Advances in research on the pathogenesis of chronic stress and depression
Advances in research on the pathogenesis of chronic stress and depression
Abstract: Chronic stress life events are risk factors for depression. Chronic unpredictable stress (CUS) can induce behaviors similar to depression, including passive behavioral responses, lack of pleasure, and many other emotional and cognitive behavioral symptoms. At the same time, chronic stress also shows negative regulation of adult hippocampal nerves. Stress can reduce the proliferation of adult hippocampal nerve cells. Magnetic resonance imaging of the brain in patients with major depression shows a significant decrease in hippocampal volume. Long-term chronic stress activates the peripheral and central immune systems and also leads to the release of large amounts of inflammatory mediators (including cytokines such as microglia).
Key words: depression; antidepression; stress; cytokines; hippocampus
Depression is one of the most prevalent diseases in mental illness. The prevalence of the general population is as high as 20%. It is a psychological disorder that is harmful to health and easy to relapse. The diagnosis of depression is based on the observation of emotional, cognitive and behavioral symptoms, at least five symptoms (including low mood, lack of pleasure) and lasting more than two weeks to achieve the diagnostic criteria for depression. At present, although the treatment has made some progress, the treatment plan has not achieved the best effect. For example, in general, the antidepressant method of the drug takes several weeks to improve the symptoms, and the cause of depression is largely unknown, and there are many opinions on the theory of its onset. For example, depression was once thought to be the result of a harsh social environment. Cognitive theory holds that depression is the product of subconscious desire-driven, and the cognitive model of negative irrational self-cognitive distortion, and other psychological theories that specific personality, such as introversion and pessimism, may lead to depression. disease.
The most recent theoretical hotspot is biological factors, which stress is a major cause of depression. For example, hypothalamus-pituitary-adrena-Axisl (HPA) disorders associated with chronic stress and cytotoxicity due to excessive release of glucocorticoids, disorders caused by downregulation of hippocampal neurogenesis, and genetic or Epigenetic aspects and other factors related to the development of depression. The combination of multiple factors of stress is the most important cause of depression. The theory is that depression episodes are caused by a series of biological tendencies and inherent susceptibility. On the other hand, the effects of stress include many other factors. Such as personality, inner conflicts, and positive or negative social support, which may affect the controllability of stress events. These environmental and stress factors may affect the biological system, causing excessive glucocorticoid release or dysregulation of HPA, leading to changes in the limbic system and cerebral cortex leading to depressive symptoms. To date, theories of depression involve evolution, social environment, interpersonal relationships, psychology, cognition, personality, behavior, endocrine, cellular, genetic, and epigenetic factors. Moreover, these factors do not exist in isolation, but frequently interact with each other. For example, brain-derived neurotrophic factor (BD-NF) and 5-hydroxytryptamine (5-HT) can adjust hippocampus. Neurogenesis, and in turn adjusts HPA function and response to stress.
1 depression and stress
1. 1 Stress stress refers to the non-specific adaptive response of organisms after various stimuli during their survival. Most stress organisms can gradually adapt to themselves, but if some of the stimuli can not adapt, it may cause physiological and psychological abnormalities, and many diseases such as depression evolved like this. According to the duration of stress, stress can be divided into acute stress and chronic stress. Chronic unpredictable stress (CUS) is small but persistent. Chronic or persistent stress causes damage to the central nervous system, which may lead to ability and adaptation. Gradually reduced.
Chronic stress and stressful life events are closely related. Recent studies have suggested that chronic stress is an important mediator between life events and depression. Both physical and psychological chronic stress can cause depression in people or animals, while chronic stress can aggravate the symptoms of patients with depression and mood disorders. Clinical data suggest that changes in the overall morphology of the brain are similar to chronic stress responses in patients with major depression. Computed tomography and magnetic resonance imaging have shown reduced brain volume, enlarged ventricles, lateral ventricular sulcus widening, and hippocampal volume in patients with major depression. reduce.
In short, stress is closely related to depression. In this case, scholars have different interpretations of the pathogenesis of depression. Some scholars believe that stress is the cause of illness and can directly lead to depression. Some scholars believe that stress is only a potential state and induces, but some scholars believe that there is an interaction between stress and depression. Stress events can promote depression, and depression also encourages patients to experience more. Stress event. The hypothesis related to stress and depression has a stress exposure hypothesis, a stress-sensitive hypothesis, and the like.
