“Epigenetic Changes After Trauma May Be Adaptive, Contribute to Resilience”
Originally From Psychiatric News Update
In recent years, research throughout the scientific and medical community has suggested a link between trauma and epigenetic changes, chemical modifications that affect gene activity without actually changing the gene’s DNA sequence. The assumption has been that epigenetic changes in the context of trauma are inherently bad, a form of damage that gets passed from generation to generation. But according to Rachel Yehuda, Ph.D., Endowed Professor of Psychiatry and Neuroscience of Trauma at the Icahn School of Medicine at Mount Sinai, these changes may also be adaptations that promote resilience.
“Sometimes the biological changes in response to trauma or intergenerational trauma are there to help deal with the problem of trauma, not compound its effects,” Yehuda said. “The survival advantage of this form of intergenerational transmission depends in large part on the environment encountered by the offspring themselves.”
Yehuda described this phenomenon as a paradox.
“Parental or ancestral trauma may heighten vulnerability to mental health challenges, but epigenetic adaptations may simultaneously facilitate coping mechanisms,” she said. “Trauma increases susceptibility for psychological distress, but also produces adaptations that help us cope with them.”
Yehuda described research she and her colleagues have conducted to tease out how trauma in parents can affect offspring in the context of the biology of posttraumatic stress disorder (PTSD) in Holocaust survivors and their children. As the research unfolded, Yehuda and colleagues found that survivors’ adult children were more likely to have mood disorders, anxiety disorders, and PTSD than Jewish people whose parents did not directly experience the Holocaust. This was especially true of children of Holocaust survivors who had PTSD. The researchers also found that many children of Holocaust survivors had low levels of the stress hormone cortisol, particularly if their parents had PTSD.
Yehuda and colleagues then conducted a series of studies that looked at the role of glucocorticoid receptors — the proteins to which cortisol must bind to exert its effects — and found evidence that these receptors were more sensitive in people with PTSD.
“In practical terms this means that even though someone with PTSD might have lower circulating levels of cortisol in their blood, their cells might react more strongly to the cortisol that is present,” Yehuda said.
Yehuda said that epigenetics provided further insight on the relationship between hypersensitive glucocorticoid receptors, cortisol, and PTSD. She explained the potential role of methylation, which is a chemical reaction in the body in which a small molecule called a methyl group gets added to DNA or DNA-associated proteins.
“Increased methylation generally impedes RNA transcription, whereas less methylation enhances gene expression,” Yehuda said.
In 2015, Yehuda and colleagues conducted a study involving combat veterans who had PTSD and found lower methylation on an important region on the participants’ glucocorticoid receptor gene. The changes were associated with cortisol and glucocorticoid receptor sensitivity in the study participants, suggesting a potential epigenetic explanation for the association between the trauma of combat and PTSD.
Yehuda said that stress-related epigenetic changes may be reversible. For example, one of the studies conducted by her team revealed that combat veterans with PTSD who benefited from cognitive-behavioral psychotherapy showed treatment-induced changes in the methylation of a gene that regulates glucocorticoid receptor sensitivity. Yehuda said that this finding confirmed that healing is also reflected in epigenetic change.
“That we can transform to meet environmental challenge is a superpower. That is resilience,” Yehuda said.” ?
Yehuda then went on to describe the striking and lasting effects of the psychedelics psilocybin and MDMA in trauma and in helping patients confront their fears in a positive and hopeful fashion. These agents which are given with intensive psychotherapeutic support are not yet FDA approved, but preliminary data suggest that they can have dramatic therapeutic effects in trauma and depression. They can help patients change their attitudes to themselves and the world.
Lumateperone Normalizes Pathological Levels of Acute Inflammation and Stimulates Important Pathways Involved in Mood Regulation
Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego
Sophie Dutheil of Intra-Cellular Therapies, Inc. reported that “In male and female C57BL/6 mice subjected to an acute stress or immune challenge, lumateperone reduced elevated levels of key proinflammatory cytokines. A number of key genes and pathways associated with the maintenance of tissue integrity and blood-brain barrier function were also altered by a single dose of lumateperone. Furthermore, we found that lumateperone administration conferred anxiolytic- and antianhedonic-like properties while enhancing the mTORC1 signaling pathway in the PFC.”
