Elsevier

Alcohol

Volume 51, March 2016, Pages 1-15
Alcohol

The impact of prenatal alcohol exposure on social, cognitive and affective behavioral domains: Insights from rodent models

https://doi.org/10.1016/j.alcohol.2015.12.002Get rights and content

Highlights

  • Development of a comprehensive rodent PAE behavioral phenotype from available literature.

  • Focus on social, cognitive and affective domain behavioral modifications after PAE.

  • Specially considers timing, dose and administration method effects of PAE on behavioral outcome.

  • Highlights current gaps in the literature that are needed for a full PAE behavioral phenotype.

Abstract

Fetal Alcohol Spectrum Disorders (FASD) are characterized by deficits in working memory, response inhibition, and behavioral flexibility. However, the combination and severity of impairments are highly dependent upon maternal ethanol consumption patterns, which creates a complex variety of manifestations. Rodent models have been essential in identifying behavioral endpoints of prenatal alcohol exposure (PAE). However, experimental model outcomes are extremely diverse based on level, pattern, timing, and method of ethanol exposure, as well as the behavioral domain assayed and paradigm used. Therefore, comparisons across studies are difficult and there is currently no clear comprehensive behavioral phenotype of PAE. This lack of defined cognitive and behavioral phenotype is a contributing factor to the difficulty in identifying FASD individuals. The current review aims to critically examine preclinical behavioral outcomes in the social, cognitive, and affective domains in terms of the PAE paradigm, with a special emphasis on dose, timing, and delivery, to establish a working model of behavioral impairment. In addition, this review identifies gaps in our current knowledge and proposes future areas of research that will advance knowledge in the field of PAE outcomes. Understanding the complex behavioral phenotype, which results from diverse ethanol consumption will allow for development of better diagnostic tools and more critical evaluation of potential treatments for FASD.

Introduction

Beginning with the first reports that prenatal alcohol exposure (PAE) could have severe and long-lasting consequences on the neurobehavior of offspring (Jones, 1975, Jones and Smith, 1973), there has been a consistent focus on identifying how alcohol affects the developing fetus and delineating the spectrum of behavioral changes. Although there is an increasing awareness that high levels of alcohol consumption during pregnancy can impair growth, cognition, and social behavior of the child, PAE remains one of the most common developmental insults (Day et al., 2002, Green et al., 2009, Thomas et al., 1998). Recent reports suggest that as many as one–third of women drink at some time during pregnancy, and between 5 and 10% report binge drinking incidents (Ethen et al., 2009). There is a growing consensus that even moderate alcohol intake during pregnancy, which is the more common pattern, can lead to lasting cognitive impairments even when growth and morphological changes are absent. These impairments, which fall under the category of Fetal Alcohol Spectrum Disorder (FASD), may not be evident until early adolescence and are characterized by impairments in working memory, response inhibition, and behavioral flexibility (Green et al., 2009, Mattson et al., 1999, Streissguth et al., 1991). Rodent models have become an important tool for studying the effects of alcohol on development at all levels, particularly as studies in human patients and rodent models suggest a congruent effect of blood alcohol concentration (BAC) on behavioral outcomes across species (Driscoll, Streissguth, & Riley, 1990).

Rodent models are an indispensable tool for studying causal factors of prenatal exposure effects, for several reasons: 1) inbred strains of mice and rats are genetically homogenous populations, with which the issue of genetic heterogeneity in epidemiological studies can be largely circumvented, making it more feasible to parcel out impacts of environmental factors; 2) environmental insults, such as alcohol, can be strictly timed and given in exact quantities, enabling the discoveries of sensitive time windows and threshold of harmful doses; 3) the impacts of environmental factors can be tested on the behavioral level, as well as on neuroanatomical, neurochemical, and neuronal levels, enabling the discovery of the effects of certain environmental insults on the whole organism; and 4) cross-species comparisons ensure that results are applicable and generalizable in different species. These studies have identified several factors that are involved in the impact of PAE including method of delivery, level of exposure, pattern of exposure, and timing of exposure during development.

Here we review the available literature on the behavioral impacts of PAE in rodent models, from early studies to the most recently published, with the goal of providing a comprehensive behavioral phenotype spanning the social, affective, and cognitive domains (Fig. 1). Although alcohol was recognized as a teratogen in 1973, it was not until 2002 that the CDC began developing diagnostic guidelines for FAS and FASD (Williams, Smith & Committee on Substance Abuse, 2015). However, in 2015, in a cohort of foster children who were referenced to a mental health clinic for behavioral disorders, 86.7% were either previously undiagnosed or misdiagnosed (Chasnoff, Wells, & King, 2015). FASD is commonly misdiagnosed with other conditions such as attention deficit hyperactivity disorder (ADHD) or Autism Spectrum Disorder, because behavioral profiles can be similar (Bishop et al., 2007, Peadon and Elliott, 2010). However, it should be noted that ADHD has been estimated to be co-morbid with FASD in up to 94% of individuals (Peadon & Elliott, 2010). Being able to fully characterize the FASD behavioral and cognitive phenotype based on approximate exposure level and timing would greatly improve diagnosis and therefore treatment, particularly early intervention. Therefore, this review seeks to highlight areas in which more concentrated research using rodent models is needed to fill in the missing framework.

