A Cortical Circuit for Sexually Dimorphic Oxytocin-Dependent Anxiety Behaviors

Abstract

SUMMARY The frequency of human social and emotional disorders varies significantly between males and females. We have recently reported that oxytocin receptor interneurons (OxtrINs) modulate female sociosexual behavior. Here we show that in male mice OxtrINs regulate anxiety-related behaviors. We demonstrate that corticotropin releasing hormone binding protein (CRHBP), an antagonist of the stress hormone CRH, is specifically expressed in OxtrINs. Production of CRHBP blocks the CRH-induced potentiation of postsynaptic layer 2/3 pyramidal cell activity of male but not female mice, thus producing an anxiolytic effect. Our data identify OxtrINs as critical for modulation of social and emotional behaviors in both females and males, and reveal a molecular mechanism that acts on local mPFC circuits to coordinate responses to OXT and CRH. They suggest that additional studies of the impact of the OXT/OXTR and CRHBP/CRH pathways in males and females will be important in development of gender specific therapies.

Sex differences in stress responses: a critical role for corticotropin-releasing factor

“…First, CRF-producing neurons are regulated by different types of receptors [111]. Moreover, within CRF neurons, expression of CRF is reported to be higher in females than males in some brain regions, an effect that can overcome the ability of CRFBP to buffer the effects of CRF on anxiety in females [102]. Further, at the receptor level, there are sex differences in receptor expression, distribution, trafficking, and signaling, and many, but not all, of these sex differences have been linked to increased female CRF sensitivity [67,68,82,83,85].…”

“…Despite the release of CRFBP in both sexes, oxytocin interneurons mitigated the anxiogenic effect of CRF only in males [102]. The lack of an effect in females was attributed to their higher levels of CRF expression, which are thought to exceed the capacity of CRFBPs to prevent CRF from inducing anxiety [102]. Interestingly, in the pituitary, CRFBP expression is higher in females than in males, perhaps to compensate, at least in part, for higher levels of CRF in the PVN [95][96][97]104].…”

“…Li and colleagues (2016) found that oxytocin interneurons in the medial prefrontal cortex of both male and female mice release CRF-binding protein (CRFBP), which binds free CRF reducing its bioavailability, thereby inhibiting CRF's effect on its receptors [103]. Despite the release of CRFBP in both sexes, oxytocin interneurons mitigated the anxiogenic effect of CRF only in males [102]. The lack of an effect in females was attributed to their higher levels of CRF expression, which are thought to exceed the capacity of CRFBPs to prevent CRF from inducing anxiety [102].…”

“…Excess CRF expression in females was recently associated with increased anxiety [102]. Li and colleagues (2016) found that oxytocin interneurons in the medial prefrontal cortex of both male and female mice release CRF-binding protein (CRFBP), which binds free CRF reducing its bioavailability, thereby inhibiting CRF's effect on its receptors [103].…”

Oxytocin and Rodent Models of Addiction

“…Magnocellular oxytocin neurons in the PVN express high levels of corticotrophin-releasing factor (CRF) type 2 receptors and these CRF receptor positive neurons express oxytocin receptor mRNA as do CRF receptor positive neurons in the bed nucleus of the striatal terminalis (Dabrowska et al, 2011). Oxytocin receptors have been identified on cortical somatostatin-containing interneurons (Li, Nakajima, Ibanez-Tallon, & Heintz, 2016; Nakajima et al, 2014), cortical glutamatergic and GABAergic neurons (Tan et al, 2017), parvalbumin positive interneurons and astrocytes in the NAcc (Dolen et al, 2013), and on glutamate, GABA and dopamine producing neurons in the VTA (Peris et al, 2017). These three brain areas are crucial to the circuitry regulating drug reward and reinforcement as well as relapse to drug use, and oxytocin in each of these areas may uniquely impact drug seeking.…”