Explain the Biological Mechanisms by Which Stress Can Induce Depressive Behaviour

Explain the biological mechanisms by which stress can induce depressive behaviour. Introduction Depressive behaviour is a core feature of several major psychological disorders, most obviously major depression (MD) and depressive episodes of bipolar depression (BP). Depression is also frequently found to be co-morbid with psychotic disorders such as schizophrenia and with anxiety-related disorders (e. g. social phobia or OCD). Depression is the biggest major risk factor for self-harm and suicide, thus posing a real clinical problem to try to understand and reverse the mechanisms involved.
Traditional anti-depressant treatment has only shown a modest benefit to placebos in treating the disorder; therefore, more effective drugs that target the right biological mechanisms are imminently needed. The majority of experimental research in the area has used rodents to test medication and model known psychopathological aspects of depression in humans, such as learned helplessness, cognitive deficits and increased co-morbidity with anxiety-related behaviours. There are many factors that may explain why some people (around 16% of the population) will experience a depressive episode in their lifetime and others won’t.
Genetic vulnerability and epigenetic changes, psychosocial support, socioeconomic status or even climate-related factors all have to be considered in considering the right treatment for individual cases. Whilst the causal link between many of these and the onset of depression is somewhat inconclusive, the strong association between chronic mild stress (CMS) and depressive behaviour is now a huge area of research, resulting in the stress-induced model of depression.

Even where there is evidence for the role of genes in depression, such as allele variants for the 5-HTT promoter region, it is shown to vary as a function of exposure to stressful life events. The mechanisms by which environmental stressors can lead to depressive behaviour have been explored thoroughly, with a strong focus on the role of the Hypothalamus-Pituitary-Adrenal (HPA) axis and its dysfunction in depression. The consequent rise in levels of the glucocorticoid hormone cortisol, following HPA activation, has been shown to become chronic increased in depressed patients.
This is thought to be due to the development of glucocorticoid resistance, whereby high levels of cortisol are present in the bloodstream and peripheral tissue but negative feedback to shut down the HPA axis no longer works. Due to the numerous roles of cortisol within the body, several biological processes may be affected as a consequence of CMS that may lead to depressive behaviour. Direct and indirect effects of HPA dysfunction include changes in immune response, neuronal damage, decreased rates of neurogenesis and the serotonin pathways.
These processes tend to interact and exacerbate one another; therefore, understanding each proposed biological mechanism of stress-induced depression and their impact upon each other is likely to lead to a better treatment outcome. Acute Stress and the HPA Axis The experience of acute mild stress is a normal and adaptive process, triggered by an environmental ‘stressor’ deemed to be potentially harmful. From an evolutionary perspective, this serves to protect the individual from danger via activation of the sympathetic nervous system, preparing the individual for ‘fight or flight’ mode.
Stress, as well as input from the amygdala, hippocampus and midbrain, directly activates the ‘stress response’ via the Hypothalamic-Pituitary-Adrenal (HPA) axis. The first immediate response is the release of corticotrophin releasing hormone (CRH) from the hypothalamus, which travels to the pituitary where it binds to CRH Receptor 1 (CRHR1). CRH can also act directly on other brain regions, e. g. the amygdala at this early stage. CRH1 activation stimulates the release of adrenocorticotrophin release hormone (ACTH), which travels via the bloodstream to the kidneys, stimulating the delayed release of the glucocorticoid (steroid) cortisol.
Cortisol acts throughout the body in all cells, via binding to cytoplasmic glucocorticoid and mineralocorticoid receptors (GR and MR) (see Figure 1). Figure 1: Cortisol can pass through the cell membrane due to its lipophillic properties. Binding of cortisol to the GR complex in the cytoplasm causes dissociation of GR from the complex, resulting in an active GR monomer. Two GRs then dimerise to form a GR dimer. This can act as a transcription factor in itself by attaching to Glucocorticoid Binding Elements (GBE), or it can interact with other Hormone Binding Elements and transcription factors to initiate gene transcription. http://jimlund. org/blog/? m=200910] A rise in cortisol levels, alongside CRH, leads to adaptive changes in behaviour, cognition and immune function. Importantly, this rise is followed by a negative feedback loop of cortisol and CRH acting upon its own receptors (NC3R1 and CHR2, respectively) to shut down the HPA axis once the ‘threat’ has been resolved. This homeostatic mechanism terminates the production of any more CRH and therefore brings cortisol levels back to baseline (pre-stressor), vital for returning the individual back to a normal ‘resting’ state.
