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We previously revealed that deficiency in IL\u201018 led to hippocampal abnormalities and resulted in depression\u2010like symptoms. However, the impact of IL\u201018 deficiency on other brain regions remains to be clarified. In this study, we first sought to confirm that IL\u201018 expression in neural cells can be found in human brain tissue. Subsequently, we examined the expression of genes in the prefrontal cortex of <jats:italic>Il18<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice and compared it with gene expression in mice subjected to a chronic mild stress model of depression. Extracted genes were further analyzed using Ingenuity\u00ae Pathway Analysis, in which 18 genes common to both the chronic mild stressed model and <jats:italic>Il18<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice were identified. Of those, 16 were significantly differentially expressed between <jats:italic>Il18<jats:sup>+\/+<\/jats:sup><\/jats:italic> and <jats:italic>Il18<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. We additionally measured protein expression of <jats:italic>\u03b1<\/jats:italic>\u20102\u2010HS\u2010glycoprotein (AHSG) and transthyretin (TTR) in serum and the brain. In the prefrontal cortex of <jats:italic>Il18<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, TTR but not AHSG was significantly decreased. Conversely, in the serum of <jats:italic>Il18<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, AHSG was significantly increased but not TTR. Therefore, our results suggest that in IL\u201018\u2010deficit conditions, TTR in the brain is one of the mediators causally related to depression, and AHSG in peripheral organs is one of the regulators inducing energy imbalance. Moreover, this study suggests a possible \u201csignpost\u201d to clarify the molecular mechanisms commonly underlying the immune system, energy metabolism, neural function, and depressive disorders.<\/jats:p>","DOI":"10.1155\/2021\/9975865","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T11:25:18Z","timestamp":1634642718000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Exploring Molecular Mechanisms Involved in the Development of the Depression\u2010Like Phenotype in Interleukin\u201018\u2010Deficient 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