1. 2 Chronic Stress and Animal Depression Models Researchers have found that some animal depression models are very useful test models because they can reproduce the special extrinsic and intrinsic manifestations of depression. Scholars make animal depression models by simulating childhood misfortunes, genetic factors, stress, and other incentives. For example, animal models of childhood unfortunately separate newborns from mothers; knocking gene mouse models, such as 5-HT transporter knockouts In addition to mice, cannabinoid receptor knockout mice; likewise, congenitally acquired helpless mice selectively cultured and learned helpless behavior; cholinesterase inhibitors sensitive ( flinders Sensitive Line, FSL) The mice selectively cultured an increase in the response to cholinesterase inhibitors; some scholars used a complete resection of the olfactory bulb to mimic depression and caused extensive neurodegeneration in the marginal, mid-slit, and other brain regions; Scholars use pharmacological models, including psychostimulant (such as amphetamine) withdrawal and neonatal chlorpromazine treatment; Finally, there are repeated exposure to stress or stress hormones, including long-term use of corticosterone, chronic bondage, Chronic social defeats, prolonged social isolation, repeated foot shocks, and CUS exposure have all been shown to increase glucocorticoid levels and induce depression similar symptom. Although the neurobiological basis of these models may be different from depression, these models are validated by effective behavioral testing and have very significant predictive effectiveness in screening for antidepressants, including the ability to measure stress impairment or Desperate forced swimming experiments , tail-hanging experiments and learned helplessness ; ability to measure sucrose preference experiments with lack of pleasure; ability to study new inhibition experiments on anxiety behaviors, and to be able to study social social interaction experiments .
2 chronic stress and inflammatory cytokines
Studies have shown that long-term chronic stress activates the peripheral and central immune systems, and the release of a large number of inflammatory cytokines is an important mechanism for the development of depression. Depressive symptoms in patients with autoimmune diseases and inflammation, such as diabetes and fibromyalgia, support this view to some extent. In fact, elevated levels of pro-inflammatory cytokines in serum of patients with depression have been demonstrated, such as interleukin (IL) 1β, IL-6, IL-8, IL-12, interferon-c and tumor necrosis factor- The level of a(tumor necrosis factor alpha, TNFα) is elevated. In addition, levels of IL-1β receptor antagonists in plasma, IL-5, IL-6, IL-7, IL-8, IL-10, granulocyte colony-stimulating factor and interferon-c were elevated. It is worth noting that after 12 weeks of treatment with antidepressants, cytokines were reduced to normal levels. At the same time, IL-1β is elevated in serum and decreased in IL-10 levels in depressed patients.
2. 1 Recent studies of microglia and depression have shown that chronic stress enhances neuronal activity through interactions between neurons and glial cells, thereby activating the immune response of the central nervous system. Microglia and astrocytes control the regulation of the central nervous system immune response, and the microglia counteracts the dangerous signals transmitted by the central and peripheral nervous systems to cause inflammation in the body. Interestingly, in the patients with major depression, the small glial activation of the dorsal anterior cingulate and the accumulation of macrophages increased, and the small glial activation of the ventral prefrontal white matter of suicide patients also increased. Similarly, in the anterior cingulate and anterior cingulates of patients with schizophrenia and depression, microglia activation in the anterior cingulate cortex, hippocampus, and dorsal medial nucleus of the thalamus was associated with suicide. In summary, these studies indicate that activation of microglia is an important factor leading to suicide in depression. In addition, stress causes morphological activation of microglia. Sprague-Dawley rats were exposed to a restraint stress environment, and microglia in the prefrontal cortex was observed to be activated, while minocycline, which has anti-inflammatory and anti-depressant functions, can reduce stress on neurons and small gums. The effect of cytoplasmic activation. In fact, long-term chronic stress promotes microglial derivation and astrocyte atrophy in the prefrontal cortex of rodents. In addition, mice exposed to a stressful environment, the morphology of the microglia of the thalamus, hypothalamus, hippocampus, substantia nigra and central gray matter is activated. These findings support the theory that microglia play a key role in regulating stress.
