Epigenetics and its implications for behavioral neuroendocrinology

Abstract

Individuals vary in their sociosexual behaviors and reactivity. How the organism interacts with the environment to produce this variation has been a focus in psychology since its inception as a scientific discipline. There is now no question that cumulative experiences throughout life history interact with genetic predispositions to shape the individual's behavior. Recent evidence suggests that events in past generations may also influence how an individual responds to events in their own life history. Epigenetics is the study of how the environment can affect the genome of the individual during its development as well as the development of its descendants, all without changing the DNA sequence. Several distinctions must be made if this research is to become a staple in behavioral neuroendocrinology. The first distinction concerns perspective, and the need to distinguish and appreciate, the differences between Molecular versus Molar epigenetics. Each has its own lineage of investigation, yet both appear to be unaware of one another. Second, it is important to distinguish the difference between Context-Dependent versus Germline-Dependent epigenetic modifications. In essence the difference is one of the mechanism of heritability or transmission within, as apposed to across, generations. This review illustrates these distinctions while describing several rodent models that have shown particular promise for unraveling the contribution of genetics and the environment on sociosexual behavior. The first focuses on genetically-modified mice and makes the point that the early litter environment alters subsequent brain activity and behavior. This work emphasizes the need to understand behavioral development when doing research with such animals. The second focuses on a new rat model in which the epigenome is permanently imprinted, an effect that crosses generations to impact the descendants without further exposure to the precipitating agent. This work raises the question of how events in generations past can have consequences at both the mechanistic, behavioral, and ultimately evolutionary levels.

Fig. 1

The external environment interacts with the internal environment to influence fetal development with both immediate and life-long consequences. Such environmentally-induced changes can occur at all levels of biological organization, from the molecular to the organism’s behavior, and tend to be amplified in their consequences as they ascend through these levels. Ultimately, these influences may be epigenetic in nature, inducing heritable alterations in gene expression without changing the DNA. Changes can occur at the physiological and morphological levels (Molar Epigenetics) as well as modification of normal patterns of gene expression (Molecular Epigenetics). These alterations can bring about functional differences in brain and behavior that result in changes in the phenotype. These then modify how individuals respond to conspecifics and their environment, bringing about changes at higher levels of biological organization. Whether these eventually can have an evolutionary impact is still open to question. What is known is that human society has changed the ecosystem in a manner that has had demonstrable impact on the health of humans and wildlife. Figure modified from Crews and McLachlan [21].

Fig. 2

In most instances genetically-modified mice arise from the mating of individuals heterozygous for a null mutation. This results in litters that are a mixture of different numbers of male and female young of various genotypes. Thus, the sex ratio and genotype ratio of the litter can be a confound in interpreting the results of any phenotype measure, molecular or behavioral. However, by sexing and genotyping pups at birth and then re-constituting litters of equal numbers of specific young, it is possible to deconstruct the behavioral neural phenotype of the adult. The red-outline blocks represents groups that can be used to establish the effect of sex (e.g., Mixed-Sex/Same-Genotype groups) versus the effect of genotype (e.g., Same-Sex/Mixed-Genotype groups). Finally, by creating Mixed-Sex/Mixed-Genotype groups it is possible to study the precise interaction of sex and genotype in the development of the phenotype of interest. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Frequency of aggressive and mounting behavior in genetically-modified mice raised in single sex groups with equal numbers of wildtype (WT) or knockout (KO) female or male mice; top panel: ♀WT/♀KO; bottom panel: ♂WT/♂KO. Tests with female mice involved ovariectomized female intruders (top row) and tests with male mice involved olfactory-bulbectomized male intruders (bottom row). Values are group mean and standard errors. Statistical aralysis was computed on log-transformed data. (*p < 0,05, **p < 0.01). Reprinted with Permission from Crews et al. [22].