Rodent studies have aimed to replicate prenatal exposures in humans using a variety of delivery methods including intraperitoneal (i.p.) injection, oral gavage, intragastric gavage, liquid diets, voluntary drinking, limited-access models, and vaporized alcohol inhalation (for a comprehensive review see Patten, Fontaine, & Christie, 2014). These techniques have been used to produce a wide range of doses as measured by Blood Alcohol Concentration (BAC). The question of what is considered heavy versus moderate exposure in humans and rodents is still not widely agreed upon, due to differences in alcohol metabolism, and the effects that pattern of exposure, coupled with delivery method, have on BAC (for a full discussion, see Valenzuela, Morton, Diaz, & Topper, 2012). For example, in rodents, BACs at the U.S. legal intoxicating limit (80 mg/dL) are considered low exposure; however, in clinical research this is a moderate to high dose, if it occurs repeatedly. To make conclusions drawn in this review more easily comparable to clinical literature, we have broadly categorized the reviewed studies into heavy exposure (>100 mg/dL) and more moderate exposures (<100 mg/dL). However, it should be stressed that studies categorized as moderate in the current review often result in BACs at or below 80 mg/dL. Therefore, specific BACs are reported in figures, where available.

Finally, these methods and levels of exposure have been delivered across gestation and early neonatal development in various regimens. Mammalian neural development can be split into six distinct steps: neural genesis, migration, glial proliferation, axon/dendrite proliferation, synaptogenesis, pruning/cell death, and myelination (West, 1987). Developmental time points across species are equated using these processes. For humans, the first trimester corresponds to gastrulation, the second to proliferation and migration, and the third to brain growth spurt and differentiation. Pruning and myelination occur after birth and throughout development. To ease comparisons between studies and species, the experiments discussed will be characterized by the equivalent time points in rodent gestational days (GD) or postnatal days (PD). This will broadly divide exposure windows into first-trimester (GD1–10), second-trimester (GD11–21), or third-trimester (PD0–12) equivalents (specific details regarding method and timing are given in figures). The third-trimester equivalent poses unique challenges to the PAE field, as it occurs postnatally. The largest difference is that pups are exposed directly to alcohol and not first-pass metabolites, as would occur during gestational exposure. Even with these differences, the third-trimester equivalent cannot be discounted in rodent models because human mothers continue to ingest alcohol during this developmental time window (Ethen et al., 2009).

Specific effects should, therefore, be seen based on the timing of PAE insult. For example, exposure during proliferation would result in an abnormal number of neurons, exposure during migration would result in differential placement, while disrupted axonogenesis would result in aberrant synapses and possibly differential signaling. However, most PAE models span several days, or weeks, of development when multiple developmental processes are occurring simultaneously. This means that numerous circuits and regions may be affected by a single model.

While these models have been developed to try to closely model drinking patterns in humans, this design makes it difficult to parse how a diffuse alcohol exposure results in a specific behavioral outcome. Further, the method of alcohol administration becomes increasingly important, as an administration by i.p. injection or gavage will result in rapid peak BACs and may cause a different effect on the neuronal circuitry, and therefore behavior, compared to a method yielding a lower BAC over a prolonged time course. Therefore, we take special consideration when reviewing studies using varying exposure paradigms. It should also be noted that even if the alcohol exposure does not occur during the peak of a region's development, this does not mean the region will be unaffected. For example, the bulk of hippocampal dentate gyrus development occurs postnatally (Bayer, Altman, Russo, & Zhang, 1993); however, gestational exposures affect behaviors mediated by this region (see below). This may mean connecting regions may be affected, which may influence the region of interest itself.

For these reasons, determining the causes of regional dysfunction after PAE continues to be a challenge. Complicating this picture, PAE is a global insult, affecting multiple systems developing at the time of insult. Therefore, in this review we do not examine the structural changes that have been investigated after PAE. While this is a key in determining how PAE affects the system, results are difficult to interpret without a clear behavioral outcome, which we develop here.

Section snippets

Effects on social behavior

One of the most well-studied outcomes of PAE in preclinical models is the alterations in a wide range of social behaviors. Due to the high level of control and ability to monitor across lifespan, animal models of PAE create a window to the complex mechanisms mediating social interactions, both between pups and dams and between conspecifics in adolescence and adulthood.

Maternal interaction has been studied from both the dams' and the pups' perspectives. Pups have limited behavioral repertoires,

Learning, memory, and executive control (cognitive)

Although lacking in physical malformations seen in FAS, children with less severe FASD have learning, memory, and executive control alterations (Green et al., 2009, Kodituwakku, 2007, Kodituwakku et al., 2001). However, the severity and type of impairments are highly varied. Here we aim to thoroughly and critically evaluate the literature in these domains to reach a consensus on what impairments occur after PAE in rodent models.

Affective behaviors

Although not as widely studied as the other domains, PAE is strongly implicated in anxiety-related disorders, and several studies have used preclinical models to examine the effects on anxiety- and depression-like behaviors (Fig. 7).

Conclusion

Not surprisingly, method of delivery, level of exposure, pattern of exposure, and timing of exposure during development affected behavioral outcome in PAE models. These factors appear to form a complex web of interaction that highly influences outcomes, which mirrors the often diverse manifestations of FASD in humans. In addition, the reviewed studies make it clear that age at testing and sex must also be considered, as complicated maturation and gender differences seem to play a role in

Acknowledgments

We are very grateful to Kevin K. Caldwell and C. Fernando Valenzuela for comments on this manuscript.

JLB is supported by NIAAA grants 1K22–AA020303–01 and 1P50AA022534–01. KM is supported by NIAAA grant 5T32AA014127–13.

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