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 sex-specific behavioral and neurobiological changes induced by social stress. 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 (in which social defeat protocols in females are currently unvailable). We are very interested in collaborating with labs seeking to test hypotheses in females. A sequenced brain transcriptome and online brain atlas (brainmaps.org) are available for California mice. See the main page or contact Brian Trainor for more information.
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 (in which social defeat protocols in females are currently unvailable). We are very interested in collaborating with labs seeking to test hypotheses in females. A sequenced brain transcriptome and online brain atlas (brainmaps.org) are available for California mice. See the main page or contact Brian Trainor for more information.
Neuropeptides: Anxiogenic effects of oxytocin
Steinman et al. 2016, Duque-Wilckens et al. 2016 and in press
Oxytocin (blue) and vasopressin (green) neurons in the paraventricular nucleus co-stained with c-fos (red).
Oxytocin is usually considered to be a prosocial and anxiolytic neuropeptide. However, observations that oxytocin can inhibit social interaction and increase anxiety have been persistent in the literature. These observations contributed to the social salience hypothesis of oxytocin action, that oxytocin enhances the salience of positive and negative social experiences. Using the California mouse model, Steinman et al. showed that social defeat increases the activity of oxytocin neurons in the bed nucleus of the stria terminalis and paraventricular nucleus of females but not males. Interestingly, intranasal oxytocin has no effect on social interaction behavior in stressed females, but reduces social interaction in females that have not experienced stress. Oxytocin can activate vasopressin V1a receptors (V1aR), and Duque-Wilckens et al. 2016 tested whether activation of V1aR might reduce social interaction in females. However, these studies showed that V1aR antagonists reduced social interaction behavior in both males and females. In contrast Duque-Wilckens et al. (in press) show that a single dose of systemic oxytocin receptor antagonist (OTA) injection can increase social interaction in stressed females. This is exciting because it takes four weeks of sertraline treatment (a selective serotonin reuptake inhibitor) to achieve the same effect (Greenberg et al. 2014). Local infusion of OTA in to the anterior bed nucleus of the stria terminalis (BNST), but not the nucleus accumbens also increased social interaction. In addition OTR activation facilitates a social vigilance phenotype (see video below). While unstressed females readily approach an unfamiliar female (target mouse), stressed females monitor but avoid unfamiliar females. Both systemic and local infusion of OTA reduce this social vigilance response. These results suggest that oxytocin receptor antagonists could have unappreciated therapeutic applications for social anxiety.
Nucleus accumbens: Dopamine receptors
Campi et al. 2014
Injection sites in the nucleus acumbens of California mice.
This paper shows that social defeat stress increases total dopamine and dopamine metabolite content within the nucleus accumbens of both males and females. Blocking increased dopamine activity with an infusion of D1 dopamine receptor antagonist increased social interaction in females exposed to social stress. Intriguingly, a D1 agonist infusion in to the nucleus accumbens is sufficient to induce social withdrawal in females but not males with no prior exposure to social stress. These data show that suggest that a mechanism downstream from dopamine receptors blocks social withdrawal in male California mice exposed to social stress. We are currently exploring an RNAseq dataset for to identify possible mechanisms for these effects.
Bed nucleus of the stria terminalis: Brain derived neurotrophic factor
Greenberg et al. 2014
Social stress increases BDNF protein in the BNST of females but not males. ** p < 0.01 vs control female.
The bed nucleus of the stria terminalis (BNST) sits just anterior to the nucleus accumbens and is an important node connecting the mesolimbic system with hypothalamic and limbic nuclei that regulate social behavior. Social defeat stress increases brain derived neurotrophic factor (BDNF) protein in the BNST of female but not male California mice. Infusion of an antagonist to TrkB, an important receptor activated by BDNF, blocks stress induced social withdrawal in females but not males. These data show that functional sex differences in the BNST contributes to sex differences in behavioral responses to stress.
