Stress-induced trauma in mice is inherited genetically by offspring.

 

The effects of trauma can be passed down through generations, resulting in psychiatric disorders like depression in offspring. Researchers have found small non-coding RNAs (sncRNAs), molecules that could be the link between environmental factors, like trauma, and genes (1). Both genetic make-up and environmental factors serve as important contributors to an individual’s disease risk and heritability. SncRNAs, abundant in the mature sperm of mammals and capable of relaying environmental signals to regulate gene activity, are most likely the carriers of trauma across generations (1).

Sequencing analysis of adult mouse sperm under normal conditions revealed a variety of sncRNA populations mapping to various parts of the mouse genome. Traumatic stress in early life was applied to the mouse model by subjecting experimental mice to maternal separation combined with unpredictable maternal stress (MSUS). Namely, MSUS pups were separated from dams for three hours daily from postnatal days 1-14 while control animals were left undisturbed until weaning (1). Behavioral tests showed altered responses between MSUS mice and controls across both F1 (first generation) and F2 (second generation) progeny. The elevated plus maze, light-dark box, and Porsolt forced swim tests revealed a lack of aversion in MSUS mice to typically discomforting situations such as open spaces, brightly lit areas, and swimming (1).

The effect of early stress on metabolic regulation was shown through examination of glucose metabolism. F1 and F2 MSUS mice both expressed insulin hypersensitivity when compared to the control while F2 MSUS also showed hypermetabolism. These changes were more prominent in the F2 generation, likely due to earlier presence of stress when compared to F1 (1).

Sequencing analysis of MSUS sperm sncRNAs revealed different levels of sncRNA populations when compared to the controls. Such changes were also seen in analysis of the hippocampus and hypothalamus, brain structures involved in stress responses (1). Although normal populations of sncRNAs were observed in F2 sperm and F3 animals, F3 MSUS mice still had altered behavioral symptoms, indicating the transfer of trauma-induced genetic changes to other non-genomic markers to provide further transmission (1).

To solidify the link between sperm RNAs and the genetic transmission of trauma effects, purified RNA from MSUS sperm was injected into wild-type mouse egg cells. (1) These treated mice expressed similar changes to those of MSUS F1 and F2 populations, suggesting comparable behavioral, metabolic, and molecular effects whether the trauma is induced through direct exposure or injection of sperm RNA (1).

These findings show the importance of sncRNAs in the transmission of acquired traits across generations as well as sensitivity to traumatic stress in early life. The identification of potential molecular markers of traumatic stress may be useful in the diagnosis and treatment of trauma or stress-induced disorders in humans.

Reference:

1. Gapp, Katharina. “Implication of Sperm RNAs in Transgenerational Inheritance of the Effects of Early Trauma in Mice.” Nature Neuroscience 17 (2014): 667-69. Nature Neuroscience. Nature Publishing Group, 13 Apr. 2014. Web. 4 May 2014.