Malcolm Rivera
Stress is a part of everyday life, and animals have evolved physiological and behavioral responses to cope with it. The brain, along with the immune, metabolic, and neuroendocrine systems, plays a crucial role in responding to stressful experiences. During stressful situations, our bodies produce steroid hormones called glucocorticoids, which affect many systems throughout the body. While some stress genes are expressed constitutively and are involved in basic cellular processes, others are normally silent or expressed at low levels and are upregulated when cells are subjected to stressful conditions. Research has shown that chronic exposure to stress hormones causes modifications to DNA, prompting changes in gene expression. These changes in gene expression can have behavioral and physiological effects, and they provide clues about how chronic stress might impact human behavior.
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What You'll Learn
- Chronic exposure to stress hormones causes DNA modifications
- Stress-induced expression of immediate early genes in the brain
- Genetic variations in Fkbp5 are associated with post-traumatic stress disorder
- The role of TNFα in iNOS expression surge under stressful conditions
- Stress-induced activation of the NMDA receptor increases TNFα-convertase levels
Chronic exposure to stress hormones causes DNA modifications
The body's stress response is mediated by the hypothalamic-pituitary-adrenal (HPA) axis, a network involving the hypothalamus and pituitary gland in the brain and the adrenal glands near the kidneys. During stressful situations, the body produces steroid hormones called glucocorticoids, which affect many systems throughout the body. Glucocorticoids alter gene expression in the brain.
Research has shown that chronic exposure to stress hormones causes modifications to DNA in the brains of mice, prompting changes in gene expression. In one study, corticosterone—the major hormone mice produce in stressful situations—was added to their drinking water for 4 weeks. After exposure, and again after a 4-week recovery period without corticosterone, the scientists tested the mice for behavioral and physiological changes. They examined the expression levels of 5 HPA axis genes in the hippocampus, hypothalamus, and blood. They also tested the genes' methylation levels—a common epigenetic modification that affects gene expression. The results showed that chronic exposure to corticosterone altered the expression of 3 HPA axis genes, including higher levels of Fkbp5 in the hippocampus, hypothalamus, and blood. Genetic variations in Fkbp5 have been associated with post-traumatic stress disorder and mood disorders, which are characterized by abnormal glucocorticoid regulation.
These findings provide clues into how chronic stress might affect human behavior and contribute to stress-related disorders. For example, studies have shown that inappropriate responses to repeated and/or continuous stress mediate the susceptibility to stress-related disorders such as hypertension, coronary artery disease, bipolar disorder, and unipolar depression.
Additionally, chronic stress has been linked to an increased risk of developing certain diseases, such as cancer. Stress hormones have been shown to induce DNA damage in oral keratinocytes, which could contribute to oral carcinogenesis.
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Stress-induced expression of immediate early genes in the brain
Stress has been shown to cause rapid and transient expression of immediate early genes (IEGs) in the brain. The monitoring of IEGs has enabled the visualisation of the neurocircuitry of stress.
Stressors can be divided into two categories: processive and systemic. The neural circuits of brain activation differ between these two types of stressors. Processive stressors, such as immobilisation, induce c-fos mRNA first in the cortical and limbic areas and then in the paraventricular hypothalamic nucleus (PVH). On the other hand, c-fos expression in the PVH precedes that in other areas in animals subjected to systemic stressors.
Previous studies have shown that prior exposure to immobilisation stress or implantation of corticosterone pellets suppresses the induction of c-fos, fos B, jun B and NGFI-B, but not that of NGFI-A in the rat PVH. Furthermore, chronic exposure to corticosterone, a major stress hormone in mice, altered the expression of 3 HPA axis genes, including higher levels of Fkbp5 in the hippocampus, hypothalamus and blood. Fkbp5 codes for a protein that is part of a molecular complex that interacts with the glucocorticoid receptor. Genetic variations in Fkbp5 have been associated with post-traumatic stress disorder and mood disorders, characterised by abnormal glucocorticoid regulation.
