Effects of Prenatal Ethanol Exposure on Neuroanatomy and Neuropsychology

Jenny Chong Hu

Writer’s comment: Writing has always been a challenge for me, but it is also something that I continually strive to improve on. Because of generous support from Raquel Scherr and Jared Haynes, who are my literary mentors at UC Davis, I was able to succeed in my writing. I measure this success not by my publication, but by my gradual progress during the courses I have taken from these teachers. In writing this scientific literature review, I chose to examine the research regarding prenatal ethanol exposure because of my concerns for prevalent, but preventable, diseases, such as Fetal Alcohol Syndrome. I hope that others use this paper not only as a writing model, but also as an illustration of the importance of medical research.
- Jenny Chong Hu

Instructor’s comment: Jenny does an impressive job here in handling complex material. First, her introduction leads us from prenatal alcohol exposure through to its effects on the hippocampus in such a way as to show us the relevance of the topic as well as the scope of the paper. Then, her organization divides up the topic into logical subtopics, within each of which she discusses important research. She integrates the information well, both when various researchers corroborate each other and when they seem to contradict each other. Throughout, she is in control of the material, imposing her vision on the review of how the information should be synthesized.
- Jared Haynes, English Department

Introduction

The effects of prenatal alcohol exposure have been well documented in children and adults with fetal alcohol syndrome (FAS). FAS is a developmental disorder that is usually characterized by developmental, physical, and functional anomalies. Although the consequences of prenatal alcohol exposure vary among people with FAS, children and adults with FAS may suffer from developmental delays, central nervous system dysfunction, poor coordination skills, behavioral problems, learning disabilities, memory deficits, or any combination of these difficulties. Because learning and memory are frequently affected in FAS and because they intimately involve hippocampal function, many researchers have targeted the hippocampus when studying the effects of prenatal alcohol exposure. Though most of the physiological and behavioral research has been conducted on animals, these animal studies provide significant information about the role of the human hippocampus (Uecker and Nadel, 1996). By studying how prenatal ethanol exposure influences neuroanatomical and neuropsychological modifications related to the hippocampus, researchers may develop more effective treatment for FAS.

Neuroanatomical Modifications

    Studies examining the effects of prenatal and postnatal ethanol exposures in rats consistently indicate that these exposures lead to anatomical changes in various brain regions. The hippocampus is sensitive to ethanol exposure, and, because it is involved in learning and memory, modifications in the hippocampal anatomy may lead to neuropsychological deficits in learning, memory, and spatial memory (Clausing et al., 1995; Olson et al., 1998; Uecker and Nadel, 1996; Uecker et al., 1998). Specific neuroanatomical changes of the hippocampus, as well as other brain regions, due to ethanol exposure include changes in hippocampus neuronal populations and in responses to neuroprotective factors (Miller, 1995; Mitchell et al., 1998; Bellinger et al., 1999; Sutherland et al., 1997).

