Social memory—the ability to recognize members of the same species—is the cornerstone of socialization. In neurological disorders such as schizophrenia, autism, and anxiety that are associated with aberrant social behavior, signaling pathways that regulate social memory malfunction. The lack of effective treatments for such neurological disorders is largely because the molecular pathways that regulate social memory are not clearly understood.

In a new animal behavior study, researchers reveal a new molecular pathway integral to social memory that supports the “love hormone” oxytocin (OXT) and helps mice and rats recognize and distinguish familiar cage-mates from unfamiliar conspecifics.

The findings were published in an article in the journal Science Signaling titled, “Phosphorylation-dependent positive feedback on the oxytocin receptor through the kinase PKD1 contributes to long-term social memory.”

“These findings may be helpful in identifying more efficient therapeutic strategies to [modulate] the [oxytocin] system and to improve social learning and prosocial behaviors,” the authors noted.

Social memory allows individuals to tell friends apart from strangers and adjust their behavior appropriately. It’s essential for prosocial behaviors such as cooperation and mating.

Earlier studies have shown, OXT and its G-protein coupled receptor (OXTR) are highly expressed in regions of the brain that play a major role in regulating social behaviors and emotions, but how exactly do they control social behavior and emotions at a molecular level has remained a mystery.

Clinical trials have attempted to treat deficits in social behavior using single or repeated doses of OXT, with discrepant results. “Considering the contradictory results of long-term OXT treatment in clinical trials, further investigation on the regulation and modification of OXTR is of urgent need,” the authors noted.

Yun Wang, PhD, scientist at Peking University, is a senior author of the study.

Yun Wang, PhD, and Cheng Cen, PhD, and their team at Peking University, who study social behaviors in mice and rats, discovered that their long-term social memory depended on a signaling pathway that involves the oxytocin receptor.

They saw, under normal physiological conditions, an enzyme called PKD1 (protein kinase D1) phosphorylates OXTR in the medial amygdala at a specific serine residue (Ser261) on the receptor. Rats that express a mutated form of the receptor that cannot be phosphorylated by PKD1, the researchers found, exhibited impaired long-term social memory.

To confirm whether this mechanism is indeed pivotal in controlling social memory, the investigators blocked the phosphorylation of OXTR in the medial amygdala in normal wild-type rats using an interfering peptide and selectively mutated the PKD1 gene in the medial amygdala in mice. In both animal models, the retention of social memory was reduced. On the other hand, expressing a phosphomimetic mutant of OXTR—a mutant bearing an amino acid substitution that mimics phosphorylated OXTR—rescued social memory.

Their findings indicate a positive feedback loop between PKD1 and OXTR supports OXT activity. The ability of rats and mice to recognize their littermates depends on this mechanism since rodents that harbor a mutated oxytocin receptor forgot about familiar animals and treated them as strangers if separated for a day.

“Our findings describe a phosphoregulatory loop for OXTR and its critical role in social behavior that might be further explored in associated disorders,” the authors noted.

This new study proposes a working mechanistic model where a phosphorylation-dependent positive feedback loop involving OXTR and PKD1 in the medial amygdala consolidates long-term social memory. [Wang et al., SciSignal., 2022]
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