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CRISPR-Cas9 gene editing shown to change social behaviors in animal models

A Georgia State University research team has used CRISPR gene editing technology to show how the Avpr1a receptor affects social behaviors in hamsters.

CRISPR-Cas9 technology was utilized by a team of Georgia State University researchers led by Professor of Neuroscience H. Elliott Albers and Professor Kim Huhman to disable the functions of a neurochemical signaling pathway that regulates social behaviors in mammals. Vasopressin and the Avpr1a receptor on which it activates influence a variety of social behaviors, including social bonding, teamwork, and socialization, as well as dominance and aggression.

The findings of a newly published study show that in hamsters, inactivating the Avpr1a receptor and therefore effectively eliminating vasopressin’s activity on it, changed the expression of social behavior in unforeseen ways.

Dr. Albers told Georgia State News Hub, “We were really surprised at the results. We anticipated that if we eliminated vasopressin activity, we would reduce both aggression and social communication. But the opposite happened.”

The unexpected findings showed that hamsters lacking the receptor exhibited significantly more socialization behaviors than those with receptors. Even more intriguing, traditional sex distinctions in aggressiveness were erased, with both male and female hamsters expressing significant increased levels of aggression toward other same-sex hamsters.

Dr. Albers added, “This suggests a startling conclusion. 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 counterintuitive findings tell us we need to start thinking about the actions of these receptors across entire circuits of the brain and not just in specific brain regions.”

Dr. Huhman, who is Associate Director of the Neuroscience Institute at Georgia State, explained the use of hamsters in the animal model, stating, “Their stress response is more like that of humans than it is other rodents. They release the stress hormone cortisol, just as humans do. They also get many of the cancers that humans get.”

The researchers emphasized that the utilization of CRISPR in hamsters was a significant step forward. “Developing gene-edited hamsters was not easy,” Albers said. “But it is important to understand the neurocircuitry involved in human social behavior and our model has translational relevance for human health. 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 study was published in PNAS on May 5th, 2022.

Abstract. Studies from a variety of species indicate that arginine–vasopressin (AVP) and its V1a receptor (Avpr1a) play a critical role in the regulation of a range of social behaviors by their actions in the social behavior neural network. To further investigate the role of AVPRs in social behavior, we performed CRISPR-Cas9–mediated editing at the Avpr1a gene via pronuclear microinjections in Syrian hamsters (Mesocricetus auratus), a species used extensively in behavioral neuroendocrinology because they produce a rich suite of social behaviors. Using this germ-line gene-editing approach, we generated a stable line of hamsters with a frame-shift mutation in the Avpr1a gene resulting in the null expression of functional Avpr1as. Avpr1a knockout (KO) hamsters exhibited a complete lack of Avpr1a-specific autoradiographic binding throughout the brain, behavioral insensitivity to centrally administered AVP, and no pressor response to a peripherally injected Avpr1a-specific agonist, thus confirming the absence of functional Avpr1as in the brain and periphery. Contradictory to expectations, Avpr1a KO hamsters exhibited substantially higher levels of conspecific social communication (i.e., odor-stimulated flank marking) than their wild-type (WT) littermates. Furthermore, sex differences in aggression were absent, as both male and female KOs exhibited more aggression toward same-sex conspecifics than did their WT littermates. Taken together, these data emphasize the importance of comparative studies employing gene-editing approaches and suggest the startling possibility that Avpr1a-specific modulation of the social behavior neural network may be more inhibitory than permissive.

Jack H. Taylor, James C. Walton, Katharine E. McCann, Alisa Norvelle, Qian Liu, Jacob W. Vander Velden, Johnathan M. Borland, Michael Hart, Chengliu Jin, Kim L. Huhman, Daniel N. Cox, H. Elliott Albers. CRISPR-Cas9 editing of the arginine–vasopressin V1a receptor produces paradoxical changes in social behavior in Syrian hamsters. Proceedings of the National Academy of Sciences, 2022; 119 (19) DOI: 10.1073/pnas.2121037119

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