05 Stress Induced Depression

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Stress inhibits neurogenesis at the hippocampus of adult brains and this inhibition is linked to the development of depression. As a result, patients with depression observe a reduced hippocampal volume [1]. Depression and stress also lead to a reduction in synaptogenesis in the prefrontal cortex and hippocampus and impairments in synaptic neurotransmitter release. Therefore treatment strategies, such as antidepressants, promote neurogenesis at the dentate gyrus of the hippocampus and improve synaptic connections in the prefrontal cortex in an effort to achieve remission [2][3].

1. Effects of Stress

1.1 Neurogenesis

Figure 1
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Stress reduces neurogenesis. Antidepressants, therefore, counteract this effect by promoting neurogenesis [1]

In the adult brain, neurogenesis primarily occurs in two regions, the subventicular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus [2]. Stress causes a reduction in neurogenesis at the dentate gyrus which is hypothesized to lead to the development of depression. Neurogenesis at the hippocampus is important for memory and mood regulation, therefore according to the neurogenic hypothesis of depression, the decrease in neurogenesis influences and is a factor in the expression of depressive behaviour [1][4]. Studies done by Mateus-Pinheiro et al. tested the effects of neurogenesis on depressive behaviour by blocking cell proliferation using methylazoxymethanol acetate. This blockage not only caused a decrease in spines similar to that seen in depressive brains, but also induced depressive behaviour in rats [5].

External stressors activate a number of stress pathways that have an effect on neuronal activity, one of which is the activation of pro-inflammatory cytokines which results in neurodegeneration and reduced neurogenesis. These stress pathways also lead to a decrease in brain derived neurotrophic factor (BDNF), which is also associated with decreased neurogenesis in depressive patients [6].

Figure 2
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BrdU levels represent cell proliferation. The control sample with CRH present shows higher cell proliferation
than the - CRH cells and cells treated with glucocorticoid dexamethasone[7]

As a response to stress, the body activates corticotropin-releasing hormonecorticotropin-releasing hormone (CRH). The stress response of CRH also protects neural progenitor cells (NPC) by reversing the toxic effects of glucocorticoids on the NPCs. Koutmani et al. show the effects of CRH on neurogenesis by testing CRH null mice. The null genotype resulted in a significant decrease in neural proliferation of a developing mouse embryo. To demonstrate the protective characteristic of CRH, mouse NPCs were treated with glucocorticoid dexamethasone and with a combination of glucocorticoids and CRH. The glucocorticoid treatment resulted in a significant decrease in cell proliferation whereas the combination treatment reversed those effects [7]. BrdU was used as an indicator of proliferation in the brain slices. This study showed the detrimental effects of stress induced secretion of glucocorticoids on NPCs.

1.2 Synaptogenesis

Figure 3
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Reduction in dendritic spines caused by exposure to CUS. Treatment with ketamine restores the dendritic spines[9]

Stress also affects the synaptic connections of the brain and decreases synaptogenesis in the prefrontal cortex, as seen in depressive patients. Along with the impairment in neurogenesis, depression leads to a decrease in synaptic density in the hippocampus and prefrontal cortex [3]. Exposure to chronic unpredicted stress (CUS) causes a decline in synaptic proteins and dendritic atrophy in the prefrontal cortex [8]. In a study done by Li et al. rats were exposed to CUS for 21 days after which there was a significant decrease in dendritic spines on the prefrontal cortex pyramidal neurons compared to the control animal [9]. The reduction in synaptic branches causes a reduction in serotonin and in excitatory postsynaptic potentials which is a factor in depressive behaviour [8].

1.3 Neurophysiology

Both stress and depression change the neurophysiology of the patient's brain. The reduction in neurogenesis had been shown to be responsible for a reduced hippocampal volume in depressive patients [4]. Similarly, the decrease in synaptic connections in the prefrontal cortex leads to a decreased prefrontal cortex volume [8]. Chronic stress influences neural plasticity and inhibitory networks as well. stress-induced-plasticity-in-the-glumatergic-syst inhibits the inhibitory neuron GAD67 and causes a decrease in GABA, changing the structure of the medial prefrontal cortex interneurons. This alteration of the GABA system, reduction in GABA concentration, and reduction in GAD67 proteins is also observed in depressive patients, suggesting its correlation to depressive behaviour [10].

2. Effects of Depression on Bodily Functions: the Circadian Rhythm

Figure 4
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High corticosterone (HR) mice exhibit more motor activity during the resting light period
than intermidiate (IR) or low corticosterone (LR) mice[11]

Stress and depression also affect the body's circadian rhythm. Depressive patients exhibit altered REM sleep behaviour and many experience insomnia-like behaviour. Stress causes disruptions in the circadian rhythm through glucocorticoid release as a response to stress [11][12]. Different levels of cortisol release as a stress response show different sleep patterns in mice. Touma et al. test the correlation of glucocorticoid release and sleep patterns using generations of mice that represent three levels of corticosterone release: generations with high (HR), intermediate (IR), and low (LR) corticosterone levels. HR mice exhibit disrupted sleep during the resting period while IR and LR mice do not experience significant fluctuation in sleep patterns. HR mice correspond with a subtype of major depression called melanholic depression. In this subtype, patients experience insomnia and disrupted sleep. The LR mice correspond with the depression subtype known as atypical depression, in which patients experience longer than regular sleep durations. REM sleep in the high corticosterone mice was longer than usual and the opposite was observed in the low corticosterone mice [11].

Sleep also affects depressive behaviour. CLOCK and BMAL are transcriptional factors found in the suprachiasmatic nucleus (SCN) and are important in the circadian system. Exposure to CUS alters CLOCK expression inducing depressive behaviours such as anhedonia, helplessness, and circadian abnormalities [13].

3. Treatment Strategies

Treatments for depression include the use of antidepressant drugs. These drugs target neurogenesis and synaptogenesis to achieve remission. By promoting neurogenesis at the dentate gyrus, the antidepressants are able to reverse the effects of stress on neurogenesis. Synaptogenesis at the prefrontal cortex is also improved through antidepressant treatment [14][15]

3.1 Ketamine

Ketamine is an NMDA receptor antagonist with antidepressant properties that targets the rapamycin (mTOR) pathway to promote synaptogenesis and formation of synaptic proteins. Ketamine produces fast antidepressant responses and reverses depressive behaviour [16]. In the study done by Li et al. ketamine was administered to the rats after a 21 day period of CUS exposure [9]. The ketamine reversed the effects of CUS and restored the synaptic proteins and dendritic spines affected by CUS (Figure 3). While ketamine's effects on depressive animal models is promising, its use as an antidepressant drug has limitations. Ketamine is also a street drug and can be toxic in high quantities [17]. Nevertheless, it shows the importance of the promotion of synaptogenesis in fast acting treatments of depression.

See also

Stress and Sleep
Exercise Induced Hippocampal Neurogenesis

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