Commentary

Stress, Depression, and Inflammation: Molecular and Microglial Mechanisms

Parishin C (Par), a prominent bioactive compound in Gastrodia elata Blume with little toxicity and shown neuroprotective effects. However, its impact on depression remains largely unexplored.

This study aims to investigate the antidepressant effects of Par using a chronic social defeat stress (CSDS) mouse model and elucidate its molecular mechanisms.

The CSDS-induced depression mouse model was used to evaluate the therapeutic efficacy of Par. The social interaction test (SIT) and sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were conducted to assess the effects of Par on depressive-like behaviours. The levels of corticosterone, neurotransmitters (5-HT, DA and NE) and inflammatory cytokines (IL-1β, TNF-α, and IL-6) were evaluated by enzyme-linked immunosorbent assay (ELISA). Activation of a microglia was assessed by immunofluorescence labeling Iba-1. The protein expressions of NLRP3, ASC, caspase-1, and IL-6 verified by Western blot.

Oral administration of Par (4 and 8 mg/kg) and fluoxetine (10 mg/kg, administration significantly ameliorate depression-like behaviors induced by CSDS, as shown by the increase social interaction in SIT, increase sucrose preference in SPT and the decrease immobility in TST and FST. Par administration decreased serum corticosterone level and increased the 5-HT, DA and NE concentration in the hippocampus and prefrontal cortex. Furthermore, Par treatment suppressed microglial activation (Iba1) as well as reduced levels of IL-1β, TNF-α, and IL-6) with decreased protein expressions of NLRP3, ASC, caspase-1, and IL-6.

our study provides the first evidence that Par exerts antidepressant-like effects in mice with CSDS-induced depression. This effect appears to be mediated by the normalization of neurotransmitter and corticosterone levels, inhibition of NLRP3 inflammasome activation. This newfound antidepressant property of Par offers a novel perspective on its pharmacological effects, providing valuable insights into its potential therapeutic and preventive applications in depression treatment.

Major depressive disorder (MDD) is a highly prevalent condition and one of the most common psychiatric disorders worldwide. Circular RNA (circRNA) has been increasingly implicated in MDD. However, a comprehensive understanding of circRNA and microglial apoptosis in depression is incomplete. Here, we show that circDYM inhibits microglial apoptosis induced by LPS via CEBPB/ZC3H4 axis. CircDYM prevents the translocation of CEBPB from cytoplasm to the nucleus by binding with CEBPB. Moreover, LPS-induced CEBPB nuclear entry downregulates the expression of ZC3H4, in which promotes autophagy and apoptosis in microglia. Taken together, our findings provide new insights into the relationship between circDYM and microglial apoptosis and shed new light on the function of this novel mechanism in depression-associated complex changes in the brain.

The field of psychoneuroimmunology has made significant advances in understanding mechanisms underlying signaling between the immune system and central nervous system since the initial coinage of the term in 1975 and especially in the past 25 years. The current review explores the research supporting the premise that the immune system impacts behavior, including risk of developing stress-related psychiatric disorders (e.g., anxiety disorders, affective disorders, and trauma- and stressor-related disorders such as posttraumatic stress disorder). Beginning with the recent call to examination of interoception as a mental health-relevant signal, inflammation is explored as an important interoceptive signal. Inflammation is viewed through the lens of sickness behavior, before broadening to include the impact of the immune system on a collection of mental-health-related symptoms. This is explored mechanistically through the direct effects of cytokine signaling on the brain, the impact of afferent vagus nerve signaling, and through examination of the role of bone-marrow-derived monocytes in relaying peripheral immune signals to the brain. Immature bone-marrow-derived monocytes contribute to increased peripheral inflammation, but also have the capacity to traffic to brain regions relevant to stress-related psychiatric disorders. This trafficking can increase neuroinflammation causing anxiety-like defensive behavioral responses in mouse models and has been linked to symptoms of stress-related psychiatric disorders in humans. Additionally, the commensal bacteria inhabiting the gut (gut microbiota) exert a modulating effect on inflammation and behavior through several mechanisms, including signaling in the systemic circulation, shifting the body's stress dynamics, and altering inflammatory balance in the gut and the rest of the body. These mechanisms are discussed in the context of mental health conditions, including mood disorders, anxiety disorders, and trauma- and stressor-related disorders. There is a preponderance of evidence supporting the fact that peripheral immune activity and neuroinflammation impact behavior and mental health. Further research will continue to elucidate the mechanisms involved.

