A new experimental design to study inflammation-related versus non-inflammation-related depression in mice

Abstract

Background Major depressive disorder (MDD) represents a major public health concern, particularly due to its steadily rising prevalence and the poor responsiveness to standard antidepressants notably in patients afflicted with chronic inflammatory conditions, such as obesity. This highlights the need to improve current therapeutic strategies, including by targeting inflammation based on its role in the pathophysiology and treatment responsiveness of MDD. Nevertheless, dissecting the relative contribution of inflammation in the development and treatment of MDD remains a major issue, further complicated by the lack of preclinical depression models suitable to experimentally dissociate inflammation-related vs. inflammation-unrelated depression. Methods While current models usually focus on one particular MDD risk factor, we compared in male C57BL/6J mice the behavioral, inflammatory and neurobiological impact of chronic exposure to high-fat diet (HFD), a procedure known to induce inflammation-related depressive-like behaviors, and unpredictable chronic mild stress (UCMS), a stress-induced depression model notably renowned for its responsivity to antidepressants. Results While both paradigms induced neurovegetative, depressive-like and anxiety-like behaviors, inflammation and downstream neurobiological pathways contributing to inflammation-driven depression were specifically activated in HFD mice, as revealed by increased circulating levels of inflammatory factors, as well as brain expression of microglial activation markers and enzymes from the kynurenine and tetrahydrobiopterin (BH4) pathways. In addition, serotoninergic and dopaminergic systems were differentially impacted, depending on the experimental condition. Conclusions These data validate an experimental design suitable to deeply study the mechanisms underlying inflammation-driven depression comparatively to non-inflammatory depression. This design could help to better understand the pathophysiology of treatment resistant depression.

Connexin 43: An Interface Connecting Neuroinflammation to Depression

“…A chronic mild stress depression model, commonly used as the animal model of depression, has the greatest validity and translational potential with a similar phenotype, risk factors, and response to routine treatments used in MDD patients [ 113 ]. Various experiments show that chronic unpredictable mild stress leads to increased inflammation-related symptoms when induced in an animal model of depression [ 114 , 115 , 116 ], suggesting that inflammation may be an intermediate link between the mechanisms of depression.…”

“…The proportion of MDD patients classified as TRD is as high as 15–30% [ 142 ]. Inflammatory processes are involved in the pathophysiology of TRD, and enhanced baseline levels of inflammatory markers predict poorer antidepressant efficacy in depressed patients [ 113 ]. The elevated inflammatory factors in the patients’ bodies are an example.…”

α7 Nicotinic acetylcholine receptor: a key receptor in the cholinergic anti-inflammatory pathway exerting an antidepressant effect

“…Inflammation is an immune response during infection or trauma. It is the coordinated activation of inflammatory cytokines-mediated signal cascade and is considered a healthy defense mechanism of the body [ 40 – 42 ]. Normal inflammation is necessary for the damages caused by infection, trauma, or neurodegenerative diseases and neuritis is also a method of restoring neural homeostasis.…”

“…Studies have shown that the activation of NLRP3 inflammasome is closely related to NF-κB [ 59 ] and generally requires the initiation and activation of two signals, including the initiation signal and activation signal. The initiation signal involves the activation of NF-κB induced by the activation of TLR, while in the activation signal, the sustained stimulation induces the inflammasome components to assemble into complete NLRP3 inflammasome and promotes the conversion of pro-caspase-1 into activated caspase-1, which subsequently cleaves the pro-IL-1β and pro-IL-18 into active forms, ultimately leading to an inflammatory response and induction of cytotoxicity [ 42 , 212 , 213 ]. In addition, studies have also shown that ROS can activate the NLRP3 inflammasome [ 214 , 215 ].…”

Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice

“…Stress is, arguably, the most common factor associated with depression, and both clinical and preclinical research have demonstrated robust causal links [31][32][33][34][35][36][37]. While our understanding of stress-induced depressive symptoms is still developing, reduced synaptic plasticity and inhibited neurogenesis have been strongly implicated [33,35,[38][39][40].…”