It is this negative feedback mechanism which has been shown to be disrupted in patients with depression. Chronic Stress and Glucocorticoid Resistance In a situation of CMS, the prolonged activation of the HPA axis leads to abnormally elevated cortisol levels. However, chronically elevated cortisol can be dangerous, due to its role in suppressing the immune system and increasing vulnerability to infection. It is possible that in order to counteract the constant influx of circulating cortisol causing potentially unwanted downstream effects, GRs in lymphocytes become unresponsive or resistant to glucocorticoids.
This dysfunction of GRs is typically seen in depressed patients and has been shown numerous times using the dexamethasone suppression test (DST). Dexamethasone (a synthetic glucocorticoid) mimics cortisol by binding to GRs and shutting down HPA activity in healthy controls. Therefore, dexamethasone-treated individuals have almost no detectable cortisol over the course of the following day. On the other hand, in depressed patients, the DST doesn’t show any significant repression of HPA activity.
Whilst they already show significantly higher overall levels of cortisol, they also show reduced suppression of dexamethasone during the DST. This shows that the GRs are unresponsive to glucocorticoids, leading to the typical feature of glucocorticoid resistance in depressed patients. The Inflammation/Cytokine Hypothesis Glucocorticoid resistance has important implications for immune system function. Under normal acute stress, cortisol suppresses lymphocytes in peripheral tissue from producing pro-inflammatory cytokines by activating intracellular GRs and leading to transcription of downstream regulatory genes.
Key targets of GR-mediated transcription related to immune function include the upregulation of anti-inflammatory genes annexin-1, IL-10 and I? B? (inhibits NF-? B) and down-regulation of pro-inflammatory cytokine genes, such as IL1-6, 9, 11-13, 16-18 and TNF-?. However, glucocorticoid resistance following chronic stress can mean that lymphocytes stop responding to cortisol, so there is an increase in the proliferation of leukocytes and production of pro-inflammatory cytokines.
The proposed mechanism for how these peripherally-generated cytokines are able to affect the central nervous system (CNS) involves several pathways. These cytokines (IL-1? , TNF-? and IL-6) cannot typically diffuse across the blood-brain-barrier, but they can enter the CNS in regions of high BBB permeability or be actively transported across the BBB by endothelial cell transporters. Additionally, without crossing the BBB, cytokines are able to activate endothelial cells to produce soluble factors (e. g.
PG-E2) to indirectly activate neurons, as well as activating certain afferent neurons (e. g. the vagus nerve) that carry information to the CNS about the inflammation. In these ways, peripheral inflammation can cause typical changes in the CNS and ‘sickness behaviour’ seen in depressed patients: lethargy, anhedonia, reduced locomotor activity and sleep and weight disturbances. Support for this proposed mechanism comes from findings that clinically depressed patients show an abnormally high production of pro-inflammatory cytokines (IL-1? IL-6 and TNF-? ), cytokine-based immunotherapy often causes depression in cancer or hepatitis C patients and cytokine administration causes depressive behaviour in animal models. Reversal of this depressive behaviour can be seen by administration of anti-depressants, which target and reduce the inflammatory response in both patients and animal models. In a similar fashion, anti-inflammatories such as cyclooxygenase (COX)-2 inhibitors or omega-3 have strong anti-depressant effects on behaviour. Inflammation-Induced Neurodegeneration
Another approach to modelling stress-induced depression has focused on the controversial findings of clinically depressed patients show changes in volume of structural brain regions, including the hippocampus, amygdala, anterior cingulated, prefrontal cortex and basal ganglia. The mechanisms by which some brain regions, in particular the hippocampus as implicated in stress-induced depression, might decrease in volume appear to be a combination of both neurodegeneration (increased apoptosis of neurons) and a decrease in adult neurogenesis in the subgranular zone of the dentate gyrus (DG).
Stress-induced HPA hyper-activity may explain the atrophy seen in some brain regions of clinically depressed patients. Glucocorticoids stimulate the breakdown of tissue into glucose for the quick release of energy; therefore, chronically increased levels may result in brain tissue loss in regions where cortisol acts, such as the hippocampus. Furthermore, the link between stress, inflammation and an increase in oxidative stress may also explain a large portion of the neurodegeneration apparent in depression.
