Current Research Interests

Social defeat stress has emerged as an important model of stress-induced psychiatric disease. Although depression is more common in women, most studies of social defeat are conducted on male mice or rats. We study a monogamous species (the California mouse) to investigate how social stress impacts brain and behavior in both males and females. Unlike domestic rats and mice, female California mice aggressively defend territories. Our work has discovered behavioral and neurobiological changes induced by social stress that differ in males and females. Further understanding of how stress impacts the brain in males and females could lead to more optimized treatment for depression and anxiety.

New NIH policies encourage basic research programs to consider sex as a biological variable (SABV) and include both males and females in experiments. Our research with California mice provides an outlet for testing hypotheses in females that are developed with transgenic mice. We are very interested in collaborating with labs seeking to test hypotheses in females. A genome and online brain atlas (brainmaps.org) are available for California mice. See the main page or contact Brian Trainor for more information.

Complementary neural circuits of social approach and vigilance

Oxytocin (blue) and vasopressin (green) neurons in the paraventricular nucleus co-stained with c-fos (red).

Oxytocin is a well-known modulator of social behaviors and has been put forth as a possible therapeutic for anxiety and depression. In some studies using human participants, intranasal oxytocin enhances social approach related behaviors. However, other studies (especially in women) report that intranasal oxytocin increases social anxiety. How can the same neuropeptide exert such different effects on behavior? Our central hypothesis is that oxytocin acts in the mesolimbic dopamine system to promote social approach, whereas oxytocin acts in the bed nucleus of the stria terminalis (BNST) to enhance social anxiety (Steinman, Duque-Wilckens & Trainor 2019). Dr. Natalia Duque-Wilckens showed that oxytocin neurons in the BNST project to brain regions that modulate defensive behaviors (Duque-Wilckens et al. 2020). If oxytocin synthesis is inhibited in the BNST, stress-induced decreases in social approach can be largely reversed. She also showed that infusing oxytocin into the BNST of unstressed males or females can increase anxiety-related behaviors like social vigilance (avoiding a social context while simultaneously orienting toward it). In contrast, Dr. Alexia Williams showed that oxytocin receptors in nucleus accumbens promote social approach in both males and females (Williams et al. 2020). Previous work by Dr. Michael Steinman showed that social stress induces a long-term increase in reactivity of oxytocin neurons in the BNST in females but not males (Steinman et al. 2016), and we will be using RNASeq to identify molecular changes that may underlie this effect. Collaborative work with the Robison lab at Michigan State Univesity is examining the electrophysiological properties of BNST oxytocin neurons. This project is supported by an R01 from NIMH.

Effects of Adolescent Development on Stress Sensitivity

In 2011 we found that social defeat stress induced a long-term decrease in social approach of female California mice but not males (Trainor et al. 2011). Effects of stress did not differ across the estrous cycle, but we tested whether removal of gonadal hormones in adults modulated this sex difference. Although gonadectomy had strong effects on corticosterone responses to social stress, stress still reduced social approach in ovariectomized females and had no effect on social approach in castrated males (Trainor et al. 2013). Dr, Emily Wright discovered that effects of defeat stress on social approach were identical in male and female juvenile California mice (Wright et al. 2020), suggesting that the critical window for the development of sex differences occurs during adolescence. She showed that removal of the testes before adolescence in males produced a female-like stress response in adults and that replacement with testosterone or dihydrotestosterone (DHT) during adolescence resulted in a male-typical stress response. These data indicate that androgen receptors play a key role during adolescence in shaping stress responses. We are currently working to determine which parts of the brain are shaped by androgens during adolescence. These projects are supported by NSF.

Juvenile (left) and adult (right) California mice

We have also established fiber photometry methods for GCaMP imaging in California mice and recently upgraded our Doric system for optogenetics. We are recruiting lab members who are interested in applying these methods to study stress, adolescent development, and social behavior.