Behavior Vs. Genetics: How Does the Father’s Role Affect Offspring?

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Eric J. Nestler, M.D., Ph.D., with members of the Nestler Lab
Eric J. Nestler, M.D., Ph.D.

From The Quarterly, Fall 2011

A recent study by Dr. Eric Nestler’s team explored how an acquired behavior such as stress due to “social defeat” could cause behavioral changes in an individual’s offspring.  It is well known that the way a mother treats her offspring during development can influence their subsequent behavior. But, Dr. Nestler notes, “Recently the field has focused on paternal transmission, in an effort to distinguish behavioral transmission from another kind, called epigenetic.”

He refers to the theory that events that occur during adulthood–for instance, becoming addicted to cocaine or subjected to stress from social defeat–can cause permanent alterations in the way an individual’s genes are regulated, and that these or related changes might be carried into the next generation via the “marking” of genes with groups of methyl molecules (called “methylation”) or via other epigenetic mechanisms, which don’t affect the genes themselves, but do affect the way they are expressed.

Are epigenetic changes induced by social-defeat stress imprinted in a male mouse’s sperm, and subsequently carried over into offspring?  Dr. Nestler’s team mated socially defeated male mice with normal females. As soon as the females became pregnant, the males were immediately removed, so that their abnormal behavior could not be a direct factor in the pups’ upbringing.  Still, however, the team found that the pups of these unions were notably disturbed, behaviorally (for instance, they were abnormally prone to stress and anxiety) compared with pups produced by two healthy parents.  But were epigenetic changes in sperm at the root of this?

Dr. Nestler’s team used the sperm of the same defeated males to fertilize eggs in vitro and implanted the eggs in normal females.  “The behavioral deficits in these pups were far, far less noticeable,” he says.  In a paper published recently in Biological Psychiatry, the team said it was unlikely (but not impossible) that the defeated males transmitted epigenetic patterns to offspring that adversely affected their behavior.  In the affected sets of pups, however, raised by mothers who had procreated with defeated males, the team proposed that the behavioral changes were transmitted behaviorally.  

But how could that be, if the defeated fathers were not present during the pups’ upbringing?  Dr. Nestler suggests that “the mother may know when she’s procreating with a ‘loser!’  She knows it, and it changes the way she raises her pups—perhaps because of stress during pregnancy, or perhaps it’s reflected in the treatment she gives the pups after they’re born.  Both mechanisms may be occurring (epigenetic and behavioral), but we still lack proof.”  In the end, the behavior of the father did seem to matter; what remains uncertain is the mechanism by which abnormal behaviors were transmitted to offspring.

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