Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong, 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China.
Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong, 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China.
Neuropharmacology. 2022 Sep 15;216:109175. doi: 10.1016/j.neuropharm.2022.109175. Epub 2022 Jul 3.
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.
TLR4 属于 TLR 受体家族，可诱导对入侵病原体的促炎反应。最近的研究表明，TLR4 与主要的焦虑障碍有关。Tph2 是 5-HT 生物合成的限速酶，在 DRN 中高表达，包括对海马体和前额叶皮层的主要 5-HT 投射，并调节焦虑障碍。在这里，我们表明，DRN 中 Tph2 神经元表达的 TLR4 可以以性别依赖的方式调节类似焦虑的行为。在 Tph2 神经元中敲除 TLR4 会降低雄性而不是雌性小鼠的类似焦虑行为。同时，使用 AAV-Cre-GFP 病毒选择性地在成年雄性而非雌性小鼠的 DRN 中敲除 TLR4 也发现了类似的表型。通过在 Aq 内输注 LPS-RS 抑制 DRN 中的 TLR4，足以逆转慢性束缚应激（CIS）引起的类似焦虑行为。潜在的机制似乎涉及 Tph2 神经元和 5-HT 传递的关键组成部分，包括合成、再摄取和传递的活性改变。我们的研究结果表明，Tph2 神经元中的 TLR4 是大脑中不同性别之间类似焦虑行为和 5-HT 系统的关键调节剂。