Study in Mice Suggests that Compound in Turmeric May Reduce Anxiety and Promote Resilience to Stress
Chronic stress is a risk factor for the development of mood and anxiety disorders. Researchers have begun to focus on how to promote resilience to stress. Curcumin is a micronutrient found in turmeric that has anti-inflammatory and antidepressant effects and may promote such resilience.
Researchers studying human depression often design studies to see how mice with chronic social defeat stress respond to various interventions. Mice who are repeatedly menaced by a larger mouse begin to show symptoms that resemble human depression, such as social avoidance, lack of interest in saccharin compared to plain water (a stand-in for loss of enjoyment or anhedonia in humans), and anxiety.
In a 2018 article in the journal Neuropsychopharmacology, researcher Antonio V. Aubry and colleagues described the effects of curcumin on mice undergoing chronic social defeat stress. Mice who were given a diet that consisted of 1.5% curcumin showed a 4.5-fold increase in resilience to social defeat stress, measured by their performance during a test of social interaction. Among the 129 mice in the study, 64% showed the increase in resilience, the remaining 36% did not respond to the curcumin diet and had the normal ‘depressed’ response. The mice who responded well to curcumin released less of the stress hormone corticosterone, and they also had lower levels of the inflammatory marker IL-6.
All of the mice on the curcumin diet showed reduced anxiety during tests that forced them to travel through open spaces (when they prefer to stay in more enclosed spaces or move along the edges of an enclosure).
Chronic Fatigue Linked to Low Metabolism
A 2016 article in the journal PNAS suggests that people with chronic fatigue syndrome, also known as myalgic encephalopathy, share a low metabolic profile.
In the study, researcher Robert K. Naviaux and colleagues measured 612 different metabolites in 63 metabolic pathways. They found abnormalities in 20 of these pathways in people with chronic fatigue. Eighty percent of the abnormal measurements were low.
The low metabolic profile resembled a stage of development some worm larvae go through when environmental conditions are harsh. The phase, called dauer, can be brought on by harsh temperatures, low food supply, or pheromones that indicate high population density. It resembles hibernation in some ways, including changes to mitochondrial function. Dauer allows larvae to live for 4 months rather than their normal lifespan of 3 weeks. They can resume normal development when conditions improve.
The authors suggest that chronic fatigue is a metabolic response to environmental stress, and hope to clarify the link between mitochondrial function and the illness.
Immune Response to Repeated Stress Alters Behavior in Mice
In research presented at the 2016 meeting of the Society of Biological Psychiatry, Jonathan P. Godbout described how an immune reaction to repeated stressors may lead to anxious behaviors in mice.
Mice were repeatedly defeated by a larger animal, a form of stress that produces a depression-like state. This provoked an immune response in the mice—the release of a type of white blood cells called monocytes from the bone marrow into the circulatory system. These inflammatory monocytes then traveled to the brain and spleen, attracted by signaling proteins called chemokines. The monocytes in turn produced inflammatory marker interleukin-1beta.
The defeat stress also provoked a reaction in the central nervous system, where microglia were activated.
These changes produced inflammation and anxiety-like behaviors in the mice. Blocking the microglial activation, monocyte recruitment to the brain, or interleukin-1beta signaling each reversed the anxiety-like behaviors.
Another researcher, Scott Russo, has shown that leukocytes, another type of white blood cells, secrete inflammatory interleukin-6 following defeat stress, and blocking this secretion prevents defeat stress–related behaviors.
How Stress Triggers Inflammation and Depression
Depression and bipolar disorder are associated with increases in markers of inflammation that can be found in the brain and blood. It is increasingly clear that the mechanisms that cause depression are not just in the brain, but actually throughout the body. These include two signaling systems that begin in the bone marrow and the spleen.
When a small mouse is repeated defeated by a larger animal, they show depression-like symptoms known as defeat stress. Animal studies have shown that stress and danger signals are perceived and relayed to the amygdala and the hypothalamus. The sympathetic nervous system releases the neurotransmitter norepinephrine into bone marrow, where stem cells are turned into activated monocytes (a type of white blood cells) that are then released into the blood. The monocytes travel to the brain, leading to the activation of more inflammatory cells.
Blocking part of this process can prevent the depression-like behaviors from occurring. If the bone marrow monocytes are blocked from entering the brain, inflammation and defeat stress behaviors like social avoidance do not occur. However, if there is a second bout of defeat stress, primed monocytes that have been stored in the spleen are released and travel to the brain, producing further increases in inflammatory cells and even more defeat stress behaviors.
