TLR4 in Tph2 neurons modulates anxiety-related behaviors in a sex-dependent manner

TLR4 belongs to the TLR receptor family and can induce a proinflammatory response to invading pathogens. Recent studies have identified that TLR4 is associated with major anxiety disorder. Tph2 is a rate-limiting enzyme for 5-HT biosynthesis that is expressed at high levels in the DRN, which includes the main 5-HT projection to the hippocampus and prefrontal cortex and regulates anxiety disorder. Here, we show that TLR4 expressed in Tph2 neurons in the DRN can modulate anxiety-like behaviors in a sex-dependent manner. Deletion of TLR4 in Tph2 neurons decreases anxiety-like behaviors in male but not in female mice. Meanwhile, a similar phenotype was found by selectively ablating TLR4 in the DRN of adult male but not female mice using AAV-Cre-GFP virus. Inhibition of TLR4 in DRN by infusion of LPS-RS via intra-Aq is sufficient to reverse anxiety-like behavior induced by chronic immobilization stress (CIS). The underlying mechanisms seem to involve alterations in the activity of Tph2 neurons and key components of 5-HT transmission, including synthesis, reuptake, and transmission. Our results suggest that TLR4 in Tph2 neurons is a key modulator in anxiety-like behaviors and the 5-HT system in the brain between different sexes. [Display omitted] •Deleting TLR4 in Tph2 neurons decreases anxiety-like behaviors in male but not female mice.•Selective knockdown of TLR4 in DRN decreased anxiety-like behaviors in male mice.•Inhibiting TLR4 in DRN is sufficient to reverse anxiety-like behaviors induced by CIS.•Conditional deletion of TLR4 in Tph2 neurons decreased the activity of Tph2 neurons.•Deleting TLR4 in Tph2 neuron altered key components of 5-HT projecting to hippocampus and PFC.