Other studies have found that genes involved in the sympathetic system or the hypothalamic-pituitary-adrenocortical axis are associated with altered stress responses. For example, the GR gene has been implicated in the genetics of the stress response, with elevated cortisol responses to the dex/CRH test observed in depression, suggesting dysregulation of the HPA axis. Additionally, the angiotensin-converting enzyme (ACE) gene has been linked to the hormonal response to stress, affecting water regulation, blood volume, and blood pressure.
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Genetic variations in Fkbp5 are associated with post-traumatic stress disorder
Chronic exposure to stress hormones causes modifications to DNA, prompting changes in gene expression. During stressful situations, our bodies produce steroid hormones called glucocorticoids that affect many systems throughout the body. These effects are mediated by the hypothalamic-pituitary-adrenal (HPA) axis, a network involving the hypothalamus and pituitary gland in the brain, and the adrenal glands near the kidneys. Past studies have found that glucocorticoids alter gene expression in the brain.
Genetic variations in Fkbp5 have been associated with post-traumatic stress disorder (PTSD) and mood disorders, which are characterized by abnormal glucocorticoid regulation. FKBP51 acts as an inhibitor for GRs' translocation to the cellular nucleus and is also associated with the negative feedback mechanism of these receptors. GR activation affects both inhibitory and excitatory synapses in the hippocampus. However, this regulatory function is dependent on the presence of FKBP51, as evidenced by studies indicating that such mediation does not occur in its absence.
Genomic Wide Association Studies (GWAS) have revealed a correlation between certain allelic variants of FKBP5 and various mental health conditions, including aggression, bipolar disorders, suicide, PTSD, negative personality traits, and peritraumatic dissociation. Rs9296158 has been identified as a susceptibility factor for anxiety sensitivity and MDD. Patients with cancer who possess rs9296158 after prolonged stress exposure may experience heightened levels of anxiety and depression. In addition, this SNP can affect the signal transducer and activator of transcription 5B (STAT5B) mRNA levels. STAT5B is a protein involved in the translocation of GRs to the nucleus of cells. The reduction of STAT5B can cause excessive signaling induced by GRs, exacerbating stress-related effects.
The FKBP5 gene, located on the short arm of chromosome 6, harbors several common polymorphisms in high linkage disequilibrium, found to be associated with different psychological disorders. Single-nucleotide polymorphism (SNP) rs1360780 is located closest to a functional glucocorticoid response element. PTSD symptom severity was assessed before and 4 and 10 months after treatment completion. At the 4-month follow-up, there were no genotype-dependent differences in therapy outcome. However, the FKBP5 genotype significantly moderated the long-term effectiveness of exposure-based psychotherapy. At the 10-month follow-up, carriers of the rs1360780 risk (T) allele were at increased risk of symptom relapse, whereas non-carriers showed continuous symptom reduction.
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The role of TNFα in iNOS expression surge under stressful conditions
Stress is a complex biological process that involves the activation of various physiological systems and the production of steroid hormones called glucocorticoids, such as cortisol and corticosterone. These hormones affect multiple systems throughout the body and can lead to changes in gene expression, particularly in the brain.
Tumor Necrosis Factor-alpha (TNF-α) is a cytokine that plays a crucial role in the body's immune and inflammatory responses, especially under stressful conditions. TNF-α is produced primarily by macrophages, but also by other cell types, including T cells, B cells, dendritic cells, and mast cells. It is rapidly synthesized in response to various stimuli, including pathogenic substances, cytokines, and environmental stressors.
Under stressful conditions, stressed keratinocytes secrete TNF-α along with other pro-inflammatory cytokines such as IL-1, IL-6, and IL-10. These cytokines activate dendritic cells (DCs), which induce the differentiation of T cells into Th1 and Th17 cells. Th1 cells, in turn, secrete more TNF-α, creating a positive feedback loop that amplifies the immune response.
The increased production of TNF-α under stressful conditions can lead to a surge in the expression of inducible nitric oxide synthase (iNOS). iNOS is an enzyme that catalyzes the production of nitric oxide (NO), a critical signaling molecule in various physiological processes. TNF-α induces the expression of iNOS through the activation of several signaling pathways, including the NF-κB pathway and the mitogen-activated protein kinase (MAPK) pathway.
