Epigenetic and transgenerational reprogramming of brain development

Key Points

  • Neurodevelopmental programming is defined as the implementation of the genetic and epigenetic blueprints that guide and coordinate normal brain development.

  • Epigenetic processes are also responsible for the reprogramming that occurs in response to environmental challenges, such as maternal stress or infection, making the organism more or less adaptive depending on the future environment and the challenges presented.

  • Developmental windows of susceptibility exist such that exposures occurring during these dynamic periods are more likely to produce marked and broad changes to the epigenome.

  • Alterations to the germ cell epigenome as a result of environmental influences throughout life can result in transgenerational transmission of traits that are able to increase or to decrease disease risk in future offspring.

  • Seemingly different environmental perturbations, such as maternal stress or infection, can produce similar neurodevelopmental changes and phenotypes, which suggests that common downstream cellular mechanisms are responsible for transmitting information from the in utero environment to the developing fetus.

  • Sex specificity of the parent and the offspring is also an important factor in determining the effect of the exposures and the epigenetic mechanisms involved.

Abstract

Neurodevelopmental programming — the implementation of the genetic and epigenetic blueprints that guide and coordinate normal brain development — requires tight regulation of transcriptional processes. During prenatal and postnatal time periods, epigenetic processes fine-tune neurodevelopment towards an end product that determines how an organism interacts with and responds to exposures and experiences throughout life. Epigenetic processes also have the ability to reprogramme the epigenome in response to environmental challenges, such as maternal stress, making the organism more or less adaptive depending on the future challenges presented. Epigenetic marks generated within germ cells as a result of environmental influences throughout life can also shape future generations long before conception occurs.

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Figure 1: Complex interactions between the maternal milieu, placenta and fetal compartments during gestation.
Figure 2: Modes of maternal and paternal transgenerational epigenetic transmission.
Figure 3: Programming of phenotypes and disease risk can skip generations.
Figure 4: Windows of vulnerability to environmental reprogramming in spermatogenesis.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health MH099910, MH104184, MH091258, MH087597 and MH073030.

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Glossary

Birth cohort studies

Longitudinal prospective studies in which pregnancies are followed through birth and into childhood to correlate the risk for given outcomes with specified experiences or exposures during gestation. These cohorts of individuals differ from other epidemiological studies in which the outcome measures are mainly retrospective.

Biomarkers

Specific biochemical, molecular, anatomical or physiological characteristics that are used to predict, measure or indicate the presence or progress of disease or the effects of treatment.

Executive function

A set of cognitive abilities that include inhibition (resisting habits, temptations or distractions), switching (adjusting to change) and working memory (mentally holding and using information).

Stress responsiveness

Behavioural or physiological measures in response to a stress provocation. In all mammals, the physiological hypothalamic–pituitary–adrenal stress axis is the standard measure of stress experience. Behavioural changes in response to stress or threat can also be examined as an indication of stress state.

Imprinted gene

A gene expressed from only one allele in a manner that depends on the parent of origin and that is regulated by DNA methylation.

Hypothalamic–pituitary–adrenal stress axis

(HPA stress axis). The neuroendocrine core of the stress system. Its activation results in the release of corticotropin-releasing factor from the hypothalamus, adrenocorticotropic hormone from the pituitary and cortisol (corticosterone in rats and mice) from the adrenal glands.

Endophenotypes

Quantifiable phenotypes with an assumed intermediate role in the pathway from genes to complex phenotypes. It is thought that the action of an endophenotype is easier to understand biologically and genetically than the action of the complex phenotype of primary interest. They enable the examination of specific aspects of complex human diseases in animal models.

Barnes maze

A spatial learning and memory task in which the animal is placed on a large, open table that has holes around the circumference. Only one of the holes has an escape tunnel, and the animal must learn to use distal cues to identify this hole and escape in the shortest possible time. Learning in this task involves the hippocampus.

Microglia

Glia of mesodermal origin and the resident macrophages of the CNS.

Social defeat

A behavioural model in which rodents (predominantly males) are repeatedly exposed to a more aggressive conspecific. The outcomes of these confrontations are repeated losses for the subject. This exposure is then followed by a period of housing the defeated animal in close proximity to the aggressor to establish the conditioning.

Pre-pulse inhibition

A reduction in the magnitude of the startle reflex that occurs when an organism is presented with a non-startling stimulus (a pre-pulse) before being presented with the startling stimulus. Deficits in pre-pulse inhibition have been observed in patients with schizophrenia.

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Bale, T. Epigenetic and transgenerational reprogramming of brain development. Nat Rev Neurosci 16, 332–344 (2015). https://doi.org/10.1038/nrn3818

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