Gender specific differences in stress resilience in mice

In humans, gender specific differences in the prevalence of emotional disorders have been observed. A new study reveals the circuit and molecular mechanism that is responsible for gender biases in the occurrence of social and anxiety related disorders.

HFSP Long-Term Fellow Kun Li and colleagues
authored on Fri, 21 October 2016

It has been wildly reported that sexual differences exist in several psychiatry disorders. For example, men are more likely to develop autism, while females are more vulnerable to anxiety-related disorders, such as posttraumatic stress disorder. Recent studies have suggested that differences in hormonal balance and brain circuitry between males and females may contribute to these variations. However, the specific mechanism responsible for gender biases in the prevalence and treatment of social and emotional disorders is not understood.

Oxytocin is a hormone that is made in the brain and has been shown to contribute to many aspects of emotional behaviors. It is released in response to social cues and stressful or anxiogenic stimuli. Oxytocin acts through oxytocin receptors (OXTR), which are widely expressed in the brain and periphery body. Researchers in the Heintz lab have identified a specific class of OXTR interneurons (OxtrINs) in the mouse medial prefrontal cortex (mPFC). Genetic and pharmacological manipulation indicated that these neurons are capable of promoting sociosexual behavior in female mice during the estrous cycle, but has no effect on male mice. Thus, the function of this particular cell type in male mice is still a mystery.

Figure: (A) Oxtr-EGFP-L10A mice express EGFP, which is detected in OxtrINs in the coronal sections of the mPFC. Scale bars: 600µm left and 300µm right. (B) Sex-specific behavioral response to OxtrINs stimulation in mPFC. Activation of OxtrINs in mPFC with optogenetic stimulation increased sociosexual behavior in female mice (left panel) and decreased anxiety behavior (explore the open arms) in male mice (right panel).

To determine the role of OxtrINs in the male brain, Kun Li and her colleagues in the Heintz lab at The Rockefeller University have screened different mouse behaviors after manipulating OxtrINs by optogenetic activation. The results revealed that activation of these neurons in male mice has a strong anxiolytic effect and no impact on social interaction, whereas activation of these neurons in female mice results in increased sociosexual behavior and no change in anxiety-related behaviors.

Translational ribosome affinity purification (TRAP) developed by the Heintz lab was used to identify proteins actively synthesized in particular cell types. To identify the molecular mechanism that might contribute to the anxiolytic effect of OxtrINs in males, we employed TRAP to profile mRNA synthesized in OxtrINs in the mPFC samples. The corticotrophin releasing hormone binding protein (CRHBP) was among the most highly enriched mRNAs in OxtrINs. CRHBP is a small and secreted protein that can bind to corticotrophin releasing hormone (CRH) and inhibit CRH function. CRH and CRH receptor 1 (CRHR1) are critical regulators of stress responses and anxiety. CRHR1 is specifically expressed in layer 2/3 pyramidal neurons in the mPFC. Through combing electrophysiological recording and behavioral approaches, they demonstrated OxtrINs suppressed anxiogenic effects of CRH on postsynaptic layer 2/3 pyramidal neurons by releasing CRHBP.

Taken together, coordination of local oxytocin and CRH in the mPFC by OxtrINs and CRHBP may be involved in the modulation of gender specific cognitive behaviors. The balancing between Oxytocin/OXTR and CRHBP/CRH pathways in male and female mice is important for the development of gender specific therapies.


A Cortical Circuit for Sexually Dimorphic Oxytocin-Dependent Anxiety Behaviors. Kun Li, Miho Nakajima, Ines Ibanez-Tallon, Nathaniel Heintz. Cell 167,60-72, (2016).

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