The activation of these pathways leads to the transcription and translation of the iNOS gene, resulting in increased levels of iNOS protein. This surge in iNOS expression enhances the production of NO, which can have both beneficial and detrimental effects. While NO plays a vital role in vasodilation and neurotransmission, excessive NO production can lead to oxidative stress and tissue damage.
In summary, TNF-α plays a pivotal role in the surge of iNOS expression under stressful conditions. The activation of immune cells and the subsequent cytokine secretion, including TNF-α, lead to the induction of iNOS expression through complex signaling cascades. While NO produced by iNOS can have important physiological functions, its excessive production may contribute to inflammatory diseases and tissue damage. Understanding the role of TNF-α in iNOS expression provides valuable insights into the development of therapeutic strategies for inflammatory and autoimmune disorders.
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Stress-induced activation of the NMDA receptor increases TNFα-convertase levels
Corticosteroids, such as the stress hormone corticosterone, have been found to modulate the transmission of hippocampal glutamatergic synapses and NMDA receptor (NMDAR)-dependent synaptic plasticity. This modulation can favour salient behavioural responses to the environment. Corticosterone has been shown to increase the trapping of GluN2B-NMDAR within synapses, which may play an important role in triggering AMPAR synaptic potentiation.
The NMDA receptor has been found to be involved in the stress response. In a study by Kim et al. (1996), behavioural stress was found to modify hippocampal plasticity through NMDA receptor activation. Furthermore, stress-induced activation of the NMDA receptor has been shown to increase TNFα-convertase (TACE) levels in the brain cortex. This increase in TACE activity was observed as soon as 30 minutes after immobilization stress in adult male rats.
The underlying mechanisms of neurodegeneration due to physical or psychological stress are still not fully understood. However, studies have shown that repeated or continuous stress can lead to overexpression of inducible NO synthase (iNOS) in the brain cortex, which has been linked to neurodegenerative changes. The role of the cytokine tumor necrosis factor-α (TNF-α) released during stress has been investigated, and increased levels of TNF-α have been observed after a short duration of stress.
The activation of the NMDA receptor has been associated with hypoxia-induced TRPM2 channel activation, mitochondrial oxidative stress, and apoptosis in neuronal cells. This activation can increase intracellular free Ca2+ ([Ca2+]i) concentration, leading to upregulation of inflammatory cytokines such as TNF-α. The use of NMDA receptor blockers, such as memantine and MK-801, has been shown to decrease hypoxia-induced changes and reduce neuronal death.
In summary, stress-induced activation of the NMDA receptor has been implicated in increasing TNFα-convertase levels in the brain cortex. This activation is associated with the stress response and can contribute to oxidative stress and apoptosis in neuronal cells. Further research is needed to fully understand the underlying mechanisms involved in stress-induced neurodegeneration and the potential therapeutic targets for treatment.
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Frequently asked questions
Stress hormones are steroid hormones called glucocorticoids that are produced during stressful situations. They affect many systems throughout the body and are mediated by the hypothalamic-pituitary-adrenal (HPA) axis.
Chronic exposure to the stress hormone corticosterone has been found to cause modifications to DNA in the brains of mice, leading to changes in gene expression. Specifically, it altered the expression of 3 HPA axis genes, including higher levels of Fkbp5, which is associated with post-traumatic stress disorder and mood disorders.
Genes involved in the stress response include those in the sympathetic system or the hypothalamic-pituitary-adrenocortical axis, which can exhibit altered stress responses. Additionally, genes related to the renin-angiotensin-aldosterone system and inflammation/immune response are associated with cardiovascular disorders. The GR gene and ACE gene have also been implicated in the hormonal response to stress. Other genes involved in the stress response include SLC6A4 and P2X ligand-gated ion channel 7125, which are associated with bipolar disorder and unipolar depression. Additionally, heat shock transcription factors (HSFs) play a role in cellular homeostatic control mechanisms by activating gene expression in response to stress.
