Early Life Stressors Lead to Lifetime Increase in Inflammation in Mice

March 9, 2015 · Posted in Risk Factors · Comment 

mother mouse and pups

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.

Young Rats That Witness Maternal Abuse Show Depression-Like Behavior in Adulthood

March 5, 2015 · Posted in Risk Factors · Comment 

rat mother and baby

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.

Oxytocin Can Block Stress-Induced Relapse of Cocaine Seeking in Animals

February 23, 2015 · Posted in Comorbidities · Comment 

cocaine

Stress can trigger former drug users to begin taking drugs again. In clinical trials, the bonding hormone oxytocin has been found to reduce stress-induced cravings for certain drugs, including alcohol and marijuana. A new study in animals suggests that oxytocin may be able to reduce stress-induced cocaine cravings as well.

Brandon Bentzley and colleagues combined an unpredictable shock to the foot with an alkaloid called yohimbe that comes from a particular tree bark to apply stress to animals who had previously developed a cocaine self-administration habit that had since been extinguished. The combination of the foot shocks and yohimbe brought back robust reinstatement of the animals’ cocaine seeking behaviors, but pretreatment with oxytocin (at doses of 1 mg/kg) prevented this reinstatement.

This research suggests that oxytocin has potential to prevent stress-induced cocaine cravings in people.

HDAC Inhibitors Treat Mania-Like Symptoms in Mice

February 18, 2015 · Posted in Current Treatments · Comment 

mouse

Mice with a particular genetic mutation affecting circadian rhythms exhibit symptoms that resemble those of human mania: disruption of sleep and wake cycles, hyperactivity, and reduced anxiety and depression. It has been found that these behaviors can be normalized by inhibiting a type of enzyme called histone deacetylases (HDACs). HDACs bring about epigenetic changes to gene transcription by removing acetyl groups from histones, the structures around which DNA is wrapped. Removal of the acetyl group tightens the structure of the DNA, making it more difficult to transcribe. The drug valproate (trade name Depakote) is one type of HDAC inhibitor. It prevents the removal of the acetyl groups, loosening the structure of the DNA, making it easier to transcribe.

A recent study by Ryan Logan and colleagues compared the effects of valproate and other HDAC inhibitors on mice with a mutation in the Clock delta 19 gene, which causes mania-like symptoms. Valproate and the HDAC inhibitor SAHA both normalized the mice behavior. MS275, another HDAC inhibitor that targets only class I HDACs, also normalized the behaviors. The researchers were able to determine that all of these treatments targeted a specific class I HDAC called HDAC2, which has been implicated in schizoaffective and bipolar disorders.

These data link epigenetic mechanisms (HDAC inhibition) to the antimanic effects of valproate in this animal model of mania. It appears that maintaining the presence of acetyl groups on histones has antimanic effects in mice with a mutation in the Clock delta 19 gene.

Anti-Inflammatory Treatment Prevents the Effects of Stress in Female Rats

February 2, 2015 · Posted in Potential Treatments · Comment 

rat

Women are more likely than men to experience depression, and this difference begins in adolescence, when girls show more sensitivity to stress. Researchers are studying how animals react to stress in the hopes of learning what mediates these gender differences in mental illness.

At a recent scientific meeting, researcher Jodi Lukkes and colleagues presented a recent study of stress and inflammation in female rats. The rats were exposed to different types of stressors. Some were separated from their mothers for four hours a day during the first 20 days of their lives. Later, some rats were exposed to an acute stressor, witnessing another rat receiving shocks. All the rats were placed in a box in which they could escape a shock by jumping to the other end of the box, in order to measure their motivation. Because drugs that inhibit the inflammatory enzyme COX-2 had reversed the effects of maternal separation in earlier studies, the researchers also treated some rats with these anti-inflammatories.

The researchers found that anti-inflammatory treatment could prevent behavioral consequences of stress in adolescent female rats. Witnessing another rat being shocked brought about deficits in motivation (a depression-like behavior), but in rats that had received treatment with a COX-2 inhibitor, these deficits were reduced. The COX-2 treatment was only helpful to rats that had experienced an acute stressor in their lifetime, either maternal separation in infancy, or witnessing another rat receive the shocks. A history of stress was required for the anti-inflammatories to improve motivation.

Lukkes and colleagues hope that this research begins to clarify the relationship between stress, inflammation, and gender. This may eventually lead to new targets in the treatment of depression.

