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In the brain, NLRP3 (Nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin-domain-containing 3) inflammasome is mainly expressed in microglia located in the hippocampus and other mood-regulated regions, which are particularly susceptible to stress. The activation of NLRP3 inflammasome and production of the activation products may contribute to the development of depressive disorder and memory deficits. Indoleamine 2, 3-dioxygenase (IDO) is a key factor mediating inflammation and major depressive disorder (MDD). We here generated NLRP3 and apoptosis-associated speck-like protein containing caspase recruitment domain (ASC)-knockout mice, respectively, to verify the effects of NLRP3 or ASC deficiency on lipopolysaccharide (LPS)-induced depressive-like behaviors, neuroinflammation, and regulation of IDO expression. Furthermore, we treated these mice with the antidepressant clomipramine (CLO) to observe its effect on depressive-like behaviors and the expression of the NLRP3 inflammasome and LPS-induced IDO. We found that intraperitoneal LPS administration led to marked depressive-like behavior and neuroinflammation. NLRP3 or ASC deficiency attenuated LPS-induced depressive-like symptoms and increased IDO gene expression, which was accompanied by inhibition of LPS-induced microglial activation, suggesting that IDO may be a downstream mediator of the NLRP3 inflammasome in inflammation-mediated depressive-like behaviors. Clomipramine administration ameliorated depressivelike behavior in LPS-treated mice by regulating the expression of ASC and IDO. In conclusion, NLRP3 inflammasome is involved in LPS-induced depressive-like behaviors, and that NLRP3 and ASC may play roles in regulating IDO expression

Leptin, secreted by peripheral adipocytes, binds the leptin receptor (Lepr) in the hypothalamus, thereby contributing to the regulation of satiety and body weight. Lepr is expressed in the embryonic brain as early as embryonic day 12.5. However, the function of Lepr in neural precursor cells in the brain has not been resolved. To address this issue, we crossed the Lepr flox/flox mice with each of Shh-Cre mice (Shh, sonic hedgehog) and Nestin (Nes)-Cre mice. We found that deletion of Lepr specifically in nestin-expressing cells led to extreme obesity, but the conditional null of Lepr in Shh-expressing cells had no obvious phenotype. Moreover, the level of leptin-activated pSTAT3 decreased in the anterior and central subregions of the arcuate hypothalamus of Shh-Cre; Lepr flox/flox mice compared with the controls. By contrast, in Nes-Cre; Lepr flox/flox mice, the level of leptin-activated pSTAT3 decreased in all subregions including the anterior, central, and posterior arcuate hypothalamus as well as the dorsomedial, ventromedial, and median eminence of the hypothalamus, revealing that the extensive lack of Lepr in the differentiated neurons of the hypothalamus in the conditional null mice. Notably, conditional deletion of Lepr in nestin-expressing cells enhanced the differentiation of neural precursor cells into neurons and oligodendroglia but inhibited differentiation into astrocytes early in postnatal development of hypothalamus. Our results suggest that Lepr expression in neural precursor cells is essential for maintaining normal body weight as well as the differentiation of neural precursor cells to the neural/glial fate in the hypothalamus shortly after birth.

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