Abstract
Major depressive disorder (MDD) is a common psychiatric disorder that involves marked disabilities in global functioning, anorexia, and severe medical comorbidities. MDD is associated with not only psychological and sociocultural problems, but also pervasive physical dysfunctions such as metabolic, neurobiological and immunological abnormalities. Nevertheless, the mechanisms underlying the interactions between these factors have yet to be determined in detail. The aim of the present study was to identify the molecular mechanisms responsible for the interactions between MDD and dysregulation of physiological homeostasis, including immunological function as well as lipid metabolism, coagulation, and hormonal activity in the brain. We generated depression-like behavior in mice using chronic mild stress (CMS) as a model of depression. We compared the gene expression profiles in the prefrontal cortex (PFC) of CMS and control mice using microarrays. We subsequently categorized genes using two web-based bioinformatics applications: Ingenuity Pathway Analysis and The Database for Annotation, Visualization, and Integrated Discovery. We then confirmed significant group-differences by analyzing mRNA and protein expression levels not only in the PFC, but also in the thalamus and hippocampus. These web tools revealed that hepatocyte nuclear factor 4 alpha (Hnf4a) may exert direct effects on various genes specifically associated with amine synthesis, such as genes involved in serotonin metabolism and related immunological functions. Moreover, these genes may influence lipid metabolism, coagulation, and hormonal activity. We also confirmed the significant effects of Hnf4a on both mRNA and protein expression levels in the brain. These results suggest that Hnf4a may have a critical influence on physiological homeostasis under depressive states, and may be associated with the mechanisms responsible for the interactions between MDD and the dysregulation of physiological homeostasis in humans.
Highlights
Major depressive disorder (MDD) is recognized as one of the most common mental disorders in developed countries, including Japan [1,2]
We examined the functions of lipid metabolism, coagulation, hormonal activity, immunological function, and amine synthesis because they had a p value less than 0.05
The results of the present study that have crucial implications regarding the pathophysiology of MDD were: 1) the chronic mild stress (CMS) model clearly engendered a set of behaviors indicative of depressive symptoms observed in humans, 2) the CMS model animals were significantly more likely than the controls to show lipid metabolic dysfunction, especially hypertriglycemia, 3) the presence of the hepatocyte nuclear factor 4 alpha (Hnf4a) protein was confirmed in 3 parts of the brain: the prefrontal cortex (PFC), thalamus, and hippocampus, and 4) Hnf4a may have affected molecules related to lipid metabolism, hormonal activity, coagulation, immunological function, or amine synthesis under a depressive state, indicating that Hnf4a may play a role in the interactions between MDD and dysfunctions of physiological homeostasis
Summary
Major depressive disorder (MDD) is recognized as one of the most common mental disorders in developed countries, including Japan [1,2]. The etiological and psychobiological mechanisms responsible for the development of MDD remain unclear, even though pharmacological treatments for MDD have been investigated extensively. The hippocampus is a key limbic area that is located at the “cross-roads” of circuitry It regulates stress responses by providing inhibitory feedback to the HPA axis and plays a role in mood modulation and memory function. These findings support a close association between the PFC, thalamus, and hippocampus in MDD, the molecular mechanisms responsible for physiological aspects of MDD remain unknown [9,10,11]
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