Spatial learning deficits induced by chronic prenatal ethanol exposure can be overcome by non-spatial pre-training
Introduction
Alcohol consumption during pregnancy can lead to a number of physical, behavioural, and psychological problems in affected children, and may result in the fetal alcohol syndrome (FAS). The FAS is defined by three principal characteristics in infants: damage to the brain, facial malformations, and growth delays [22]. Of these three principal features, it is the brain injury that is the most debilitating and persistent throughout life. The brain injury of FAS involves decreased brain size, and damage to specific regions including the hippocampus, a brain structure involved in learning, memory, and regulation of behaviour [2]. In the guinea pig, a reliable model of ethanol teratogenicity [25], chronic prenatal ethanol exposure (CPEE) induces hippocampal growth restriction and selective neuronal cell loss [11]. Behaviourally, CPEE offspring demonstrate performance deficits in spatial learning tasks such as the Morris water maze [18], [30], a task sensitive to hippocampal injury [25]. Similarly, in the rat, deficits in spatial acquisition in the water maze have been found after chronic prenatal ethanol exposure [3], [41], and after binge-like exposure to ethanol during the neonatal brain growth spurt [24], [21].
Environmental intervention during postnatal life can accelerate development and facilitate recovery from brain injuries [31]. It is well established that environmental enrichment can provide improvement of performance deficits in the Morris water maze for CPEE rats compared with control rats [13]. For example, group housing of CPEE rat offspring with a variety of “toys” included in the home cage, together with daily handling, results in significant improvement in offspring performance in spatial learning paradigms such as the water maze [14]. Similarly, male CPEE rat offspring raised in home cages containing a running wheel demonstrate an improvement in spatial memory [7], suggesting that voluntary exercise also can improve the performance of CPEE offspring in learning tasks. Another approach that does not involve improving the home cage environment is behavioural intervention, or non-spatial pre-training. Non-spatial pre-training has been used as an intervention to overcome drug-induced water-maze performance deficits induced by NMDA antagonists [16], acute ethanol exposure [5] and brain lesions [17]. To the best of our knowledge, non-spatial pre-training has not previously been tested in CPEE-induced learning deficits. For non-spatial pre-training, animals swim in the water maze under conditions in which distal visuo-spatial cues are absent, and the hidden platform is moved to a new random location after every trial [28]. Thus, the animal is afforded the opportunity to acquire the general behavioural requirements of the water maze (swimming away from the walls, finding and climbing on to a hidden platform for escape) in the absence of information about the spatial environment. It is important to understand that performance deficits in the water maze can be a result of many factors, including impaired motor or sensory ability, swim stress associated with the task, impaired acquisition of the appropriate behavioural strategy, and/or impaired spatial navigation and acquisition. Optimally, one should determine the effects of prenatal treatment in a number of water-maze tasks to better understand and interpret the nature of performance deficits and cognitive impairment.
The objective of the present study was to test the hypothesis that a behavioural intervention, involving non-spatial pre-training of the animal in the environment to be encountered during testing, overcomes CPEE-induced deficits in water-maze performance in the guinea pig. More specifically, we were interested in determining whether the behavioural intervention would provide a global benefit in multiple water-maze paradigms. Moreover, we recently demonstrated that CPEE induces very high maternal cortisol concentration during gestation, and alters glucocorticoid receptor function in the hippocampus of the young adult guinea pig [19]. Ethanol consumption by the pregnant female rat increases glucocorticoid activity by increasing the set point of HPA axis function, thereby resulting in increased basal and stress-induced plasma corticosterone concentrations [37]. Moreover, this effect of CPEE is associated with altered adrenocortical development in young postnatal offspring [38], and HPA axis hyper-responsiveness to stressors in adult offspring [26], [35], [39]. We, therefore, also determined the effect of CPEE on the stress response of guinea pig offspring for first exposure in the water maze, and whether non-spatial pre-training caused adaptation in this stress response.
Section snippets
Experimental animals
The experimental protocol was approved by the Queen's University Animal Care Committee, and was conducted in accordance with the guidelines of the Canadian Council on Animal Care. Female, nulliparous Dunkin–Hartley-strain guinea pigs (Charles River Canada Inc.), approximately 600 g body weight, were bred using an established procedure [9]. Gestational day 0 was defined as the last day of full vaginal-membrane opening, and term is about gestational day 68. Animals were housed individually in
Results
The chronic maternal ethanol regimen employed produced a peak maternal blood ethanol concentration of 346 ± 40 mg/dl on gestational day 57 at 1 h after the second divided dose. The ethanol regimen had no effect on the length of gestation, offspring birth weight, average number of littermates per litter, or distribution of male and female offspring compared with the offspring of the isocaloric-sucrose/pair-fed and water control groups (Table 1). However, offspring birth weight was lower in the
Discussion
Enrichment experiments, conducted with mice, rats and primates, typically involve increased social interaction among offspring, more variety and variability in sensory experience, more opportunity for varied locomotor activity and exploration, and sometimes even specific learning trials or training [12]. In the current study, we investigated whether behavioural intervention, in the form of non-spatial pre-training, can mitigate deficits in water-maze performance in CPEE offspring in multiple
Acknowledgements
Supported by the Canadian Institutes of Health Research, Grant No. MOP-15150. Umar Iqbal was the recipient of a Wilson Fellowship from the School of Graduate Studies and Research, Queen's University.
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