Neurons of the Hippocampus

    Investigating how ethanol exposure disrupts hippocampal neuron populations, various studies have exposed rats to ethanol during two critical terms: prenatal and early postnatal periods. The prenatal period in rats corresponds to the first and second trimesters of human pregnancy, whereas the early postnatal period in rats parallels the third trimester of human pregnancy (Diaz-Granados et al., 1997). During the prenatal period in rats, the neurons in the hippocampus and other brain regions are proliferating (Miller, 1995). By the cessation of the prenatal period, the hippocampus is fully matured (Miller, 1995).
     Because the rat hippocampus is prenatally matured, prenatal and postnatal ethanol exposure influence the size of hippocampal neuron populations differently (Miller, 1995). Following prenatal ethanol exposure, Miller (1995) reported a 17.5 % decrease in CA1 region pyramidal neurons and a 16.7% decrease in hippocampal volume. Similarly, in an in vitro experiment, hippocampal neuron cultures exhibited decreases in survival as ethanol exposure increased (Mitchell et al., 1998). These results reveal the neurotoxicity of ethanol, which inhibits neuronogenesis occurring in the hippocampus (Miller, 1995). Berman et al. (2000) support this explanation by noting that the reduction in hippocampal neuron population is due to interruptions in neuron generation and not to increases in cell death. In contrast, postnatal ethanol exposure did not significantly affect hippocampal neuron population (Miller, 1995). This difference is attributed to the prenatal maturation of the hippocampus; after the hippocampus has fully developed, ethanol exposure does not markedly influence it (Miller, 1995).
     Investigating hippocampal neurons through a different approach from Miller (1995) and Mitchell et al. (1998), Heaton et al. (1995) examined the tolerance of ethanol-treated rats to further ethanol exposures. After administering ethanol to neuron cultures from control, sucrose-treated, and ethanol-treated rats, Heaton et al. (1995) showed that previous exposure to ethanol helped maintain neuronal survival after further ethanol exposure. Following moderate ethanol administrations (1.8 g/dl), both control and sucrose-treated neuron cultures exhibited reduced neuronal survival and neurite outgrowth, whereas ethanol-treated neuron cultures displayed no notable change in neuronal survival and neurite outgrowth (Heaton et al., 1995). This increase in tolerance may be due to the prior ethanol exposure that up-regulates dihydropyridine-sensitive calcium channels (Heaton et al., 1995). However, further studies should be conducted to investigate this phenomenon.
     To examine ethanol’s influence on learning and memory, researchers studying FAS have induced either prenatal or postnatal ethanol exposure and investigated alterations in hippocampal synaptic efficacy and plasticity. Deficits in synaptic efficacy and plasticity are reflected as deficits in long-term potentiation (LTP), which models learning and memory within the hippocampus and other brain regions (Bellinger et al., 1999). Sutherland et al. (1997) found that, after prenatal exposure to ethanol, rats displayed depressed hippocampal synaptic plasticity, which is measured by changes in field excitatory post-synaptic potential (EPSP) and population spike responses. In this study, control rats demonstrated extensive enhancement of the field EPSP and of population spike response following sets of tetanizing stimulations, whereas rats with prenatal ethanol exposure showed minute enhancements (Sutherland et al., 1997). However, a few rats with prenatal ethanol exposure exhibited similar enhancements as control rats, indicating that the study may contain variables not yet recognized (Sutherland et al., 1997). Overall, the general trend of reduced hippocampal synaptic plasticity may contribute to the cognitive and behavioral deficits observed in rats and humans with prenatal ethanol exposure (Sutherland et al., 1997).
     In contrast, Bellinger et al. (1999) investigated ethanol’s influence on hippocampal synaptic efficacy and plasticity during the rat postnatal period, which corresponds to the third trimester of human pregnancy, when the human central nervous system develops rapidly (Bellinger et al., 1999). Bellinger et al. (1999) found that, regarding synaptic efficacy, the postnatal ethanol-treated rats required significantly greater stimulus strengths to elicit quarter-maximal and half-maximal population spikes as compared to control rats. However, no LTP differences were found between control rats and ethanol-treated rats (Bellinger et al., 1999). The maintenance of LTP, and thus plasticity, following postnatal ethanol exposure conflicts with experimental results of Sutherland et al. (1997), in which hippocampal synaptic plasticity was reduced following prenatal ethanol exposure. These discrepancies may be due to ethanol exposure during different developmental periods (Bellinger et al., 1999).

Neuroprotection of Neurotrophic Factors

    Researchers have studied neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), to investigate their neuroprotective properties during adverse conditions including chronic ethanol exposure. Many studies have used fetal rat hippocampal cultures for various reasons. First, the developing hippocampus generates excessive amounts of neurotrophins, including NGF, BDNF and others (Mitchell et al., 1998). Second, the developing hippocampus also expresses receptors for both NGF and BDNF (Mitchell et al., 1998). These fetal hippocampuses of rats with prenatal ethanol treatment — which were removed, cultured, and further exposed to ethanol — exhibited substantial decreases in responsiveness to neurotrophic factors (Heaton et al., 1995). Although neurotrophic factors afford less neuroprotection following further ethanol exposure, NGF provided hippocampal neurons with the most neuroprotection out of several neurotrophic factors including BDNF, ciliary neurotrophic factor (CNTF), and a combination of BDNF and CNTF (Mitchell et al., 1998).
     Several mechanisms have been proposed to explain how neurotrophic factors contribute neuroprotection to hippocampal neurons. The most considered hypothesis regards stabilization of intracellular calcium levels (Mitchell et al., 1998). With an upsurge of intracellular calcium levels above a certain concentration, sequences of events are unleashed that result in neuronal apoptosis (Mitchell et al., 1998). Neurotrophic factors, such as NGF, are believed to help maintain intracellular calcium homeostasis, and therefore decrease the incidence of neuronal apoptosis (Mitchell et al., 1998).

Neuropsychological Deficits

    In both animal and human studies, rats and children with prenatal ethanol exposure demonstrate neuropsychological impairments that are related to the hippocampus including spatial memory, delayed object recall, and various others (Clausing et al., 1995; Olson et al., 1998; Uecker and Nadel, 1996; Uecker et al., 1998). Studying these deficits may provide additional information about the function of the hippocampus in learning and memory (Uecker and Nadel, 1996).

Learning Impairments

    Studies on rat and human subjects regarding learning after prenatal ethanol exposure have consistently supported each other. Researchers have tested learning in adult rats, with and without prenatal ethanol exposure, using a learned taste aversion task (Clausing et al., 1995). Both ethanol-treated rats and control rats fully learned to avoid saccharine when paired with a noxious stimulus (Clausing et al., 1995). However, after ten days, the rats with prenatal ethanol exposure did not retain this learned task, whereas the controls did, indicating that prenatal ethanol exposure damages learning well into rat adulthood (Clausing et al., 1995). Studies involving children with FAS have also revealed impaired learning following prenatal ethanol exposure. For example, Olson et al. (1998) found that FAS children were less accurate in comprehending short passages than children with similar intelligence quotients (IQs) but without FAS.

