Lateral habenula IL-10 controls GABAA receptor trafficking and modulates depression susceptibility after maternal separation.

Maternal separation (MS), a form of early life adversity, increases the risk of psychiatric disorders in adulthood by intricately linking cytokines and mood-regulating brain circuits. The Lateral Habenula (LHb) encodes aversive experiences, contributes to negative moods, and is pivotal in depression development. However, the precise impact of MS on LHb cytokine signaling and synaptic plasticity remains unclear. We reported that adolescent MS offspring mice displayed susceptibility to depression behavioral phylotypes, with neuronal hyperactivity and an imbalance in pro-inflammatory and anti-inflammatory cytokines in the LHb. Moreover, the decreased IL-10 level negatively correlated with depressive-like behaviors in susceptible mice. Functionally, LHb IL-10 overexpression restored decreased levels of PI3K, phosphorylated AKT (pAKT), gephyrin, and membrane GABAA receptor proteins while reducing abnormally elevated GSK3ß and Fos expression, rescuing the MS-induced depression. Conversely, LHb neuronal IL-10 receptor knockdown in naive mice increased Fos expression and elicited depression-like symptoms, potentially through impaired membrane GABAA receptor trafficking by suppressing the PI3K/pAKT/gephyrin cascades. Hence, this work establishes a mechanism by which MS promotes susceptibility to adolescent depression by impeding the critical role of IL-10 signaling on neuronal GABAA receptor function.

Programmed cell death factor 4-mediated hippocampal synaptic plasticity is involved in early life stress and susceptibility to depression.

Early life stress (ELS) increases the risk of depression later in life. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases. However, its involvement in a person's susceptibility to ELS-related depression is unknown. To examine the effects and underlying mechanisms of PDCD4 on ELS vulnerability, we used a "two-hit" stress mouse model: an intraperitoneal injection of lipopolysaccharide (LPS) into neonatal mice was performed on postnatal days 7-9 (P7-P9) and inescapable foot shock (IFS) administration in adolescent was used as a later-life challenge. Our study shows that compared with mice that were only exposed to the LPS or IFS, the "two-hit" stress mice developed more severe depression/anxiety-like behaviors and social disability. We detected the levels of PDCD4 in the hippocampus of adolescent mice and found that they were significantly increased in "two-hit" stress mice. The results of immunohistochemical staining and Sholl analysis showed that the number of microglia in the hippocampus of "two-hit" stress mice significantly increased, with morphological changes, shortened branches, and decreased numbers. However, knocking down PDCD4 can prevent the number and morphological changes of microglia induced by ELS. In addition, we confirmed through the Golgi staining and immunohistochemical staining results that knocking down PDCD4 can ameliorate ELS-induced synaptic plasticity damage. Mechanically, the knockdown of PDCD4 exerts neuroprotective effects, possibly via the mediation of BDNF/AKT/CREB signaling. Combined, these results suggest that PDCD4 may play an important role in the ELS-induced susceptibility to depression and, thus, may become a therapeutic target for depressive disorders.

Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice.

Major depressive disorder (MDD) is a chronic, remitting and debilitating disease and the etiology of MDD is highly complicated that involves genetic and environmental interactions. Despite many pharmacotherapeutic options, many patients remain poorly treated and the development of effective treatments remains a high priority in the field. LPM570065 is a potent 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) triple reuptake inhibitor and both preclinical and clinical results demonstrate significant efficacy against MDD. This study extends previous findings to examine the effects and underlying mechanisms of LPM570065 on stress vulnerability using a "two-hit" stress mouse model. The "two-hit" stress model used adult mice that had experienced early life maternal separation (MS) stress for social defeat stress (SDS) and then they were evaluated in three behavioral assays: sucrose preference test, tail suspension test and forced swimming test. For the mechanistic studies, methylation-specific differentially expressed genes in mouse hippocampal tissue and ventral tegmental area (VTA) were analyzed by whole-genome transcriptome analysis along with next-generation bisulfite sequencing analysis, followed by RT-PCR and pyrophosphate sequencing to confirm gene expression and methylation. LPM570065 significantly reversed depressive-like behaviors in the mice in the sucrose preference test, the tail suspension test, and the forced swimming test. Morphologically, LPM570065 increased the density of dendritic spines in hippocampal CA1 neurons. Hypermethylation and downregulation of oxytocin receptor (Oxtr) in the hippocampal tissues along with increased protein expression of Dnmt1 and Dnmt3a in mice that experienced the "two-hit" stress compared to those that only experienced adulthood social defeat stress, and LPM570065 could reverse these changes. Combined, these results suggest that methylation specificity of the gene Oxtr in the hippocampus may play an important role in early life stress-induced susceptibility to depression and that the5-HT/NE/DA triple reuptake inhibitor LPM570065 may reduce depression susceptibility via the reversal of the methylation of the gene Oxtr.

