Miklos Toth


Non-DNA mediated transmission of behavior across generations

Biological information is typically considered as being transmitted across generations by DNA but evidence indicates the existence of non-genetic inheritance. One important mechanism with significant health implications is maternal (parental) non-genetic effects. The mother (parents) provides not only genetic material for the offspring but also the environment including various factors such as cytokines and hormones that are essential for the normal development of the offspring.

Background: Maternal programming of brain development and adult emotional and cognitive behavior in health and disease

"Maternal programming" is a term that reflects the action of maternal factors during sensitive periods of development that produces persistent effects in the offspring. For example, maternal factors are essential for the proper development of the fetal and neonatal brain and for the establishment of normal, species specific adult emotional and cognitive behavior. Genetic and/or environmental perturbations of the maternal physiology and behavior can lead to developmental abnormalities in the offspring that are manifested in adolescence of adulthood as mental and cognitive disorders.

Additional similar models are used in our laboratory to study the non-genetic transfer of behavior from mother to offspring. These include a model in which the mother is deficient in tumor necrosis factor alpha (TNF) that leads to increased learning of spatial details similar to that seen in obsessive compulsive disorder (see figure below) and another model in which the mother lacks the fragile X protein that leads to inappropriate social interaction (lack of stranger anxiety seen in for example in Williams' syndrome) and hyperactivity seen in attention deficit hyperactivity disorder.

Ongoing projects

1. Mediators of mother-offspring communication: By using a total of three different mother-offspring models, first we want to understand of how the maternal environment communicates with the developing offspring brain. Then we would like to understand how this communication is altered when the maternal environment is suboptimal (for example maternal genes are perturbed or the mother is stressed). We hypothesize that transplacental and milk-mediated transfer of maternal immune cells and/or their cytokines is essential for normal brain development and for the establishment of adult behavior in the offspring (see figure below). It is conceivable that the original maternal factors reach the developing brain across the placenta through a cascade of maternal/fetal cytokines. Cytokine receptors are abundant in the brain, providing a means to convey the maternal effect to developing neurons. This in turn can influence neuronal circuit formation and consecutively the behavioral output of these circuits. Postnatally, a similar pathway, initiated by milk-derived maternal factors and mediated by gut immune system-derived cytokines in the offspring, can be hypothesized.

2. Epigenetic marks produced by the maternal effect in the offspring: Second, we want to specify the molecular "imprints" in the fetal brain that are elicited by the maternal effect and which are responsible for the lifelong behavioral abnormalities in the offspring. Among the various epigenetic modifications, CpG methylation is probably the longest lasting because it is thermodynamically very stable. Methylated cytosine is often considered to be the fifth letter of the DNA code and there is abundant evidence for its role in gene regulation and other cellular processes. Altered methylation caused by a maternal effect can be viewed as mutation (epimutation) that has a similar effect than genetic mutation on gene expression and ultimately on neuronal function/behavior.

Although DNA methylation assays have long been available, finding DNA methylation changes that underlie environmental effects, including maternal genotype effects, is complicated by the necessity to use homogenous neuronal populations and genome-wide methylation assays. The genome-wide assay used in the laboratory consists of several biochemical and computational processes as well as validation steps.

Research Topics

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