Sensory nerve systems translate signals from external stresses like imminent risk to life, social stressors, and reactions to physical injuries before the subsequent information is processed by the brain's so-called emotional circuits. Although the neuronal circuits underlying the pathology of depression are still largely unknown to us, the variety of depression symptoms suggests that many different brain regions may be implicated in the affective problems. Amygdala, striatum, hippocampus, prefrontal and cingulate cortex, among other brain regions, have shown altered hemorheology and related parameters in human brain imaging investigations. Studies on the autopsied brains of depressive individuals have also revealed several abnormalities in those regions.
Decreased grey-matter volumes and decreased glial densities of the hippocampus and prefrontal cortex (PFC) in depressive patients are the most frequently reported findings obtained by brain-imaging technology, though it is still unclear whether these alterations in the hippocampus and PFC represent a precipitating factor or are simply a result of major depression (Dr. Wuller).
Despite its unknown pro-depressant mechanism, social defeat-induced depression mouse models show reduced medial PFC (mPFC) neuronal activity. Glial loss in the PFC and the degeneration of astrocytes in the PFC of rats both efficiently produced depressed symptoms and behaviours. In the PFC of depressed patients who committed suicide, the ERK1/2 MAPK pathway activity as well as the levels of mRNA expression and protein of ERK1/2 drastically decreased. P2X2 receptors in PFC were found to influence the antidepressant effects of ATP. Recent research demonstrated that the prelimbic region of the medial prefrontal cortex (mPFC), in particular, regulates the vulnerability to stressful events. Cholecystokinin (CCK)-Breceptor activity is suppressed by the overexpression of the transcription factor FosB, which increases the vulnerability to stress. In contrast to the ligand CCK injected into the mPFC in mice, which causes depressive symptoms resembling those brought on by social defeat stress, blocking the CCKB receptor in mice results in a flexible phenotype (Dr. Thomas).
These findings imply that CCKB and FosB may represent novel, effective targets for the prevention and/or treatment of depression. Although optogenetic stimulation of mPFC projections to the nucleus accumbens (NAc) or basolateral amygdala (BAC) following CCK infusion in mPFC can block the anxiogenic effect of CCK, no other antidepressant-like effect was observed in social defeat stress models, indicating that more thorough explanations of those effects are required.
Ventral Tegmental Area
The vulnerability or resistance to social defeat stress is determined by dopamine neurons in the ventral tegmental region (VTA), and the vulnerable phenotype will show depressive behaviours. In mice that experienced a social defeat stress below the threshold, optogenetic methods used to induce phasic rather than tonic firing in VTA dopamine neurons—which project to NAc rather than to mPFC—caused a rapid vulnerable phenotype characterised by increased social avoidance and decreased sucrose preference. Additionally, resistant mice who had previously endured recurrent social defeat stress were changed into a vulnerable phenotype by optogenetic activation of VTA phasic firing. Optogenetic suppression of dopamine projections in the VTA-NAc led to resilience, whereas suppression of those in the VTA-mPFC led to susceptibility. These discoveries on projection-specific and fire-pattern-specific dopamine neurons enhance our comprehension of the roles of VTA dopamine neurons in stress susceptibility and in depression pathology (Dr. Timmie).
Major depression is characterised by structural and neurochemical abnormalities of the hippocampus, including hippocampal cell atrophy and decreased ERK1/2 MAP kinase activity (detected in the post-mortem brain of depressed individuals). Chronic stress exposure results in decreased neurotrophic factor expression, smaller hippocampal volumes, and a reduction in neurogenesis in the region called dentate gyrus of the adult brain. Antidepressants may be used to undo those changes. The hippocampus of depressed rats exposed to psychological stress showed lower levels of total zinc and mRNA expression of zinc transporting-associated proteins, despite zinc acting as a cofactor for enzymes essential for biochemical processes, particularly in the brain. Antidepressant medication or zinc supplements may be used to reverse the aforementioned alterations. Drugs (like resveratrol) and antidepressants (like fluoxetine, for instance) may both increase the amounts of BDNF mRNA and protein in the mPFC and the hippocampal formation. In contrast to the resilient mice, the animals susceptible to persistent social defeat stress had less ATP in their interstitial fluid from the hippocampus and PFC. Mice subjected to chronic unexpected stress had different phospholipidomic profiles in the hippocampus, including catalase, superoxide dismutase (SOD), and glutathione reductase. To produce antidepressant behavioural effects, miR-16 and miR-598-5p, two micro-RNAs in the hippocampus, may be targeted. These findings all indicate that the hippocampus region may have a variety of functions in the psychopathology of depression.