Stress vulnerability promotes an alcohol-prone phenotype in a preclinical model of sustained depression.

Major depression and alcohol-related disorders frequently co-occur. Depression severity weighs on the magnitude and persistence of comorbid alcohol use disorder (AUD), with severe implications for disease prognosis. Here, we investigated whether depression vulnerability drives propensity to AUD at the preclinical level. We used the social defeat-induced persistent stress (SDPS) model of chronic depression in combination with operant alcohol self-administration (SA). Male Wistar rats were subjected to social defeat (five episodes) and prolonged social isolation (~12 weeks) and subsequently classified as SDPS-prone or SDPS-resilient based on their affective and cognitive performance. Using an operant alcohol SA paradigm, acquisition, motivation, extinction, and cue-induced reinstatement of alcohol seeking were examined in the two subpopulations. SDPS-prone animals showed increased alcohol SA, heightened motivation to acquire alcohol, persistent alcohol seeking despite alcohol unavailability, signs of extinction resistance, and increased cue-induced relapse; the latter could be blocked by the α2 adrenoreceptor agonist guanfacine. In SDPS-resilient rats, prior exposure to social defeat increased alcohol SA without affecting any other measures of alcohol seeking and alcohol taking. Our data revealed that depression proneness confers vulnerability to alcohol, emulating patterns of alcohol dependence seen in human addicts, and that depression resilience to a large extent protects from the development of AUD-like phenotypes. Furthermore, our data suggest that stress exposure alone, independently of depressive symptoms, alters alcohol intake in the long-term.

Evaluation of the Wistar-Kyoto rat model of depression and the role of synaptic plasticity in depression and antidepressant response.

In order to expand the prospects of developing novel antidepressants for treatment-resistant populations, animal models should incorporate not only various stress-induced behavioural, neurochemical and endocrine parallels to major depressive disorder (MDD), but also aspects of heightened stress susceptibility and resistance to conventional drugs. This review focuses on the available literature supporting the Wistar-Kyoto (WKY) rat as a model of endogenous stress susceptibility and depression, and the role of synaptic plasticity in depression and antidepressant response in the context of this model. Accumulating evidence implicates a dysregulation of synaptic plasticity in the etiology of depression, leading to synaptic weakening and neuronal atrophy in vulnerable brain regions (hippocampus, prefrontal cortex). Furthermore, novel antidepressant treatments, particularly ketamine, may reverse the stress-induced loss of connectivity in these key neural circuits by engaging synaptic plasticity processes to "reset the system". Incorporating synaptic plasticity into the current framework of antidepressant action may serve to bridge understanding of an antidepressant's molecular and cellular effects with those related to regional structural plasticity and neural circuit functioning.

Neural Substrates of Depression and Resilience.

There is an urgent need for more effective medications to treat major depressive disorder, as fewer than half of depressed patients achieve full remission and many are not responsive with currently available antidepressant medications or psychotherapy. It is known that prolonged stressful events are an important risk factor for major depressive disorder. However, there are prominent individual variations in response to stress: a relatively small proportion of people (10-20%) experiencing prolonged stress develop stress-related psychiatric disorders, including depression (susceptibility to stress), whereas most stress-exposed individuals maintain normal psychological functioning (resilience to stress). There have been growing efforts to investigate the neural basis of susceptibility versus resilience to depression. An accumulating body of evidence is revealing the genetic, epigenetic, and neurophysiological mechanisms that underlie stress susceptibility, as well as the active mechanisms that underlie the resilience phenotype. In this review, we discuss, mainly based on our own work, key pathological mechanisms of susceptibility that are identified as potential therapeutic targets for depression treatment. We also review novel mechanisms that promote natural resilience as an alternative strategy to achieve treatment efficacy. These studies are opening new avenues to develop conceptually novel therapeutic strategies for depression treatment.