Mice subjected to chronic defeat stress (being placed in the home cage of a larger, more aggressive mouse) behave in ways that resemble human anxiety and depression. In new research by Miles Herkenham and colleagues at the National Institute of Mental Health, in which they explored the adaptive immune system’s affect on mood, mice exposed to this type of stress showed increases in inflammatory cytokines in the blood (including TNFalpha, IL-1beta, IL-2, IL-3, IL-6, IL-17, and IFNgamma) compared to a control group. Interestingly, when white blood cells (lymphocytes) from stressed animals were transferred to a new set of animals, the recipient mice seemed to benefit from greater resilience to stress in a variety of ways.
Mice that received white blood cells from defeat-stressed animals had lower levels of TNFalpha, IL-1beta, IL-2, IL-3, and IL-17 than a control group that received white blood cells from unstressed mice. The recipient mice also exhibited reduced anxious and depressive behaviors in a litany of behavioral tests compared to both the group that received white blood cells from unstressed mice and a group that received a saline injection instead. Lastly, the recipients of the white blood cells from stressed animals showed more new neurons in the dentate gyrus of the hippocampus. (Hippocampal neurogenesis is decreased by stressors and increased by antidepressants.)
Herkenham and colleagues concluded that psychopathology is not just a downward spiral—the immune system plays an active role in adapting to stress, with lymphocytes being programmed by stress to provide antidepressant functions.
Editor’s Note: These data add a new twist to the studies of Scott Russo, who found that IL-6 secreted by white cells of animals subject to defeat stress was the cause of the depressive-like behaviors they exhibited. If IL-6 was blocked, the behaviors did not occur. Now it would appear from Herkenham’s work that something about the timing, the type of cytokines, or the transfer of the white cells conveyed protective antidepressant-like effects in this case.
Life experiences such as adversity in childhood have been linked to epigenetic changes to DNA. These changes do not affect the sequence of DNA, but can change how tightly DNA is wound, and thus how easily it is transcribed. One epigenetic change that can occur following adversity in childhood is methylation of the gene for the glucocorticoid receptor (NR3C1). A recent study by Kathryn Ridout and colleagues examined links between early adversity, methylation of this gene, and behavioral problems in childhood. Adversity was linked to methylation of the gene at exons 1D and 1F in the promoter of NR3C1. Methylation of the gene was associated with internalizing behaviors (e.g. depression, anxiety) but not externalizing behaviors (e.g. attention deficit hyperactivity disorder (ADHD) or oppositional defiant disorder) in children of preschool age. The NR3C1 methylation was a significant mediator of the internalizing behaviors in children who had experienced adversity.
Editor’s Note: Similar associations of methylation of the glucocorticoid receptor with childhood adversity have been reported in other clinical and animal studies and provide a mechanism for the long-lasting adverse effects of stressors in childhood.
Events like surgery or heart attacks that cause inflammation can lead to cognitive deficits or depression for months or years afterward, even though the direct effects of inflammation wear off within weeks. In a recent study, Natalie Tronson and colleagues subjected mice to surgical heart attack, sham surgery, or no operation, and observed how well they absorbed new learning eight weeks later.
Both male and female mice had impairments in fear learning following surgical heart attacks. Female mice that received sham surgery also showed deficits in fear learning. When the researchers dissected the mice, analyzing their blood and hippocampi after the eight-week period, inflammatory cytokine measures had normalized as expected, but the researchers found other abnormalities.
Intracellular signaling was dysregulated, and there had been epigenetic changes in cells of the hippocampus. (Epigenetic changes refer to those that change the structure of DNA, such as how tightly it is wound, rather than its sequence. For example, the addition of acetyl groups to DNA or the histones around which it is wound.) The researchers observed increased histone acetylation and phospho-acetylation following the heart attacks.
The researchers concluded that a systemic inflammatory event, such as heart attack or surgery, can cause long-term memory impairment and changes in mood through epigenetic mechanisms. They compared the findings to those of other studies in which normal aging and memory-impairing treatments such as chemotherapy had also been associated with increases in histone acetylation or decreases in histone deacetylase activity.
Stressors in early life can contribute to the risk of developing mood disorders. Given that many treatments for mood disorders work by blocking the serotonin 5-HT transporter, Nicole Baganz and colleagues designed a study to see whether an early life stressor, in this case maternal separation, would affect immune processes that in turn affect serotonin signaling.