2. 2 Corticosteroids and depression are well known, corticosteroid receptors have a certain number of expression in neurons and microglia. In addition, researchers have shown that chronic corticosterone can enhance the gene expression of inflammasome and strengthen the resection of the adrenal gland. The inflammatory response of lipopolysaccharide (LPS) in rodent microglia. Therefore, cortisol plays an important role in the signals produced by microglia and in the inflammatory process associated with depression.
2. 3 Glutamate and depression Glutamate is an important neurotransmitter in the central nervous system. Studies have shown that inflammatory cytokines can reduce the expression of glutamate transporters and promote the release of glutamate from astrocytes. At the same time, inflammatory cytokine-activated microglia can cause neuronal damage due to glutamate release.
3 depression and hippocampal formation
From a structural point of view, the hippocampus is divided into two parts: hippocampus and dentate gyrus. Hippocampus (CA) includes CA1, CA2, CA3, and CA4, which are mainly composed of some pyramidal neurons, while the dentate gyrus is mainly formed by granulosa cells. Studies have shown that the hippocampus is a region of high density accumulation of microglia, especially in the CA1 region. It has been suggested that the density of microglia causes a vulnerability in the specific location of the hippocampus, and the heterogeneous distribution of microglia is involved in the regulation of neuronal activity in the hippocampus. It is worth noting that many studies have pointed out that chronic stress affects the activation of microglia in the hippocampus, which is not only associated with the pathophysiology of major depression, but also with other mental and stress-related diseases, such as trauma. Post traumatic stress disorder (PTSD). Recent studies have shown that PTSD differs from prenatal stress depression in that the activation of microglia in the hippocampus is aggravated with abnormal cell proliferation. On the other hand, scholars believe that depression is caused by insufficient 5-HT function of monoamine transmitters in the brain and abnormal metabolism of dopamine (DA) and noradrenaline (NA). The decrease in 5-HT and norepinephrine is associated with an increase in glucocorticoids, which can degrade the tryptophan and tyrosine in the blood, resulting in a decrease in the synthesis of 5-HT and NA in the central nervous system. It has been reported that 5-HT can antagonize the binding of glucocorticoids to the corresponding receptors in the hippocampus to alleviate the toxic effects of glucocorticoids on cells. Therefore, the hippocampal structure plays an important role in the related mechanisms of depression.
4 Depression and antidepressants
An important feature of antidepressants is that they can promote neurogenesis in the hippocampus. Studies have shown that long-term mild antidepressant treatment increases the neurogenicity of the hippocampal dentate gyrus. Other researchers have found that antidepressants not only improve cell survival, but also up-regulate hippocampal neurogenesis. Moreover, this up-regulation is directly related to the clinical efficacy of antidepressants. To date, antidepressants including 5-HT reinhibitors, atypical antidepressants, cyproterone and electroconvulsive therapy, and mood stabilizers have been shown to enhance the proliferation of dentate gyrus neurons. The nature of survival. On the other hand, antidepressants are also used to regulate microglia. For example, selective serotonin reuptake inhibitors can strongly inhibit the production of microglia TNF-a and LPS, and c AMP signaling is involved in the regulation. Anti-inflammatory response. Fluoxetine-selective Serotonin Reuptake Inhibitor (SSRI) drugs also reduce activated microglia in animal models of dopamine neurons and are regulated by tissue microglia Oxidative stress prevents LPS-induced degeneration of dopaminergic neurons in the substantia nigra. In addition, some preclinical and clinical studies have shown that N-methy1-D-aspar-tate (NMDA) antagonists, such as ketamine, memantine, and amantadine, have antidepressant effects. Furthermore, ketamine has been shown to contain anti-inflammatory properties by inhibiting the expression of TNF-a and IL-6 genes in LPS-activated macrophages.
5 Conclusion and outlook
In recent years, scholars have conducted in-depth research on the pathogenesis, research programs, and treatment methods of depression, but the pathogenesis of depression is complicated and has not yet been fully elucidated. At present, the depression model developed by scholars has further discovered the mechanism of depression. In future research, focusing on whether cognitive susceptibility and stress interaction are independent, and how it relates to the type of depression, further clarifying the relationship between hippocampal formation and depression, will open up a new path for the treatment of depressive diseases.
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