Memory Impairments

    In addition to learning disabilities, FAS children have also exhibited memory impairments. Compared to children without FAS but of similar IQs, FAS children have performed just as well with immediate object recall (Uecker and Nadel, 1996; Uecker et al., 1998). However during delayed object recall, FAS children performed less successfully than non-FAS children did (Uecker and Nadel, 1996; Uecker et al., 1998). Furthermore, FAS children have exhibited deficits in declarative memory, which requires recalling learned information (Olson et al., 1998). Nevertheless, studies indicate that FAS children do not have impairments in procedural memory, which requires recalling procedures such as brushing teeth (Olson et al., 1998). Concerning spatial memory, studies have repeatedly disclosed spatial memory deficits in children with FAS. Olson et al. (1998), Uecker and Nadel (1996), and Uecker et al., (1998) agree that children with FAS showed reduced ability to recall spatial locations. Also compared to children without FAS but with matched IQs, children with FAS had significant difficulty completing mazes, which involves visuospatial competency (Uecker and Nadel, 1996).

Conclusion

    In animal models, animals with prenatal ethanol exposure display decreases in hippocampal size and neuron number (Miller, 1995). These same animals also often exhibit deficits in learning and memory (Miller, 1995). During memory tasks, children with FAS have performed similarly to patients with right temporal lobectomies and a large portion of their hippocampus removed (Olson et al., 1998). Thus, many researchers have been investigating the relationship between hippocampal damage and neuropsychological impairments (Uecker and Nadel, 1996). However, although substantial evidence shows that ethanol adversely affects the hippocampus and behavior, deficits in spatial behaviors unrelated to the hippocampus have also been observed (Uecker and Nadel, 1996). Therefore, further research is needed to examine ethanol’s influence on different brain regions, and consequently on differing behaviors.

References

Bellinger, F.P., K.S. Bedi, P. Wilson, and P.A. Wilce. 1999. Ethanol exposure during the third trimester equivalent results in long-lasting decreased synaptic efficacy but not plasticity in the CA1 region of the rat hippocampus. Synapse 31: 51-58.

Berman, R.F. and J.H. Hannigan. 2000. Effects of prenatal alcohol exposure on the hippocampus: Spatial behavior, electrophysiology, and neuroanatomy. Hippocampus 10 (1): 94-110.

Clausing, P., S.A. Ferguson, R.R. Holson, R.R. Allen, and M.G. Paule. 1995. Prenatal ethanol exposure in rats: Long-lasting effects on learning. Neurotoxicology and Teratology 17 (5): 545-552.

Diaz-Granados, J.L., K. Spuhler-Phillips, M.W. Lilliquist, A. Amsel, and S.W. Leslie. 1997. Effects of prenatal and early postnatal ethanol exposure on [3H] MK-801 binding in rat cortex and hippocampus. Alchoholism: Clinical and Experimental Research 21 (5): 874-881.

Heaton, M.B., M. Paiva, D.J. Swanson, and D.W. Walker. 1995. Alterations in responsiveness to ethanol and neurotrophic substances in fetal septohippocampal neurons following chronic prenatal ethanol exposure. Developmental Brain Research 85: 1-13.

Miller, M.W. 1995. Generation of neurons in the rat dentate gyrus and hippocampus: Effects of prenatal and postnatal treatment with ethanol. Alcoholism: Clinical And Experimental Research 19 (6): 1500-1509.

Mitchell, J.J., M. Paiva, D.B. Moore, D.W. Walker, and M.B. Heaton. 1998. A comparative study of ethanol, hypoglycemia, hypoxia and neurotrophic factor interactions with fetal rat hippocampal neurons: Multi-factor in vitro model for developmental ethanol effects. Developmental Brain Research 105: 241-250.

Olson, H.C., J.J. Feldman, A.P. Streissguth, P.D. Sampson, and F.L. Bookstein. 1998. Neuropsychological deficits in adolescents with fetal alcohol syndrome: Clinical findings. Alcoholism: Clinical and Experimental Research 22 (9): 1998-2012.

Sutherland, R.J., R.J. McDonald, and D.D. Savage. 1997. Prenatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal synaptic plasticity in adult offspring. Hippocampus 7: 232-238.

Uecker, A. and L. Nadel. 1996. Spatial locations gone awry: Object and spatial memory deficits in children with fetal alcohol syndrome. Neuropsychologia 34 (3): 209-223.

Uecker, A. and L. Nadel. 1998. Spatial but not object memory impairments in children with fetal alcohol syndrome. American Journal on Mental Retardation 103 (1): 12-18.