In this study as in many before it, mice that were removed from their mothers exhibited behaviors that resembled human anxiety and depression. They were also found to have elevated messenger RNA for several inflammatory cytokines (including IL-1beta and IL-6) in their brain and blood. Mice that had a gene for the interleukin-1 receptor (IL-1R) removed exhibited neither the depressive behavioral effects nor the changes in cytokine levels following maternal separation, showing that the IL-1R gene plays a necessary role in the signaling process that leads to this type of depression. Levels of the stress hormone corticosterone in the blood did not differ in the mice with and without the IL-1R gene.
The researchers concluded that early life stressors can cause lifelong changes in inflammatory cytokine levels in mice.
Rodents that are subjected to social defeat (being overpowered by a bigger, more aggressive animal) develop a syndrome that resembles human depression—they avoid social interaction, lose interest in sucrose, and do less exploring of new places or other animals. A recent finding showed that even witnessing the social defeat of a peer was enough to bring about the depressive behaviors. The same researchers, led by Samina Salim, recently found that young rats (aged 21–27 days) that witnessed their mother go through the trauma of social defeat showed depression-like behavior themselves as adults (at age 60 days).
The rats saw their mothers defeated by the larger rat every day for seven days. As adults, those who witnessed this abuse exhibited depression-like behavior compared to rats of the same age and gender that had not witnessed abuse. The depressive rats gave up more quickly on a test of forced swimming. Male rats showed great depression-like behavior than female rats.
It has been estimated by the American Psychological Association that 15.5 million children in the US witness physical or emotional abuse of a parent (usually their mother). Children who witness domestic violence often show symptoms of post-traumatic stress disorder (PTSD). This rodent research may lead to a better understanding of the consequences of witnessing trauma in childhood, and potential treatments that could help.
Editor’s Note: These data show that rats have something like empathy, and that the psychological aspects of stress (including verbal abuse in humans and witnessing another’s abuse in rodents) may have profound and lasting consequences on behavior.
Mild Traumatic Brain Injury and Deployment Associated with Inflammatory Abnormalities in Veterans of the Iraq and Afghanistan Wars
Mild traumatic brain injury from improvised explosive devices is an injury particular to veterans of the wars in Iraq and Afghanistan. As has been seen in some athletes who sustain repeated mild traumatic brain injuries, such as boxers and football players, neurodegenerative dementias such as chronic traumatic encephalopathy can follow these repeated brain injuries. Researchers are hoping to identify biomarkers that would help in the diagnosis and monitoring of repeated blast-induced mild traumatic brain injury. Researcher Elaine Peskind and colleagues have determined that both deployment to these wars and mild traumatic brain injuries received there are associated with increased inflammatory cytokines in cerebrospinal fluid.
In the study, veterans who had been deployed to Iraq or Afghanistan and had received mild traumatic brain injuries were compared to veterans who were deployed but who were not similarly injured and community participants who had neither been deployed nor experienced a brain injury. The average number of concussion-inducing blasts veterans in the first group had experienced was 14, with the latest occurring an average of four years prior to the study.
Inflammatory cytokine IL-7 was elevated in the spinal fluid of those veterans who had sustained brain injuries. IL-6 was higher both in those deployed and in those who sustained blasts. Eotaxin and granulocyte colony stimulating factor were higher in all of the veterans who had been deployed.
These cytokine abnormalities could account for behavior and cognitive difficulties associated with traumatic brain injury. The researchers concluded that both deployment and mild traumatic brain injury were associated with neural damage and neuroimmune responses.
Editor’s Note: Michael E. Hoffer et al. reported in the journal PLosOne in 2013 that veterans with blast-induced mild traumatic brain injury had a better acute outcome when they were given the antioxidant N-acetylcysteine (NAC) within the first 24 hours after the trauma. It is interesting to speculate whether this could be explained by NAC’s anti-inflammatory effects, its enhancement of another antioxidant (glutathione), or its ability to increase glial glutamate transporters.
Researcher Dewleen Baker reported in a personal communication to this editor (Robert Post) that in her patients, traumatic brain injury was also associated with white matter abnormalities, and that these injuries conveyed an increased risk of developing PTSD as well.
Telomeres sit at the end of DNA strands and shorten with each 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, avoiding smoking, and even being married can help maintain telomere length. New data from researcher Elizabeth Hoge and colleagues suggests that a particular type of meditation can lengthen telomeres.
