Therapeutic effects of complex motor training on motor performance deficits induced by neonatal binge-like alcohol exposure in rats

Abstract

The effects of complex motor task learning on subsequent motor performance of adult rats exposed to alcohol on postnatal days 4 through 9 were studied. Male and female Long–Evans rats were assigned to one of three treatments: (1) alcohol exposure (AE) via artificial rearing to 4.5.g kg⁻¹ day⁻¹ of ethanol in a binge-like manner (two consecutive feedings), (2) gastrostomy control (GC) fed isocaloric milk formula via artificial rearing, and (3) suckling control (SC), where pups remained with lactating dams. After completion of the treatments, the pups were fostered back to lactating dams, and after weaning they were raised in standard cages (two–three animals per cage) until they were 6 months old. Rats from each of the postnatal treatments then spent 20 days in one of three conditions: (1) inactive condition (IC), (2) motor control condition (MC) (running on a flat oval track), or (3) rehabilitation condition (RC) (learning to traverse a set of 10 elevated obstacles). After that all the animals were tested on three tasks, sensitive to balance and coordination deficits (parallel bars, rope climbing and traversing a rotating rod). On parallel bars, both male and female rats demonstrated the same pattern of outcomes: AE-IC rats made significantly more mistakes (slips and falls) than IC rats from both control groups. After 20 days of training in the RC condition, there were no differences between AE and both SC and GC animals in their ability to perform on the parallel bars test. On rope climbing, female animals showed a similar pattern of abilities: AE-IC rats were the worst group; exercising did not significantly improve the AE rats' ability to climb, whereas the RC groups (SC, GC and AE) all performed near asymptote and there were no significant differences among three neonatal treatment groups. There was a substantial effect of the male rats' heavier body weight on climbing ability, and this may have prevented the deficits in AE rats behavior from being detected. Nevertheless, male animals from all three postnatal treatments (SC, GC and AE) were significantly better on this task after RC. Female and male rats from all three postnatal groups demonstrated significantly better performance on the rotarod task after 20 days of `rehabilitation'. These results suggest that complex motor skill learning improves some of the motor performance deficits produced by postnatal exposure to alcohol and can potentially serve as a model for rehabilitative intervention.

Introduction

Children with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) exhibit numerous cognitive problems, hyperactivity and motor deficits (e.g. Refs. 14, 34, 47, 71, 72, 76). Some of the consequences of this prenatal exposure to alcohol appear to be lifelong while others may dissipate with age 46, 69, 75, 76. In cases lacking distinct facial abnormalities (sometimes called FAE), a predominant behavioral characteristic that provides a basis for the diagnosis has been cognitive deficits [47]and deficits in motor development and performance 13, 14, 70. Not all mothers who consume alcohol during pregnancy produce children with FAS or FAE: the factors that are thought to determine the occurrence of the behavioral and anatomical pathology include the developmental stage(s) when the drinking episode(s) occurred, the pattern of exposure and the peak blood alcohol concentration (BAC) reached during drinking episodes 23, 35, 68, 73, 93. Social drinking during pregnancy or lactation has been reported to cause impaired motor development that lasted through adolescence 43, 74.

Animal models of developmental exposure to alcohol exhibit many of the behavioral changes observed in children with FAS and FAE: memory and learning impairments 2, 17, 26, 64, 97, developmental impairment of motor skills, poor locomotion and coordination, altered gait 1, 20, 22, 31, 39, 49, 50, 56and hyperactivity 8, 9, 65, 67, 82. Poorly developed motor skills in prenatally and neonatally ethanol-exposed animals prevent them from successfully performing on balance-challenging tasks 20, 22, 39, 49, 50, 80.

The behavioral deficits appear to reflect underlying structural damage resulting from exposure to ethanol during development: while damage is widespread, impaired motor control appears to be associated primarily with cerebellar damage (e.g., Refs. 4, 10, 44, 59, 60, 81).

A few attempts have been made to reverse or mitigate behavioral incompetence resulting from developmental exposure to ethanol. Early behavioral experience (e.g., complex environment rearing, or familiarization with the radial maze) brought about improvement on learning tasks, such as the Morris water maze and the radial arm maze 30, 32, 57, 58, 83and preweaning handling eliminated the deficit in response inhibition in prenatally alcohol-exposed rats [19]. These studies demonstrated that animals exposed to alcohol prenatally can benefit from the effects of an enriched postweaning environment or other behavioral experiences, and that postnatal factors can ameliorate some of the deficits resulting from prior exposure to alcohol.

Rearing rats in an enriched environment after prenatal exposure to alcohol significantly improved behavioral performance, but failed to produce a detectable increase in the density of spines on CA1 pyramidal neurons in hippocampus [5]or an increase in the depth of the occipital cortex [83], although these changes normally occur in control animals (e.g., Refs. 5, 33, 37, 38, 66, 95). Berman et al.'s [5]findings were interpreted to reflect reduced neural plasticity after prenatal exposure to alcohol. This hypothesis was supported by the demonstration that prenatal alcohol exposure reduced reactive axonal sprouting in basal ganglia induced by nigrostriatal lesions [24]. In contrast, an increase of lesion-induced sprouting was reported in hippocampus of prenatally ethanol-exposed rats after enthorinal cortex lesions 15, 89. Hippocampal synaptic plasticity in the form of long-term potentiation exhibits long-lasting deficits after prenatal exposure to alcohol as shown by Swartzwelder et al. [78]and Sutherland et al. [77].

In a previous report [42], we demonstrated that Purkinje neurons, the sole output neurons of the cerebellum, retained a substantial capacity for synaptic plasticity after alcohol exposure on postnatal days 4–9, a model of human maternal binge alcohol consumption during the third trimester of pregnancy. Exposure to a program of complex motor skill training resulted in a significant increase in the number of parallel fiber synapses per Purkinje neuron. Furthermore, performance on the task improved across training such that by the end of 10 days, there were no significant differences between alcohol-exposed animals and controls in terms of time to complete the set of tasks used for the motor training.

Because of the forced nature of the training, however, it was not possible to conclude that there was significant improvement in the specific behavioral performance of the ethanol-impaired animals. In the present study, we report that motor learning, but not simple exercise, produces a true therapeutic effect on balance and coordination impairments resulting from neonatal ethanol exposure.