Inflammation has been shown to increase oxidation and the fact that the CNS has no proper defence against oxidative damage makes it very vulnerable to oxidative stress (OS). This has been demonstrated as a key feature in neurodegenerative diseases and depression, implicating a causal role of stress-induced inflammation in triggering degeneration. The damage caused by OS can lead to mitochondrial dysfunction, which can lead to further intracellular build up of damaging oxidised proteins.
The only way for cells to cope in this situation is to activate programmed cell death (apoptosis), or in less controlled circumstances, necrosis can occur, leading to a decline in cell numbers and lateral effects on the neural network. This mechanism of oxidative stress-induced neurodegeneration can be slowed down and treated by the application of antioxidant enzymes, which serve a neuro-protective role. These enzymes eradicate free radical oxidising particles and also suppress pro-inflammatory cytokine action.
A further damaging feature seen in neurodegeneration and depression is nitrosative stress (NS), which may contribute to neurotoxicity and therefore cell death. An increase in the production of cortisol after acute stress will temporarily cause a suppression of neurogenesis in the DG. Neurogenesis in the DG has been demonstrated to be vital for healthy cognition and memory, impacting mood, the sleep-wake cycle and appetite; all affected in depression. Therefore, CMS leads to prolonged suppression of neurogenesis and may explain the behavioural outcomes typical of depression.
The decrease in neurogenesis following exposure to stress may possibly involve the neurotrophin Brain Derived Neurotrophic Factor (BDNF), shown to be greatly reduced in regions that also show a decrease in neurogenesis and related to brain regions typically affected in depression. Animal models exposed to CMS show decreased neurogenesis and BDNF levels in overlapping brain regions and elicit depressive behaviours associated with dysfunction of these regions. Furthermore, anti-depressant treatment that successfully increases BDNF levels also leads to recovery from depressive behavioural symptoms.
However, the causation here is not clear; whether the BDNF levels dropping are a result of other stress-induced mechanisms or whether it is partly the cause of the behaviour. Some evidence suggests that anti-depressants can work independently of BDNF restoration. Hagen and colleagues set out to control for possible variables such as age, time of cortisol readings and overall brain volume. Whilst there has been no robust evidence for a link between baseline cortisol levels and hippocampal volume, this study did find that hippocampal volume was negatively correlated with length of depressive episode pre-hospitalisation.
Furthermore, better responsiveness (lowering of cortisol levels) after treatment was predicted by greater hippocampal volume (relative to overall brain volume). b) antineurogenic effects and reduced brain-derived neurotrophic factor (BDNF) levels; and c) apoptosis with reduced levels of Bcl-2 and BAG1 (Bcl-2 associated athanogene 1), and increased levels of caspase-3. Stress-induced inflammation, e. g. increased IL-1? , but not reduced neurogenesis, is sufficient to cause depression. Antidepressants a) reduce peripheral and central inflammatory pathways by decreasing IL-1? TNF? and IL-6 levels; b) stimulate neuronal differentiation, synaptic plasticity, axonal growth and regeneration through stimulatory effects on the expression of different neurotrophic factors, e. g. trkB, the receptor for brain-derived neurotrophic factor; and c) attenuate apoptotic pathways by activating Bcl-2 and Bcl-xl proteins, and suppressing caspase-3. It is concluded that external stressors may provoke depression-like behaviours through activation of inflammatory, oxidative, apoptotic and antineurogenic mechanisms.
The clinical efficacy of antidepressants may be ascribed to their ability to reverse these different pathways. Neuronal damage and apoptosis Activation of the Kynurenine Pathway (KP) 5-HT Accumulated evidence indicates a role of the hippocampal 5-hydroxy-tryptamine (5-HT) and neuropeptide Y (NPY) in the response to stress and modulation of depression, but it is unclear whether and how the hippocampal 5-HT and NPY systems make contributions to chronic unpredicted mild stress (CUMS)-induced depression.
Here we observed that rats receiving a variety of chronic unpredictable mild stressors for 3 weeks showed a variety of depression-like behavioral changes, including a significant reduction in body weight, sucrose preference, and locomotion, rearing and grooming in open field test, and a significant increase in immobility time in forced swimming test. These CUMS-induced behavioral changes were suppressed or blocked by intra-hippocampal injection of 5-HT (31. 25 microg/microl) or NPY (10 microg/microl). These data suggest a critical role of reduced hippocampal 5-HT and NPY neurotransmission in CUMS-induced depression.

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