Saturday, 5 September 2009

Epigenetics - Implications for behavioral neuroendocrinology

ResearchBlogging.orgIndividuals vary in their sociosexual behavior and reactivity. How an organism interacts with the environment to produce these variations 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 the 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 an individual and its descendants all without changing the sequence of the DNA.

The early stages of life, beginning before birth and up to weaning in mammals, are the time of maximum neuronal plasticity.It is during this early period that hormones and genotype predispose an individual's responses to future experiences throughout the life cycle. Suites of genes underlie the fundamental plasticity of an organism, particularly during development and life history transitions. How do these gene networks interact with the experiences that cumulate during an individual's life history?

An important interface between the environment (both internal and external) is that of epigenetic modifications. Exactly how these modifications occur is still relatively unknown, but recent studies indicate that origin of such effects may occur at in the previous generations. That is, experience of previous generations may modify regulatory factors affecting gene expression without changing the sequence of the DNA, but the physiology and behavior of the organism may be substantially influenced. Thus understanding how such events really occur will enhance our understanding of how the environment influences the relationship between genotype and behavior during sensitive periods of development.

Molecular vs Molar epigenetics

There have been several reviews recently as to the origin of the field of epigenetics, all of which recognize the multiple roots of the current tree of research. The debates in the 16th-17th century pitted preformationism against epigenesis, with a central question of how a multicellular organism develops from a single cell, the zygote. The former camp believed that adult characters were present fully formed in the egg and simply unfolded during growth, while the latter held that traits arose due to interactions between the multiple constituent parts of the zygote. Spawned after the resolution of this conflict were two different groups, one rooted in anatomy and geology, which later became the broad science of biology, and the other focused on sensation, perception and mind, which ultimately became the study of psychology. Thus though both have a common origin, they evolved very differently both in perspective and substance. These the author labels respectively as, 'Molecular epigenetics' and 'Molar epigenetics'.
Molar epigenetics arises from historical literature in psychilogy, particularly functionalism. Rather than measuring sensory processes, the functionalists focused on the organism itself and development of behavior in relation to its natural environment. Molecular epigenetics arose from molecular biology and modern genetics and its emphasis was on gene regulation and its developmental significance.Thus the object of study in Molecular epigenetics is gene expression during embryogenesis, while in Molar epigenetics, it is on the individual's interactions with the biotic and physical environment usually after birth.

Molecular epigenetics

Conrad H. Waddington proposed the term 'epigenetics' from classical embryology, ascribing it to the study of processes by which genotype gives rise to a phenotype. His concept was central to what became the modern era of epigenetics when Robin Holliday proposed a molecular model of heritable gene activation and inactivation during development by DNA methylation and demethylation respectively. Since then the term epigenetics is used to connote the study of change in gene expression without changing the DNA sequence. There are several mechanisms that can achieve this end, such as DNA methylation and modification of histones by processes of methylation, deacetylation and phosphorylation. While DNA methylation is clearly involved in genomic imprinting, the signal for the imprint is still not known.

Molar epigenetics

Early comparitive psychologists were also interested in epigenetics, but from the perspective of interaction of an organism's heredity and the nature of species typical behaviors or 'instincts'. Work principally by Konrad Lorenz and Niko Tinbergen emphasized that such behaviors were a product of natural selection, the result of genes acting in the brain to generate behaviors that were unlearned and innate. Thus, these studies laid the foundation of psychobiology, a field that focuses on how experiences cumulate throughout life to shape the way in which an individual interacts with its environment.
It is necessary to emphasize that, an approach that integrates both Molecular and Molar epigenetics, will be required to reveal the mechanisms that underlie behavioral evolution.

Context dependent vs Germline dependent epigenetic modification 

In context dependent epigenetic modification, the change is transmitted within a generation, within an individual's own lifetime, including the interaction of parent and young. An example of this is exposure to endocrine disrupting chemical in utero during childhood, in which case the disease manifests itself later. The extent to which the modification is perpetuated is by the simple presence of the environmental factor, that brings about the epigenetic modification. The modification is present until the effect of the factor is present. Later it declines and to reestablish the effect the individual has to be exposed to the same agent again. This effect is called context dependent epigenetic modification. In germline dependent modification, the genetic imprint is independent of the original causative agent. Here the epigenetic modification is transferred to the subsequent generations because, the change in the epigenome has been incorporated in the germline. Thus the effect is manifest in each generation without the need for re-exposure. The DNA methylation of heritable epialleles are passed through to subsequent generations without being erased as occurs normally during gametogenesis or shortly after fertilization.
If the context in which an individual is nurtured affects its behavior as an adult, it is likely that the activities of the neural circuitry underlying this behavior is also affected. This should apply to both context dependent and germ line dependent epigenetic modifications.

