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.
Oxytocin, the hormone that promotes emotional bonding, also regulates a variety of behaviors. Two recent studies suggest that in rats, an injection of oxytocin can prevent drug-seeking behavior.
In the first study, researcher Gary Aston-Jones found that oxytocin reduced the rats’ interest in methamphetamine. The effect was strongest in the rats that started out with the strongest interest in the methamphetamine.
In the second study, researcher Luyi Zhou and colleagues determined that oxytocin also reduced cocaine-seeking behavior in rats. In addition, the oxytocin reversed changes in the brain’s glutamate signaling pathway that were caused by cocaine use.
Both studies, which were presented at the 2016 meeting of the Society of Biological Psychiatry, suggest that oxytocin is a promising potential treatment for drug addictions.
In the study, published by Jesse D. Eclarinel and colleagues in The FASEB Journal, pregnant mother rats were placed in cages that each contained an exercise wheel. One group had access to a working wheel on which they could run. The other group had the same wheel, but it was locked so that they couldn’t use it for running. Daughters of the rats who ran during pregnancy ran more in adulthood (both at 60 days and 300 days after birth) than daughters of the rats who couldn’t run during pregnancy.
While it is a mystery why this occurs, it is consistent with other data about the ways that a parent’s experiences can influence the next generation, even when the offspring don’t grow up with the parents.
For example, father rats conditioned to associate a specific smell with fear of an electric shock have offspring that also fear that smell (but not other smells).
Drug use is another example. Father rats given access to cocaine have offspring that are less interested in cocaine. Interestingly, father rats exposed to marijuana have offspring that are more interested in opiates.
Experiences with drugs or stress are thought to affect the next generation via ‘epigenetic’ marks on ova or sperm. These marks change the way DNA is packaged, with long-lasting effects on behavior and chemistry. Most marks from a mother’s or father’s experiences are erased at the time of conception, but some persist and affect the next generation.
The nature versus nurture debate is getting more and more complicated. Parents can influence offspring in a number of ways: 1) genetics; 2) epigenetics in the absence of contact between parent and offspring after birth; 3) epigenetic effects of behavioral contact—that is, parents’ caring and warmth versus abuse and neglect can affect offspring’s DNA expression too. All these are in addition to any purely behavioral influence a parent may have on their offspring via discipline, teaching, being a role model, etc.
Editor’s Note: The moral of the story is, choose your parents wisely, or behave wisely if you yourself become a parent.
Patients with bipolar disorder often show increases in signs of inflammation, including levels of the proteins IL-2, IL-4, Il-6, IL-10 and tumor necrosis factor in their blood. Lithium is the most effective treatment for bipolar disorder, but it is not yet clear how it works. A recent study by researcher Joao de Quevado and colleagues determined that lithium can reduce the same inflammatory markers in rats.
Rats were treated with amphetamine to induce mania-like behavior, which was accompanied by increases in some of the same inflammatory markers in the blood and brain that are increased in people with bipolar disorder. Lithium treatment reduced both the manic behavior and levels of these inflammatory proteins in the rats.
The researchers concluded that lithium may treat mania by reducing inflammation.
Stress is a risk factor for depression and other mental health disorders. Researchers are currently working to clarify how stress leads to depression, anxiety, and post-traumatic stress disorder, and why trauma early in life has lasting consequences.
Two recent studies in mice examined whether just witnessing a stressful event leads to depression-like behaviors. In one, adult female mice watched a male mouse as it was repeatedly attacked by a larger mouse. After ten days of this, the female mice were socially withdrawn, had lost interest in drinking sucrose, and gave up more easily during a physical challenge. They also lost weight and showed higher levels of the stress hormone corticosterone in their blood. The researchers, led by Sergio Iniguez, believe their study clarifies how witnessing traumatic events can lead to stress-induced mood disorders.
In the other study, by Carlos Bolanos-Guzman, adolescent male mice witnessed another mouse being attacked. Both the mice that went through the physical stress of being attacked and the mice that went through the emotional stress of watching the attacks occur showed similar depressive behaviors to the mice in the previous study—social withdrawal, loss of interest in sucrose, decreased food intake and exploration of the environment, and decreased motivation in physical challenges. These behaviors persisted into adulthood. Both groups of mice also had increased levels of corticosterone and reduced expression of a particular protein in the ventral tegmental area, a part of the brain linked to stress response. Bolanos-Guzman suggests that both physical and emotional stress have lifelong consequences in mice.
The studies were presented at a scientific meeting in December.
Stress increases the risk of psychiatric illnesses such as major depression and post-traumatic stress disorder. Not everyone who experiences stress goes on to develop these illnesses, though. Researchers are currently trying to find out why, exploring treatments that might increase resilience and prevent mental illnesses.
