Grin1 deletion in CRF neurons sex-dependently enhances fear, sociability, and social stress responsivity

• Male CRF-specific Grin1 knockout mice exhibit elevated fear expression.
• Male knockouts also display enhanced social interaction.
• Male knockouts susceptible to social defeat display exaggerated social withdrawal.
• Fear and social behavior of female knockouts do not differ from wildtypes.
• NMDA-mediated CRF neuron excitation is important in promoting adaptive behaviors.

The corticotropin releasing factor (CRF) system plays a critical role in responses to stressful stimuli, and is expressed in many areas of the brain involved in processing fear, anxiety, and social behaviors. To better understand the mechanisms by which the CRF system modulates responses to stressful events and social stimuli, we employed a mouse model that selectively disrupts NMDA receptor function via NMDA receptor subunit NR1 (Grin1) knockout specifically in Cre-expressing CRF neurons. These animals (Cre+/fGrin1+) were compared with littermates lacking Cre expression (Cre−/fGrin1+). Following cue discrimination fear conditioning, male Cre+/fGrin1+ mice showed increased fear expression to the tone paired with a foot shock (CS+) while still discriminating the CS+ from a tone never paired with a foot shock (CS−). In contrast to males, female mice learned and discriminated fear cues equivalently across the genotypes. Similarly, no genotype differences in sociability or social novelty were observed in female mice, but Cre+/fGrin1+ males displayed greater naive sociability and preference for social novelty than Cre−/fGrin1+ littermates. Furthermore, the level of social withdrawal exhibited by male Cre+/fGrin1+ mice susceptible to social defeat stress relative to same genotype controls was significantly more pronounced than that displayed by susceptible Cre−/fGrin1+ mice compared to control Cre−/fGrin1+ mice. Together, these results demonstrate increased fear, social, and stress responsiveness specifically in male Cre+/fGrin1+ mice. Our findings indicate that NMDA-mediated glutamatergic regulation of CRF neurons is important for appropriately regulating fear and social responses, likely functioning to promote survival under aversive circumstances.