Previous research has found that three months of full-time meditation increased telomerase, an enzyme that repairs telomeres. Loving-Kindness meditation, which comes from the Vipassana Buddhist tradition and focuses on positive intentions, unselfish kindess, and warmth towards all people, has been found to produce positive effects in individuals who practice it, including increasing positive emotions and sense of purpose, and bringing about improvement in physical symptoms including headaches, nasal congestion, and weakness. Hoge and colleagues hypothesized that people who practice Loving-Kindness meditation would have longer telomeres than control participants of the same age, gender, education level, and experience of depression.
Participants who practiced Loving-Kindness meditation had been doing so near-daily for at least four years, and averaged 512 lifetime hours of this particular type of meditation, and 4,927 lifetime hours of any type of meditation.
The researchers found a trend toward longer relative telomere length in the Loving-Kindess meditation group compared to the control group, and significantly longer telomeres in women who meditated than in women who did not. The researchers conclude that meditation may have a positive effect on mortality.
Other habits that are focused on others, such as caring for a spouse, volunteering in the community, and practicing compassion, forgiveness, and altruism have been found to have health benefits. In a 2012 longitudinal study of elderly participants by Loren Toussaint et al. in the Journal of Behavioral Medicine, forgiveness was associated with longevity. Thaddeus W.W. Pace et al. reported in a 2009 article in Psychoneuroendocrinology that compassion meditation reduced levels of certain inflammatory markers.
Editor’s Note: People with affective disorders or at risk for them should consider making some of these positive lifestyle practices part of their daily routine.
Telomeres sit at the end of DNA strands and shorten with each cell replication. Shorter telomeres are associated with aging and an increase in multiple medical and psychiatric disorders. New research draws connections between the production of mitochondrial DNA, telomere length, the experience of childhood adversity, and mental illness.
Researcher Audrey Tyrka and colleagues divided 290 healthy adults into four categories based on whether or not they had experienced adversity in childhood and whether they had been diagnosed with a mental illness in their lifetime, including depression, anxiety, and substance abuse. The researchers also analyzed the participants’ telomere lengths and the copy number of their mitochondrial DNA. Both stressful events in childhood (such as maltreatment or the loss of a parent) and a history of mental illnesses (depression and anxiety) were associated with shorter telomeres and higher mitochondrial DNA copy numbers, a measure of cellular aging. Substance abuse was associated with higher mitochondrial DNA copy numbers.
Editor’s Note: This research replicates earlier findings that adversity is associated with shortening telomeres. The finding that mitochondrial DNA could play a role in the long-term effects of early life adversity and mental illnesses is new.
Sensory gating is a process by which the brain filters out unimportant information, to avoid flooding higher cortical centers with irrelevant stimuli. New research from Randal Ross and colleagues shows that infants of mothers with anxiety have deficits in the way their brains inhibit response to this type of irrelevant information.
Mothers who were rated higher on the trait of anxiety had paradoxically lower levels of the inflammatory cytokine interleukin 6 at week 16 of their pregnancy, and their one-month-old infants showed more deficits in sensory gating. The reasons for these relationships requires further investigation.
Choline is a nutrient found in liver, muscle meats, fish, nuts, and eggs, and it may help. In a 2013 article in the American Journal of Psychiatry, Ross and colleagues showed that the supplement phosphatidylcholine (which converts to choline), taken during the second and third trimesters of pregnancy (at doses of 6300 mg/day, the equivalent of about three eggs) and followed up with 700 mg/day in the infant, led to improvements in sensory gating in the infants. These infants went on to have fewer behavioral problems as toddlers.
Ross and colleagues suggest that pre- and post-natal choline supplementation may be able to reverse the effects of maternal anxiety on infants. The researchers believe it could be helpful in the prevention of schizophrenia, as insufficient cerebral inhibition (decreased sensory gating) is a characteristic of that illness as well.
Depression is common following heart attacks, and it can complicate recovery. A recent study by Jae-Min Kim and colleagues investigated the safety of treating depression with escitalopram in people recovering from acute coronary syndrome. In a 2015 article in the Journal of Clinical Psychiatry, they reported that 217 people with depression and acute coronary syndrome were randomized to receive either escitalopram (in flexible doses ranging from 5–20 mg/day) or placebo for 24 weeks. Patients who received escitalopram saw more improvement in their depression on a variety of scales, and also showed improvements in social and occupational functioning. There were no adverse cardiac effects from escitalopram, though some people taking it did experience dizziness.