Depression is an incapacitating neuropsychiatric disorder. The serotonergic system in the brain plays an important role in the pathophysiology of depression. However, due to the often delayed and/or poor performance of selective serotonin reuptake inhibitors in treating depressive symptoms, the serotonergic system’s role in depression has recently been questioned further. Evidence from recent studies has suggested that increased inflammation and oxidative stress may play significant roles in the pathophysiology of depression. The consequences of these factors can lead to the neuroprogression of depression, which includes neurodegeneration, astrocyte apoptosis, reduced neurogenesis, reduced plasticity (neuronal and synaptic), and enhanced immunoreactivity. Specifically, increased proinflammatory cytokine levels have been shown to lead to the activation of the kynurenine pathway, which causes an increase in the production of quinolinic acid [QA, an N-Methyl-D-aspartate (NMDA) agonist] and decreases the synthesis of serotonin. QA exerts many deleterious effects in the brain via mechanisms including NMDA excitotoxity, increased oxidative stress, astrocyte degeneration, and neuronal apoptosis. QA may also act directly as a pro-oxidant. Additionally, the nuclear translocation of antioxidant defence factors, such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2), is downregulated in depression. Hence, in the present review, we discuss the role of QA in increasing oxidative stress in depression by modulating the nuclear translocation of Nrf2 and thus affecting the synthesis of antioxidant enzymes.

Environmental enrichment (EE) is an environmental paradigm encompassing sensory, cognitive, and physical stimulation at a heightened level. Previous studies have reported the beneficial effects of EE in the brain, particularly in the hippocampus. EE improves cognitive function as well as ameliorates depressive and anxiety-like behaviors, making it a potentially effective neuroprotective strategy against neurodegenerative diseases such as Alzheimer’s disease (AD). Here, we summarize the current evidence for EE as a neuroprotective strategy as well as the potential molecular pathways that can explain the effects of EE from a biochemical perspective using animal models. The effectiveness of EE in enhancing brain activity against neurodegeneration is explored with a view to differences present in early and late life EE exposure, with its potential application in human being discussed. We discuss EE as one of the non pharmacological approaches in preventing or delaying the onset of AD for future research.

Early-life adversity caused by poor social bonding and deprived maternal care is known to affect mental wellbeing and physical health. It is a form of chronic social stress that persists because of a negative environment, and the consequences are long-lasting on mental health. The presence of social stress during early life can have an epigenetic effect on the body, possibly resulting in many complex mental disorders, including depression in later life. Here, we review the evidence for early-life social stress-induced epigenetic changes that modulate juvenile and adult social behavior (depression and anxiety). This review has a particular emphasis on the interaction between early-life social stress and genetic variation of serotonin associate genes including the serotonin transporter gene (5-HTT; also known as SLC6A4), which are key molecules involved in depression.

Stress is known to have a significant impact on mental health. While gender differences can be found in stress response and mental disorders, there are limited studies on the neuronal mechanisms of gender differences in mental health. Here, we discuss gender and cortisol in depression as presented by recent clinical studies, as well as gender differences in the role of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in stress-associated mental disorders. When examining clinical studies drawn from PubMed/MEDLINE (National Library of Medicine) and EMBASE, salivary cortisol generally showed no gender correlation. However, young males were reported to show heightened cortisol reactivity compared to females of similar age in depression. Pubertal hormones, age, early life stressors, and types of bio-samples for cortisol measurement affected the recorded cortisol levels. The role of GRs and MRs in the HPA axis could be different between males and females during depression, with increased HPA activity and upregulated MR expression in male mice, while the inverse happened in female mice. The functional heterogeneity and imbalance of GRs and MRs in the brain may explain gender differences in mental disorders. This knowledge and understanding will support the development of gender-specific diagnostic markers involving GRs and MRs in depression.