Prefrontal cortex miR-874-3p prevents lipopolysaccharide-induced depression-like behavior through inhibition of indoleamine 2,3-dioxygenase 1 expression in mice.

Indoleamine 2,3-dioxygenase 1 (IDO1) is the first rate-limiting enzyme that metabolizes tryptophan to the kynurenine pathway. Its activity is highly inducible by pro-inflammatory cytokines and correlates with the severity of major depressive disorder (MDD). MicroRNAs (miRNAs) are involved in gene regulation and the development of neuropsychiatric disorders including MDD. However, the role of miRNAs in targeting IDO1 in the pathophysiology of MDD is still unknown. In this study, we investigated the role of novel miRNAs in the regulation of IDO1 activity and its effect on lipopolysaccharide (LPS)-induced depression-like behavior in mice. LPS up-regulated miR-874-3p concomitantly with increase in IDO1 expression in the prefrontal cortex (PFC), increase in immobility in the forced swimming test as depression-like behavior and decrease in locomotor activity as sickness behavior without motor dysfunction. The miR-874-3p increased in both neuron and microglia after LPS. Its mimic significantly suppressed LPS-induced IDO1 expression in the PFC. Infusion of IDO1 inhibitor (1-methyl-l-tryptophan) and miR-874-3p into PFC prevented an increase in immobility in the forced swimming test, but did not decrease in locomotor activity induced by LPS. These results suggest that miR-874-3p may play an important role in preventing the LPS-induced depression-like behavior through inhibition of IDO1 expression. This may also serve as a novel potential target molecule for the treatment of MDD.

Prefrontal cortex, dorsomedial striatum, and dentate gyrus are necessary in the object-based attention test in mice.

Disturbances of attention are a common behavioral feature associated with neuropsychiatric disorders with largely unknown underlying causes. We previously developed an object-based attention test (OBAT) as a simple and practical method for evaluating attention in mice. Since its establishment, the test has become a popular method for assessing attention and related underlying mechanisms in various mouse models. However, the underlying neuronal network involved in this test has yet to be studied. The purpose of this study was to identify the principal brain regions activated in the OBAT. Accordingly, C57BL/6J mice were subjected to the OBAT and thereafter prepared for immunohistochemical quantification of c-Fos, an immediate early gene that is frequently used as a marker of neuronal activity, in 13 different brain regions. The number of c-Fos-positive cells was significantly higher in the prefrontal cortex (PFC), dorsomedial striatum (DMS), and dentate gyrus (DG) in the test group as compared to the control group. The neuronal activation of these brain regions during the OBAT indicates that these brain regions are necessary for the regulation of attention in this test. This was supported by excitotoxic lesioning of these brain regions, leading to impaired attention without causing locomotor dysfunction. This study is one of the first attempts to analyze the brain regions that regulate attention in the OBAT. These findings provide an initial insight into the role of these brain regions and ideas for studying the underlying neural and molecular mechanisms.