Nitric oxide: A radical neurotransmitter in the central nervous 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)

Alcohol and central neurotransmission.

Alcohol dependence (“alcoholism”) is diagnosed based in part on the development of physiological adaptations to alcohol (ethanol) including tolerance and dependence, and loss of control over alcohol intake. It is believed that alcohol is initially ingested for its reinforcing effects (positive or negative), and that adaptive changes in the brain in response to alcohol exposure contribute to the development of alcohol dependence. In searching for a neurochemical basis for the effects of alcohol that lead to addiction, much work has focused on the NMDA subtype of glutamate receptor, which is very sensitive to inhibition by low concentrations of alcohol. This chapter reviews studies of the molecular mechanism of alcohol inhibition of NMDA receptor function, which may involve changes in phosphorylation of the receptor or associated proteins, as well as evidence for a role of the NMDA receptor in the reinforcing effects of ethanol. Further, the changes in NMDA receptor function that occur after chronic ethanol exposure or ingestion, as well as the role of these changes in the development of dependence and “craving” for alcohol are discussed. The potential for using compounds that modify NMDA receptor function as therapeutic agents to ameliorate the addictive properties of alcohol is also addressed.

R.A. Dodson

Papers

Effects of ethanol, arecoline, atropine and nicotine, alone and in various combinations, on rat cerebellar cyclic guanosine 3′,5′-monophosphate