Major depression disorder (MDD) is a debilitating mental illness with significant morbidity and mortality. Despite the growing number of studies that have emerged, the precise underlying mechanisms of MDD remain unknown. When studying MDD, tissue samples like peripheral blood or post-mortem brain samples are used to elucidate underlying mechanisms. Unfortunately, there are many uncontrollable factors with such samples such as medication history, age, time after death before post-mortem tissue was collected, age, sex, race, and living conditions. Although these factors are critical, they introduce confounding variables that can influence the outcome profoundly. In this regard, animal models provide a crucial approach to examine neural circuitry and molecular and cellular pathways in a controlled environment. Further, manipulations with pharmacological agents and gene editing are accepted methods of studying depression in animal models, which is impossible to employ in human patient studies. Here, we have reviewed the most widely used animal models of depression and delineated the salient features of each model in terms of behavioral and neurobiological outcomes. We have also illustrated the current challenges in using these models and have suggested strategies to delineate the underlying mechanism associated with vulnerability or resilience to developing depression.

No abstract

Recent evidence suggests that the cellular response to stress often elicits the unfolded protein response (UPR), which has an active role in major depression in emotionally relevant regions of the brain, such as the hippocampus. Much of the UPR activity has been found to be coalesced with the pro-inflammatory environment of the depressed brain. Specifically, downstream transcriptions of pro-inflammatory cytokines and increased regulation of candidate inflammatory mediators, such as toll-like receptors (TLRs), are promoted by the UPR. The present study examined the hippocampus associated expression profile of Tlr genes and their interaction with the UPR chaperone GRP94 in stress-induced rodent model of depression (restraint stress model). Also, the expression status of UPR related genes was evaluated in hippocampus using the same model. mRNA and protein levels of Tlr and UPR associated genes were examined by qRT-PCR and Western blot, respectively. Co-immunoprecipitation (Co-IP) method was used to determine the direct interaction between TLRs with GRP94 in depressed rat brain. The results showed that both UPR (Xbp-1, its spliced variant sXbp-1, Atf-6, Chop, and Grp94) and Tlr (2, 3, 4, 7 and 9) genes were significantly upregulated in the hippocampi of rats who were exposed to restraint stress. Similar upregulation was observed in the protein levels of the above-mentioned TLRs and the UPR chaperone protein GRP94 as well as total and phosphorylated forms of sensor proteins IRE1α and PERK. Further, a significantly increased interaction was observed between GRP94 and the activated TLR proteins. Since, increased inflammatory activity in vulnerable areas like hippocampus is coherently associated with depressed brain; our present data suggest that the UPR may be an integral part of increased activity of inflammatory regulations in depression.

Understanding the epigenetic role of microRNAs (miRNAs) has been a critical development in the field of neuropsychiatry and in understanding their underlying pathophysiology. Abnormalities in miRNA expression are often seen as key to the pathogenesis of many stress-associated mental disorders, including major depressive disorder (MDD). Recent advances in omics biology have further contributed to this understanding and expanded the role of miRNAs in networking a diverse array of molecular pathways, which are essentially related to the stress adaptivity of a healthy brain. Studies have highlighted the role of many such miRNAs in causing maladaptive changes in the brain’s stress axis. One such miRNA is miR-218, which is debated as a critical candidate for increased stress susceptibility. miR-218 is expressed throughout the brain, notably in the hippocampus and prefrontal cortex (PFC). It is expressed at various levels through life stages, as seen by adolescent and adult animal models. Until now, a minimal number of studies have been conducted on human subjects to understand its role in stress-related abnormalities in brain circuits. However, several studies, including animal and cell-culture models, have been used to understand the impact of miR-218 on stress response and hypothalamic-pituitary-adrenal (HPA) axis function. So far, expression changes in this miRNA have been found to regulate signaling pathways such as glucocorticoid signaling, serotonergic signaling, and glutamatergic signaling. Recently, the developmental role of miR-218 has generated interest, given its increasing expression from adolescence to adulthood and targeting the Netrin-1/DCC signaling pathway. Since miR-218 expression affects neuronal development and plasticity, it is expected that a change in miR-218 expression levels over the course of development may negatively impact the process and make individuals stress-susceptible in adulthood. In this review, we describe the role of miR-218 in stress-induced neuropsychiatric conditions with an emphasis on stress-related disorders.