Animal research is often used to study depression. Mice exposed to certain stressors behave in ways that resemble human depression—like giving up faster when they’re forced to tread water, or withdrawing from activities they once enjoyed, like eating sucrose. In a recent study by researcher Christine Denny and colleagues, mice were injected with either saline or ketamine, a rapid-acting antidepressant, and one week later they were exposed to triggers that typically produce a depressive response. Mice who received the saline injection still got depressed when, for example, they were repeatedly forced to confront a dominant mouse. But mice who received ketamine injections did better, maintaining their motivation and not showing signs of depressive behavior following the stress. The researchers concluded that ketamine may have a protective effect against stress.
Editor’s Note: These results are remarkable because ketamine’s effects are typically short-lived.
Studies of primates suggest that the amygdala plays an important role in the development of anxiety disorders. Researcher Ned Kalin suggested at the 2015 meeting of the Society of Biological Psychiatry that the pathology of anxiety begins early in life. When a child with anxiety faces uncertainty, the brain increases activity in the amygdala, the insula, and the prefrontal cortex. Children with an anxious temperament, who are sensitive to new social experiences, are at almost sevenfold risk of developing a social anxiety disorder, and later experiencing depression or substance abuse.
A study by Patrick H. Roseboom and colleagues presented at the meeting was based on the finding that corticotropin-releasing hormone (CRH) plays a role in stress and is found in the central nucleus of the amygdala (as well as in the hypothalamus). The researchers used viral vectors to increase CRH in the central nucleus of the amygdala in young rhesus monkeys, hoping to determine what impact increased CRH has on a young brain. Rhesus monkeys and humans share similar genetic and neural structures that allow for complex social and emotional functioning.
Roseboom and colleagues compared the temperaments of five monkeys who received injections increasing the CRH in their amygdala region to five monkeys who received control injections. As expected, the monkeys with increased CRH showed increases in anxious temperament. Brain scans also revealed increases in metabolism not only in the central nucleus of the amygdala, but also in other parts of the brain that have been linked to anxiety, including the orbitofrontal cortex, the hippocampus, and the brainstem, in the affected monkeys. The degree of increase in amygdala metabolism was directly proportional to the increase in anxious temperament in the monkeys, further linking CRH’s effects in the amygdala to anxiety.
Telomeres are repeated DNA sequences that sit at the end of chromosomes and protect them during cell replication. Telomeres get shorter with aging and with stressors or psychiatric illnesses. Researcher Alexandre Mathe and colleagues recently found that in a line of rats bred to be more susceptible to stress and depression-like behavior, hippocampal telomeres were shorter than in normal rats or rats bred to be less susceptible. The susceptible rats also had lower levels of enzymes that maintain telomere length. Both telomerase activity and Tert (telomerase reverse transcriptase) expression were reduced in the susceptible rat compared to the other rats. However, lithium reversed the low levels of telomerase activity and Tert expression.
Editor’s Note: Lithium increases hippocampal volume in people, and also increases human telomerase. Researcher Lina Martinsson reported in 2013 that lithium increases telomere length in white cells. Now lithium has increased hippocampal telomerase in a rat model of depression. Short telomeres are associated with aging and increased vulnerability to a wide range of medical and psychiatric disorders. Since people with bipolar disorder are prone to memory problems, medical problems, and short telomeres, they might want to talk to their physician about including lithium in their treatment regimen, if they are not already taking it.
Nicotine addiction is highly cue-dependent, meaning that certain situations or places will make smokers crave a cigarette even if they’re trying to quit. Researchers working with rodents are exploring a combination of treatments that address different behavioral and neurobiological mechanisms to reduce nicotine addiction. In a recent study by Cassandra Gipson-Reichardt and colleagues, N-acetylcysteine reduced cue-induced nicotine seeking, while varenicline reduced nicotine self-administration. Together the drugs worked better to reduce nicotine relapse than either drug on its own.
In the study, rats were trained to self-administer nicotine (with 0.02mg/kg infusions), and cues were used to reinstate nicotine seeking. The rats were treated with 10 and 30 mg/kg injections of NAC and 1 and 3 mg/kg injections of varenicline.
Relapse is associated with rapid synaptic potentiation in the reward area of the brain, the nucleus accumbens. In addition to the positive behavioral changes noted, NAC also inhibited this synaptic potentiation, limiting rapid changes in the size of spines on dendrites and reducing the ratio of AMPA to NMDA (two different compounds that mimic glutamate) in the core of the nucleus accumbens.
Editor’s Note: The combination of NAC and varenicline has not yet been studied in humans, but because both compounds are effective in reducing smoking, it is likely that this animal research on nicotine will be replicated in humans who are addicted to the nicotine in cigarettes.
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.