One-year-old Syrian hamster. Photo: Adam Jennison
In research that harkens to the current moratorium on CRISPR-Cas9 germline editing, researchers at Georgia State University (GSU) unexpectedly created gene-edited hamsters that displayed unusually high levels of aggression toward each other.
Studies from a variety of species, including hamsters, indicate that arginine-vasopressin (AVP) and its V1a receptor (Avpr1a) play a critical role in the regulation and expression of social behaviors. In an effort to further understand that role, GCU scientists Elliott Albers and Kim Huhman used CRISPR-Cas9 to completely knock out the Avpr1a receptor in a handful of hamsters, anticipating reduced aggression and social commination.
But the opposite happened.
The hamsters without the receptor showed much higher levels of social communication behavior than did their counterparts with intact receptors. Even more interesting, the typical sex differences observed in aggressiveness were eliminated.
Avpr1a activation is known to increase aggression in male hamsters, while typically reducing aggression in females. Indeed, according to the study published in PNAS, all hamsters, regardless of genotype and sex, exhibited aggression toward their same sex counterparts. However, differences soon became apparent.
Both male and female hamsters genetically modified to be without Avpr1a displayed more aggression than their wildtype littermates—with GM males showing twice as more compared with controls. But even more surprising than that, researchers reported “a significant main effect of sex,” with GM females initiating aggression much earlier than GM males.
“This suggests a startling conclusion,” said Albers, Director of the Center for Behavioral Neuroscience at GSU. “Even though we know that vasopressin increases social behaviors by acting within a number of brain regions, it is possible that the more global effects of the Avpr1a receptor are inhibitory. We don’t understand this system as well as we thought we did.”
The researchers also noted differences in flank marking, which communicates a variety of socially important information to others, such as dominance status and mate choice. Previous studies have linked flank marking to the Avpr1as gene, so the scientists wanted to see if the behavior presented the same in hamsters without the gene.
The team was surprised to find that the loss of the gene actually increased flank marking, rather than eliminated it. In the study, all hamsters exhibited robust flank marking when exposed to the odors of a same-sex member, but the genetically modified hamsters marked twice as much as the wildtypes. The researchers did not record a difference based on sex.
“The counterintuitive findings tell us we need to start thinking about the actions of [Avpr1a] receptors across entire circuits of the brain and not just in specific brain regions,” said Albers. “Understanding the role of vasopressin in behavior is necessary to help identify potential new and more effective treatment strategies for a diverse group of neuropsychiatric disorders ranging from autism to depression.”
The scientists say their results not only demonstrate the utility of CRISPR-Cas9 gene editing in Syrian hamsters, but also how translational the species is as a “nontraditional” lab model. Their social organization is far more similar to humans than that observed in mice. The same is true of their stress response as they release cortisol, just like humans. Syrian hamsters also get many of the cancers that humans do, and they are susceptible to the SARS-CoV-2 virus.
“Comparison of behavioral genetic data obtained from nontraditional model species with data obtained in mice provides important context that may help generalize findings to other rodents or to humans,” concluded Albers. “It is important to understand the neurocircuitry involved in human social behavior and our model has translational relevance for human health.”