Search

Psychosocial stress has profound effects on the body, including the immune system and the brain 1,2 . Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD) 3 , the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders., (© 2024. The Author(s).)

There is an urgent need to develop more effective treatments for stress-related illnesses, which include depression, post-traumatic stress disorder, and anxiety. We view animal models as playing an essential role in this effort, but to date, such approaches have generally not succeeded in developing therapeutics with new mechanisms of action. This is partly due to the complexity of the brain and its disorders, but also to inherent difficulties in modeling human disorders in rodents and to the incorrect use of animal models: namely, trying to recapitulate a human syndrome in a rodent which is likely not possible as opposed to using animals to understand underlying mechanisms and evaluating potential therapeutic paths. Recent transcriptomic research has established the ability of several different chronic stress procedures in rodents to recapitulate large portions of the molecular pathology seen in postmortem brain tissue of individuals with depression. These findings provide crucial validation for the clear relevance of rodent stress models to better understand the pathophysiology of human stress disorders and help guide therapeutic discovery. In this review, we first discuss the current limitations of preclinical chronic stress models as well as traditional behavioral phenotyping approaches. We then explore opportunities to dramatically enhance the translational use of rodent stress models through the application of new experimental technologies. The goal of this review is to promote the synthesis of these novel approaches in rodents with human cell-based approaches and ultimately with early-phase proof-of-concept studies in humans to develop more effective treatments for human stress disorders., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.

Understanding the transcriptional changes that are engaged in stress resilience may reveal novel antidepressant targets. Here we use gene co-expression analysis of RNA-sequencing data from brains of resilient mice to identify a gene network that is unique to resilience. Zfp189, which encodes a previously unstudied zinc finger protein, is the highest-ranked key driver gene in the network, and overexpression of Zfp189 in prefrontal cortical neurons preferentially activates this network and promotes behavioral resilience. The transcription factor CREB is a predicted upstream regulator of this network and binds to the Zfp189 promoter. To probe CREB-Zfp189 interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189 promoter in prefrontal cortex neurons. Induction of Zfp189 with site-specific CREB is pro-resilient, whereas suppressing Zfp189 expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189 and CREB-Zfp189 interactions in mediating a central transcriptional network of resilience.

Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood-brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression.

There is a strong link between tobacco consumption and mood disorders. It has been suggested that afflicted individuals smoke to manage mood, however, there is evidence indicating that tobacco consumption can induce negative mood. This study was designed to investigate whether nicotine exposure during adolescence influences emotionality/behavioral functioning later in life. Adolescent (postnatal days, PD 30-44) male rats were treated with twice-daily injections of nicotine (0, 0.16, 0.32, or 0.64 mg/kg) for 15 consecutive days, and their behavioral reactivity to various behavioral paradigms (the elevated plus maze (EPM), sucrose preference, locomotor activity in the open field, and forced swim test (FST) was assessed 24 h (short term) or 1-month (long term) after exposure. Separate groups of adult rats received nicotine (0.32 mg/kg) to control for age-dependent effects. We report that nicotine exposure during adolescence-but not adulthood-leads to a depression-like state manifested in decreased sensitivity to natural reward (sucrose), and enhanced sensitivity to stress- (FST) and anxiety-eliciting situations (EPM) later in life. Our data show that behavioral dysregulation can emerge 1 week after drug cessation, and that a single day of nicotine exposure during adolescence can be sufficient to precipitate a depression-like state in adulthood. We further demonstrate that these deficits can be normalized by subsequent nicotine (0.32 mg/kg) or antidepressant (ie fluoxetine or bupropion; 10 mg/kg) treatment in adulthood. These data suggest that adolescent exposure to nicotine results in a negative emotional state rendering the organism significantly more vulnerable to the adverse effects of stress. Within this context, our findings, together with others indicating that nicotine exposure during adolescence enhances risk for addiction later in life, could serve as a potential model of comorbidity.