Faculty Mentor: Moriel Zelikowsky (Neurobiology & Anatomy, University of Utah)

Background

Social instability stress (SIN) is a form of chronic stress marked by unstable environments, whether that be from frequent changes in peer groups or housing instability. While research has shown that SIN results in increases in mood disorders such as depression and anxiety as well as socioemotional behavior changes, the neural mechanisms of its effect on the brain are unknown. Oxytocin is a neuropeptide known for its role in maternal behavior, bonding/attachment, and social behavior. Previous studies have established that the CA2 and CA3 regions of the dorsal hippocampus (dCA2 and dCA3, respectively) are involved in social memory and interaction, and oxytocin receptors (OxtR) are highly expressed in these regions. However, the role of oxytocin in SIN is not well understood, revealing a gap in our knowledge of the relationship between oxytocin and chronic social stress.

Methods

To understand the relationship between SIN and oxytocin signaling, 18 juvenile male mice were randomized into two groups. Mice were assigned to either the stable (STBL) group, where mice were stably housed with two cage mates, or the SIN group, where cage compositions were consistently rearranged such that, each mouse received two new cage mates every 48 hours for 3 weeks. Following the 3-week SIN period, mice were euthanized, their brains were extracted, flash-frozen, and prepared for histology. Fluorescent in situ hybridization (FISH) was performed on brain slices using an OxtR probe to target and visualize OxtR mRNA, and those slices were then imaged. Images were analyzed for OxtR expression using FIJI (ImageJ) by a blinded experimenter and statistical analysis of results was performed using a student’s t-test in GraphPad Prism.

Results

We found that hippocampal OxtR expression was significantly increased in SIN mice compared to STBL mice following the 3-week SIN period (p < 0.05). This finding suggests that chronic SIN increases hippocampal OxtR expression, potentially sensitizing the dCA2 and dCA3 regions to changes in oxytocin signaling. Further, this finding implies that oxytocin signaling is impacted by SIN, highlighting a neurobiological relationship between a chronic social stressor and a “social” neuropeptide. Future directions include investigating the molecular identity of OxtR expressing neurons to determine whether SIN differentially impacts neuronal subpopulations.

Bibliography

Froemke, R. C., & Young, L. J. (2021). Oxytocin, Neural Plasticity, and Social Behavior. Annual review of neuroscience, 44, 359–381. https://doi.org/10.1146/annurev-neuro-102320-102847

Hodges, T. E., Eltahir, A. M., Patel, S., Bredewold, R., Veenema, A. H., & McCormick, C. M. (2019). Effects of oxytocin receptor antagonism on social function and corticosterone release after adolescent social instability in male rats. Hormones and behavior, 116, 104579. https://doi.org/10.1016/j.yhbeh.2019.104579

Tzakis, N., & Holahan, M. R. (2019). Social Memory and the Role of the Hippocampal CA2 Region. Frontiers in behavioral neuroscience, 13, 233. https://doi.org/10.3389/fnbeh.2019.00233