Fig. 4

The genotype of siblings in the litter influences metabolic activity in the limbic landscape of adult mice wildtype (WT) or knockout (KO) for the estrogen receptor α gene. Limbic landscapes of ♀WT or ♀KO mice raised with sisters of the same or different genotype are depicted; genotype on left of diagonal of the caption (e.g., ♀WT/♀WT) is that of the experimental individual while the right of the diagonal indicates the genotype of the sisters it was raised with. Illustrated is the mean cytochrome oxidase (CO) abundance in specific brain nuclei. The limbic landscape map on the bottom left row is the genotype difference between the ♀WT and ♀KO mice, while the map on the bottom right reflects the effect of sisters of the opposite genotype on ♀WT vs. ♀KO. On the right column, the upper map indicates the effect of KO sisters on a WT female and below that is the effect of WT sisters on a KO female. The nuclei are presented in a clockwise fashion reflecting a rostral-caudal dimension: main bed nucleus of the stria terminalis (BNSTma); anteroventral periventricular nucleus (AVPe); medial preoptic area (MPOA); anterior hypothalamus, anterior (AHA); medial amygdaloid nucleus, posterodorsal (MeAPD); medial amygdaloid nucleus, posteroventral (MeAPV); ventromedial hypothalamic nucleus, ventrolateral (VMHVL).

Fig. 5

The sex and genotype of siblings in the litter influences metabolic activity in the limbic landscape of adult mice wildtype (WT) or knockout (KO) for the estrogen receptor α gene. Limbic landscapes of ♂WT or ♂KO (or ♀WT or ♀KO) raised with brothers or sisters of the same or different genotype are depicted; sex/genotype on left of diagonal is the experimental individual while sex/genotype on right of diagonal is the type of sibling it was raised with. Illustrated is the mean cytochrome oxidase (CO) abundance in specific brain nuclei. The limbic landscape maps on the bottom row are the difference between the ♂WT/♂WT and ♀WT/♀WT and between ♂KO/♂KO and ♀KO/♀KO maps, respectively, indicating the effect of the sibling’s sex independent of genotype. The left column are maps indicating the difference between the effect of ♂WT/♂WT and ♂KO/♂KO and between ♀WT/♀WT and ♀KO/♀KO, respectively, indicating the effect of the siblings genotype independent of sex. See Fig. 4 for further details.

Fig. 6

Determination of a transgenerational epigenetic imprint on mate preference behavior in the rat. The left panel shows that three generations separate the gestational exposure to vinclozolin, a common-use fungicide with endocrine-disrupting (EDC) properties. The right panel illustrates the testing apparatus for mate preference. Two groups of animals were tested. The control group was the F3 generation of a lineage (control-lineage) of animals in which the dams were exposed to vehicle (DMSO) three generations previously. The experimental group was the F3 generation of a lineage (EDC-lineage) of animals in which the dams were exposed to vinclozolin three generations previously. This EDC exposure epigenetically alters males to express early onset of various diseases states and this modification is transmitted via the germline. Third generation females from the EDC-lineage and the Control-lineage were tested with males from both lineages in simultaneous mate preference tests; males from the EDC-lineage (indicated by red-filled male symbols) and the Control-lineage (not shown) were similarly tested with females of both stimulus types. The trials are conducted under dim red light during the nocturnal (active) phase of the rats’ light cycle. The experimental animal (here a female from the Control-lineage) was placed in the center of the chamber; a stimulus male from each lineage type was at each end of the apparatus. The female could move freely in their chamber but separated from the stimulus males by a wire mesh. This enabled the animals to communicate by olfactory, pheromonal, or behavioral cues, but physical interaction was limited to touching across the wire mesh. Left portion of figure from Anway and Skinner [3]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

Third-generation female rats whose progenitors were exposed to vinclozolin, a common-use fungicide with endocrine-disrupting (EDC) properties, and hence epigenetically altered, prefer males from the unexposed Control-lineage. Males do not show this preference. See Fig. 6 for further details. Both females and males from Control- and EDC-lineages were tested with pairs of Control- and EDC-lineage stimulus partners. Presented are the mean (+1 standard error) differences in the time spent in each behavior. Left panel: Behaviors exhibited by females from Control- and EDC-lineages towards males from Control-lineage (positive, right side) and EDC-lineage (negative, left side). Right panel: Behaviors exhibited by males from Control- and EDC-lineages towards females from Control-lineage (positive, right side) and EDC-lineage (negative, left side). The various behavioral measures and test are described in Crews et al. (2007). Reprinted by permission from Crews et al. [24].