If these monocytes from the spleen are blocked, the inflammation and the reaction to the new stressor do not occur.
Stress also activates lymphocytes (another type of white blood cells) to secrete the inflammatory cells Il-6. If this Il-6 secretion is inhibited, defeat stress behaviors can be prevented.
Defeat stress also leads to the release of the neurotransmitter glutamate. Some of this cascade begins in the brain, which evaluates stressors and releases IL-1 beta, another type of inflammatory cell. It slows down the production of glutamate, while IL-6 can endanger neurons and is associated with anhedonia—loss of interest in pleasurable activities. This cascade also leads to the production of another type of inflammatory cell, TNF-alpha, which has adverse effects on biochemistry, brain, and behavior.
This understanding of the role of the brain and body provides new targets for drug development. If inflammatory processes are blocked, defeat stress behaviors do not occur. Researcher Michael D. Weber and colleagues described this process in detail in the journal Neuropsychopharmacology Reviews in 2017.
Together these observations suggest that inflammatory processes in the body are crucial to the development of some stress- and inflammation-related depressive behaviors.
Early Life Stress Affects Volume of the Hippocampus
New research shows that there are crucial periods of early life in which a stressful event can reduce hippocampal volume in adolescence. In a study presented at the 2016 meeting of the Society of Biological Psychiatry, Kathryn L. Humphreys and colleagues found that children who experienced a significant stressor before age 8 had smaller hippocampi in early adolescence than children who did not have a significant stressor early in life.
The severity of the stressors that occurred when children were between the ages of 0 and 2 predicted the volume of the hippocampus later in life. This was true to a lesser extent for stressful events that occurred between the ages of 3 and 5. No effect was seen for stressful events that took place between the ages of 6 and 8.
The period of sensitivity to stressful events between ages 0 and 2 and its effects on hippocampal volume could influence a variety of psychiatric outcomes in conditions such as depression and post-traumatic stress disorder (PTSD).
Amygdala Hyperactivity Linked to Family History of Depression
In new research presented at the 2016 meeting of the Society of Biological Psychiatry, researcher Tracy Barbour and colleagues revealed that youth with a family history of depression showed more amygdala activation in response to a threat than people without a family history of depression. This amygdala hyperactivity was linked to low resilience to stress and predicted worsening depressive symptoms over the following year.
In the study, 72 non-depressed youth were shown images of cars or human faces or cars that seemed to loom in a threatening way. Brain scans showed increased amygdala activity in participants with a family history of depression compared to those without such a history.
The amygdala is an almond-shaped part of the brain in the temporal lobe that has been linked to emotional reactions and memory, decision-making, and anxiety.
IL-6 in Blood and Bone Marrow Linked to Lack of Resilience to Stress
Rodents who are repeatedly defeated by larger animals often exhibit depression-like behaviors. In new research that researcher Georgia E. Hodes presented at the 2016 meeting of the Society of Biological Psychiatry, animals who are susceptible to these social defeat stress behaviors showed immune irregularities, including high levels of the inflammatory marker interleukin-6.
An intervention to prevent the mice from secreting interleukin-6 in blood and bone marrow took away their susceptibility to social defeat stress. When bone marrow from rodents with no interleukin-6 was transplanted into susceptible mice, the recipients showed resilience to social defeat stress. Conversely, a transplant from susceptible mice to those mice without IL-6 led to social defeat stress in the previously “immune” mice.
This research shows that the peripheral immune system, including blood and bone marrow, plays an important role in depression-like behaviors in mice.
Crack Cocaine Use and Early Life Stressors Shorten Telomeres
Telomeres are repeated DNA sequences that sit at the end of chromosomes and protect them during cell replication. Shorter telomeres are associated with aging and an increase in multiple medical and psychiatric disorders, while some healthy behaviors including exercising, eating healthy, meditating, and avoiding smoking can help maintain telomere length. Lithium treatment also increases telomere length.
Recent research by Mateus Levandowski and colleagues found that people who were dependent on crack cocaine had shorter telomeres than elderly women without psychiatric illnesses, particularly if the crack cocaine users had also experienced stress early in life, such as maltreatment or neglect.
Since short telomeres are associated with a variety of medical and psychiatric problems and premature aging, the combined effects of drug use and early life stressors are likely to have an adverse impact on people who have experienced both.
