Chronic mild stress-induced anhedonia in rats is coupled with the upregulation of inflammasome sensors: a possible involvement of NLRP1

Abstract

INTRODUCTION: NOD-like receptors containing pyrin domain (NLRP) are cytosolic receptors belong to innate immune system and function as sensing bodies for danger signals by forming inflammasome complex which in turn produces caspase-1-mediated interleukin (IL)-1β and IL-18 proinflammatory cytokines. Latest findings indicate that NLRP3 inflammasome mainly located in microglia cells in central nervous system (CNS) is linked to depression pathophysiology. However, another important CNS inflammasome, the neuronal NLRP1 inflammasome, has not been addressed in psychological stress or depression, yet. Therefore, the aim of the present study was to investigate the possible involvement NLRP1 inflammasome together with NLRP3 in chronic unpredictable mild stress (CUMS), a well-validated animal model of depression in rats. METHODS: Adult male Sprague–Dawley rats were divided into three groups: Control (treated with saline; non-stressed), CUMS (treated with saline), and CUMS + IMI (Imipramine; 10 mg/kg/day) (n = 6–8/group). In CUMS model, various stressors were applied for a total duration of six weeks. The treatments were daily administered via intraperitoneal (i.p.) route for the last three weeks of CUMS procedure. Anhedonia-like behaviors were assessed by sucrose preference test once in every two weeks throughout the experiment. At the end of the sixth week, rats were sacrificed and hippocampal brain tissues were collected for real-time PCR gene expression analysis of inflammasome components (NLRP1, NLRP3, ASC, and caspase-1) and inflammasome-dependent two proinflammatory cytokines (IL-1β and IL-18). RESULTS: CUMS-induced anhedonia in rats was coupled with upregulated mRNA levels of NLRP1, NLRP3, ASC, caspase-1, IL-1β, and IL-18 in hippocampus which were downregulated by chronic imipramine treatment. CONCLUSIONS: Our results suggest that the activation of not only NLRP3 but also NLRP1 inflammasome together may be involved in chronic stress-induced depression. Based on these results, further investigations are of great importance in order to understand the possible crosstalk between microglial (NLRP3) and neuronal (NLRP1) inflammasomes in depression and psychological stress.