Transgenerational epigenetic imprint on the nuclear genome and its effect on behavior and brain

Two critical elements of demonstrating a germline dependent epigenetic modification are that, first a single exposure of the environmental factor that is never again repeated, and second the number of generations since that exposure. A new model system was used in which an endocrine disrupting chemical (EDC) reprograms methylation patterns that are then incorporated into the germline and hence transmitted to future generations. In this model system the exposure of gestating female rats to pesticide methoxychlor or fungicide vinclozolin during the period of embryonic sex determination, induces an epigenetic transgenerational phenotype through reprogramming the germline in a sex specific manner. Specifically, in each generation males whose ancestor have been treated underwent progressive spermatogonial apoptosis, decreased sperm count and motility and as the animals aged, adult onset disease is accelerated, including cancer and immune cell defects.

Studies were carried out to determine if this altered epigenome also influences male/partner preference behavior. For these studies F3 descendants of females were used which were treated with dimethylsulphoxide buffer alone (control) or with vinclozolin (EDC treated). Partner preference was carried out by placing an individual (male or female) in a testing arena. At either ends was a small cage containing the stimulus rats separated by a wire mesh barrier to allow exchange of visual, olfactory and tactile cues. All males were tested with both types of females as stimulus and vice versa. Behaviors directed to the stimulus animals included time spent in contact with the wire mesh during which the animals often touched noses through the mesh, grooming, aimless walking and sniffing, standing on hind paws and sniffing with nose pointed upwards, contacting the walls of the test cage and time spent in the center of the test arena.
The results were clear cut and sex specific. The females discriminate and prefer males who do not have a history of exposure, while males do not exhibit such a preference. In social engagements in rodents time is spent in mutual facial investigation. Males investigate females equally, while females spend more time investigating males from the control lineage. It is known that pheromones from the vomeronasal organ and urine are involved in mate recognition in rodents. Methylation analysis revealed that Major Urinary Protein 4 (MUP4) is one of the candidate imprinted like genes in the vinclozolin treated lineage. This MUP group of gene products binds to and releases male specific pheromones in rodents. Also males and females both explored odors of the opposite sex than familiar odors. These behaviors may reflect differences in pattern of gene expression in different brain areas.Using gene micro arrays specific ares of the brain like the hippocampus , amygdala and the whole brain have been studied in both control and test males. Of the altered genes only a limited number shows similar changes in all the three regions an some of these have been implicated in schizophrenia, autism and depression.

Cytoplasmic genes like the mitochondrial genes also have CpG islands and polymorphisms in these genes plays a significant role in adaptive evolution. These genes are important for determining sperm quality and motility and mutations result in decrease in human sperm motility. In this regard males of all five generations stemming from females treated during pregnancy with either methoxychlor or vinclozolin have decreased sperm motilty and numbers. The mitochondrial genome is also vitally involved in aging and mutations are involved in onset of age related phenotypes, including reduced fertility. Genes encoding for cytochrome oxidase were tested in transgenerationally imprinted rats. (CO is used as a measure of brain activity). None of the constituent genes of this mito-nuclear gene product, seem to be altered in the three regions of the brain. However, nuclear respiratory factor 2 which modulates CO activity, shows an increased expression in the whole brain, perhaps accounting for the behavioral differences observed between the mice of the two lineages. Thus the relative fitness of the specific mito-nuclear genotype combinations is dependent on the modified DNA environment in which they persist. Thus EDCs could act via epigenetically modifying mitochondrial DNA as well as nuclear DNA, and influence epistatic interactions between cytoplasmic and nuclear genes.

The linking of Molar with Molecular epigenetics, extensive knowledge of hormones which play a role in organizing and activating brain-behavior mechanisms and the predisposition in neuroscience research to use molecular methods to understand cellular function and development should facilitate the incorporation of epigenetics in neuroendocrinological research.


CREWS, D. (2008). Epigenetics and its implications for behavioral neuroendocrinology Frontiers in Neuroendocrinology, 29 (3), 344-357 DOI: 10.1016/j.yfrne.2008.01.003

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