susceptibilidad al pentilen-tetrazol. Por el contrario lesiones en el palido no produjeron efectos sobre el umbral convul-sivo y dieron la impresion de aumentar la susceptibilidad al pentilentetrazol.



Estos resultados apoyan la hipotesis de que: (1) la sustancia reticular mesencefalica participa de manera significativa en el proceso del progresivo desarrollo de convulsiones amigdalo-ideas, y (2) los efectos de las lesiones en la sustancia reticular mesencefalica no dependen de la presencia de la bisection del telencefalo.



ZUSAMMENFASSUNG

Tagliche elektrische Reizung des Mandel-kerns verursacht bei Katzen Auftreten und Zunahme elektro-klinischer Anfalle, die in generalisierten Konvulsionen gipfeln (“kindling”– Aufschaukelphanomen). Eine elek-trolytbedingte Lasion der Formatio reticularis im Mittelhirn, auf der Seite des gereizten Mandelkerns erhoht deutlich die Reizschwelle fur die Auslosung generalisierter Anfalle und vermindert die Empfindlichkeit gegeniiber Pen-tylentetrazol. Im Gegensatz dazu zeigen Verlet-zungen des Globus pallidus keinen verwertbaren Effekt auf die Ausloseschwelle fur generalisierte Krampfanfalle. Sie scheinen die Empfindlichkeit gegenuber Pentylentetrazol zu erhohen.



Diese Ergebnisse unterstiitzen folgende Hypothesen:



1
Die Formatio reticularis des Mesencephalon spielt eine wesentliche Rolle im Prozess der Entwicklung und Auspragung von Anfallen ausgehend vom Mandelkern.

2
Die Auswirkung einer Lasion in der Formatio reticularis des Mittelhirns ist nicht abhangig von einer Unterbrechung der Verbin-dung zum Telencephalon.

P. Halick

Papers

Fixation of experience in the rat spinal cord.