Human and animal studies have shown that exposure to moderate peak blood levels of ethanol during development results in permanent morphological changes in the cerebellum and cerebrum and in motor and other behavioral deficits. In the rat """"""""motor learning,"""""""" as opposed to simple motor activity, results in morphologically-detectable increases in synapse numbers, vasculature and glial cell processes in the cerebellar cortex and improved performance in motor tasks. This project is assessing the therapeutic effects of exposure to a program of """"""""rehabilitative motor training upon 1) the behavioral symptoms of brain dysfunction in tests of motor skill and 2) synaptic, glial, and vascular morphology in adult rats following alcohol exposure on days 4-9 postnatal. This period of exposure corresponds to third trimester fetal alcohol exposure in humans. We have found that the rehabilitation procedure, when administered in adulthood, 1) improves motor performance and 2) increases the number of synapses per Purkinje cell in the cerebellar paramedian lobule (PML) of the alcohol exposed rats. A motor control procedure, walking in a closed alleyway, run only for the behavioral study, had only small effects on motor performance. Proposed goals for the coming period are to 1) continue study of material from these animals exposed to rehabilitation in adulthood, to understand the potentially distributed nature of the rehabilitation process and 2) investigate whether intervention at an earlier age, immediately after weaning, will have greater impact, an issue of great relevance with regard to clinical applications. Data collection from the adult rehabilitation rats will focus upon the lateral cerebellar nucleus (the primary recipient of PML output, which is damaged by neonatal alcohol treatment and does not respond to this experience in normal animals), motor cerebral cortex (a separate region that may well be involved in compensation for cerebellar damage) and dorsal hippocampus (a non-motor structure), as well as upon Golgi impregnation studies of PML neuronal dendritic fields (initially cerebellar Purkinje and stellate neurons). Initial morphological studies of the postweaning rehabilitation rats will focus upon cerebellar PML and vermis lobule 1. Behavioral evaluation will involve locomotion on a rotating rod, climbing of ropes and a parallel bar walking test, motor skill tests upon which performance has been shown to be sensitive to alcohol exposure during brain development, as well as spontaneous alternation and reinforced conditional spatial delayed alternation as tests of hippocampal functioning. Morphological assessment will involve the use of state-of- the-art stereological methods, including the optical disector, to determine cell loss following alcohol exposure, the double disector to assess synapse number, and appropriate method for vasculature and glia. The overall goals of the study are 1) to obtain the most accurate possible view of the effects of postnatal alcohol exposure upon brain organization and behavioral performance and 2) to obtain a similarly accurate view of the effects of the program of motor skill intervention training upon these same measures. The long-range goal is to assess the potential therapeutic value of intervention programs in human offspring suffering from alcohol-related neurodevelopmental disorder.
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