Immune receptor toll-like receptor 4 contributes to stress-induced affective responses in a sex-specific manner

Stress activates innate immune Toll-like receptors (TLRs) and enhances susceptibility to depression, a condition that is more prevalent in females. The TLR4 receptor type is involved in inflammatory responses and its expression levels associate with depressive symptoms and their successful treatment. Yet, little preclinical research has examined the role of TLR4 in stress-induced affective responses to determine if these are sex-specific. One group per genotype of male and female Tlr4 knockout (KO) and wild type (WT) rats were exposed to predator odor in a place conditioning apparatus with others exposed to saline. Affective behaviors evaluated included distance traveled and center time in an open-field apparatus, sucrose preference and fluid intake in a two-bottle test, and conditioned place aversion to the odor-paired compartment. Predator odor exposed rats showed conditioned place aversion to the odor-paired compartment, demonstrating predator odor was aversive. Such exposure led to anhedonia (decreased sucrose preference) across genotypes and sex. Predator odor exposure decreased distance traveled, an effect that was greater in KO rats, especially in females. Tlr4 deletion also resulted in sex-specific effects on anxiety-like behavior. Compared to WTs, female KO rats showed lower center time after predator odor exposure whereas genotype did not affect this response in male rats. Across litters, fewer male KO and heterozygous rats and more WT rats were born whereas female rats showed the typical genotype distribution. Results suggest predator odor alters affective behaviors, consistent with the preclinical literature, and deletion of Tlr4 enhances some stress-induced affective responses, often in a sex-specific manner.