Depression occurs in over 10% of the US population each year, and women are reported to experience depression twice as frequently as men. Physiological reactivity to social stressors is evolutionarily conserved and both rodents and humans experience social conflicts that can alter affect and behavior. In animal models social stress induces anhedonia, a loss of interest in previously rewarding activates, which is a major diagnostic feature of depression. Diminished reward can result in reduced consumption of sucrose and reduced time engaging in social interaction. This allows for the study of how changes in the brain are associated with these changes in behavior. Aggressive interactions are infrequent in commonly used laboratory rats and mice, making it difficult or impossible to study effects of social stress on females. California mouse (Peromyscus californicus) males and females are territorial, making them suitable for studying sex differences. Female but not male California mice exposed to social stress spend less time engaging in social interactions. Oxytocin (OT) and arginine vasopressin (AVP) are related neuroproteins that play important roles in social interactions. Both proteins have been identified as potential targets for drugs in the treatment of depression. The proposed study uses three experiments to examine sex differences in how OT and AVP systems in the brain respond to social stress. In the first experiment, triple-label immunohistochemistry will be used on brain tissue acquired from mice exposed to social stress, social interaction, or control conditions. This allows for quantifying the number of OT and AVP neurons that contain c-fos, a protein whose presence suggests that the cells were recently activated. The second experiment will use real time PCR to examine how OT and AVP receptor mRNA expression in the lateral septum, central amygdala, paraventricular nucleus and pituitary is changes 4 wk after social defeat. Finally, in experiment 3, I will infuse OT or OT receptor antagonist into the lateral ventricles just before chronic social stress to determine whether manipulating OT function can block or induce the development of social aversion 4 wk later. Together these experiments should provide insight into whether OT and AVP play a role in the development and expression of social withdrawal.

Public Health Relevance

Twice as many women report suffering from depression as do men, yet the majority of studies that use animal models to investigate the biological causes of depression use males. We are using male and female California mice (Peromyscus californicus) to examine whether sex differences in the neuropeptides oxytocin and vasopressin have a role in the increased susceptibility of female as compared to male mice in developing social withdrawal following chronic social stress. A better understanding of the role of the proteins in depression and social withdrawal could aid in the development of better pharmaceutical treatments for these mood disorders in the future.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Rosemond, Erica K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Arts and Sciences
United States
Zip Code
Duque-Wilckens, Natalia; Steinman, Michael Q; Busnelli, Marta et al. (2018) Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice. Biol Psychiatry 83:203-213
Duque-Wilckens, Natalia; Steinman, Michael Q; Laredo, Sarah A et al. (2016) Inhibition of vasopressin V1a receptors in the medioventral bed nucleus of the stria terminalis has sex- and context-specific anxiogenic effects. Neuropharmacology 110:59-68
Steinman, Michael Q; Duque-Wilckens, Natalia; Greenberg, Gian D et al. (2016) Sex-Specific Effects of Stress on Oxytocin Neurons Correspond With Responses to Intranasal Oxytocin. Biol Psychiatry 80:406-14
Steinman, M Q; Laredo, S A; Lopez, E M et al. (2015) Hypothalamic vasopressin systems are more sensitive to the long term effects of social defeat in males versus females. Psychoneuroendocrinology 51:122-34
Laredo, Sarah A; Steinman, Michael Q; Robles, Cindee F et al. (2015) Effects of defeat stress on behavioral flexibility in males and females: modulation by the mu-opioid receptor. Eur J Neurosci 41:434-41
Greenberg, Gian D; Steinman, Michael Q; Doig, Ian E et al. (2015) Effects of social defeat on dopamine neurons in the ventral tegmental area in male and female California mice. Eur J Neurosci 42:3081-94
Laredo, Sarah A; Villalon Landeros, Rosalina; Dooley, James C et al. (2013) Nongenomic effects of estradiol on aggression under short day photoperiods. Horm Behav 64:557-65
Steinman, Michael Q; Valenzuela, Anthony E; Siopes, Thomas D et al. (2013) Tuberal hypothalamic expression of the glial intermediate filaments, glial fibrillary acidic protein and vimentin across the turkey hen (Meleagris gallopavo) reproductive cycle: Further evidence for a role of glial structural plasticity in seasonal reprod Gen Comp Endocrinol 193:141-8
Steinman, Michael Q; Knight, Jennifer A; Trainor, Brian C (2012) Effects of photoperiod and food restriction on the reproductive physiology of female California mice. Gen Comp Endocrinol 176:391-9