Evidences suggest that inflammatory marker-mediated neuroplasticity contributes critically to brain changes following antidepressant treatment. To date, no study has examined the relationship between changes in hippocampal volume, depressive symptoms, and inflammatory markers following repeated ketamine treatment.

Forty-four patients with major depressive disorder received six intravenous ketamine (0.5 mg/kg) infusions over 12 days. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to assess depressive symptoms, and peripheral blood was collected to test multiple cytokines and tryptophan (TRP) metabolites at baseline, 24 h and 14 days after the sixth infusion (day 13 and day 26). Magnetic resonance imaging (MRI) scans were carried out at baseline and day13, and FreeSurfer software was used to process the T1 images and analyze hippocampal volume.

Following ketamine, a significant improvement in depressive symptoms, a small increase in right hippocampal volume and alterations in inflammatory markers was found. No significant association was found between changes in inflammatory markers and changes in hippocampal volume from baseline to day 13 (P>0.05), while a weak association was found between TRP metabolite changes and other cytokine changes from baseline to day 26 (beta=-0.357, t=−2.600, P = 0.013).

The patients continued receiving previous medications during ketamine treatment, which may have impacted hippocampal volume and inflammatory markers.

Hippocampal volume increase following ketamine was an independent neurobiological effect that was not associated with changes in peripheral inflammatory markers, suggesting a likely complex neurobiological mechanism of the antidepressant effect of ketamine.

Early life experience is closely related to depression caused by stress in adulthood. Early life experience, including maternal separation (MS), has been shown to evoke stress sensitivity to depression upon re-exposure to stress in adults. However, MS has also been shown to lead to resilience to stress-induced depression, which is contradictory and rarely studied. To investigate the effects of MS on depression in adults and the related mechanism, male C57/BL6J mouse pups were exposed to different MS procedures from postnatal day (PD)1 to PD21. Body weight (BW) measurements and behavioural tests (the forced swimming test (FST) and open field test (OFT)) were performed on PD41 to explore depressive and anxiety-like behaviours. Then, as adults, the mice were exposed to chronic unpredictable mild stress (CUMS) for 28 days, and then behavioural tasks were recorded. After CUMS exposure, the mice in the MS180 group (which were separated from their mothers for 3 h on PD1-PD21) showed significantly decreased time spent in the centre of the open field and reduced velocity in the OFT, a reduced latency to immobility in the FST, and decreased BW. However, the mice in the MS15 group (which were separated from their mothers for 15 min on PD1-PD21) performed similarly to NSNC mice (which were not separated from their mothers) in the behavioural tests. We further found that the expression of Iba1, a marker of neuroinflammation, was increased in the MS180 group but not in the MS15 group. In addition, our study showed decreased mRNA and protein expression of CRMP2, an important neuroprotective factor, in the MS180 group, but CRMP2 expression was unchanged in the MS15 group. This study confirmed the generation of different behavioural responses to stress exposure in adulthood due to different degrees of MS. Neuroinflammation and neuroprotection are involved, which requires further research.

Obesity is a clinically relevant and highly prevalent somatic comorbidity of major depression (MDD). Genetic predisposition and history of childhood trauma have both independently been demonstrated to act as risk factors for obesity and to be associated with alterations in reward related brain structure and function. We therefore aimed to investigate the influence of childhood maltreatment and genetic risk for obesity on structural and functional imaging correlates associated with reward processing in MDD. 161 MDD patients underwent structural and functional MRI during a frequently used card guessing paradigm. Main and interaction effects of a polygenic risk score for obesity (PRS) and childhood maltreatment experiences as assessed using the Childhood Trauma Questionnaire (CTQ) were investigated. We found that maltreatment experiences and polygenic risk for obesity significantly interacted on a) body mass index b) gray matter volume of the orbitofrontal cortex as well as on c) BOLD response in the right insula during reward processing. While polygenic risk for obesity was associated with elevated BMI as well as with decreased OFC gray matter and increased insular BOLD response in non-maltreated patients, these associations were absent in patients with a history of childhood trauma. No significant main effect of PRS or maltreatment on gray matter or BOLD response could be detected at the applied thresholds. The present study suggests that childhood maltreatment moderates the influence of genetic load for obesity on BMI as well as on altered brain structure and function in reward related brain circuits in MDD.