Transgenerational Transmission of Drug Exposure and Stress in Rodents

January 28, 2015 · Posted in Genetics · Comment 

baby rats

New data suggest that there can be transgenerational transmission of the effects of drug exposure and stress from a paternal rat to its offspring. The father mates with a female who was not exposed to drugs or stress and never has any contact with the offspring.  Consensus is now building that this transmission occurs via epigenetic alterations in sperm.

Epigenetic alterations are those that are mediated by chemical changes in the structure of DNA and of the histones around which DNA is wrapped. These changes do not alter the inherited gene sequences but only alter how easy it is for genes encoded in the DNA to be activated (transcribed) or suppressed (inhibited).

There are three common types of epigenetic modifications. One involves the attachment of a methyl or acetyl group to the N-terminals of histones. Methylation typically inhibits transcription while acetylation activates transcription. Histones can also be altered by the addition of other compounds. The second major type of epigenetic change is when the DNA itself is methylated. This usually results in inhibition of the transcription of genes in that area. The third epigenetic mechanism is when microRNA (miRNA) binds to active RNA and changes the degree to which proteins are synthesized.

At a recent scientific meeting, researchers described the various ways epigenetic changes can be passed on to future generations.

Researcher Chris Pierce reported that chronic cocaine administration increased brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex of rats. (BDNF is important for learning and memory.) The cocaine administration led to acetylation of the promoter for BDNF.

This exposure to cocaine in male rats who then fathered offspring led to two changes in the offspring, presumably conveyed by epigenetic changes to the fathers’ sperm. The first change was a decrease in cocaine reinforcement. The offspring took longer to acquire a cocaine self-administration habit. The second change was long-lasting learning deficits in the male offspring, specifically recognition of novel objects. The deficit was associated with a reduction in long-term potentiation in the offspring. Long-term potentiation is the strengthening of synapses that occurs through repeated patterns of activity. Surprisingly, the following generation also showed deficits in learning and memory, but did not show a loss of long-term potentiation.

Editor’s Note: These data indicate that alterations in sensitivity to cocaine (in this case slower acquisition of cocaine self-administration) can be transferred to a later generation, as can learning deficits in males. These data suggest that fathers’ experience of drugs can influence cocaine responsiveness and learning via epigenetic mechanisms likely mediated via epigenetic changes to the father’s sperm.

This research suggests the possibility that, in a human clinical situation, there would be three ways that a father’s drug abuse could affect his child’s DNA. First, there is the traditional genetic inheritance, where, for example, an increased risk for drug abuse is passed on to the child via the father’s genetic code. Next, drug abuse brings about epigenetic changes to the father’s sperm. (His genetic code remains the same, but acetyl groups attach to the BDNF promoter section of his DNA, changing how those proteins get produced.) Lastly, if the father’s drug abuse added stress to the family environment, this stress could have epigenetic effects on the child’s DNA.

Researcher Alison Rodgers described how epigenetic changes involving miRNA in paternal rats influence endocrine responsivity to stress in their offspring. Rodgers put rats under stress and observed a decrease in hormonal corticosterone response to stress. When a father rat was stressed, nine different miRNAs were altered in its sperm. To prove that this stress response could be passed on transgenerationally via miRNAs, the researchers took sperm from an unstressed father, loaded it with one or all nine miRNAs from the stressed animal, and artificially inseminated female rats. Rodgers found that the sperm containing all nine miRNAs, but not the sperm carrying one randomly selected miRNA, resulted in offspring with a blunted corticosterone response to stress.

Researcher Eric Nestler showed that when a rodent goes through 10 days of defeat stress (being defeated repeatedly by a larger animal), they begin to exhibit behaviors resembling those seen in depression. Social avoidance was the most robust change, and continued for the rest of the animal’s life. Animals did not have to be physically attacked by the bigger animal to show the depression-like effects of defeat stress. Just witnessing the repeated defeats of another rat was sufficient to produce the syndrome. Again, father rats that experienced defeat stress or witnessed it passed this susceptibility to defeat stress on to their offspring (with whom they never had any contact), likely by epigenetic changes to sperm. Read more

Lithium Extends Anti-Depressant Effects of Ketamine in Mice

January 26, 2015 · Posted in Potential Treatments · Comment 

mice getting an injection

While it can sometimes take weeks for the effects of antidepressant treatments to appear, intravenous ketamine can produce antidepressant effects in as little as two hours. However, ketamine’s effects fade after three to five days. New animal research by Chi-Tso Chiu et al. explores whether adding lithium to ketamine treatment can produce more sustained antidepressant effects.

Mice who are restrained by being placed in a tube for several hours (chronic restraint stress) exhibit a behavioral and neurochemical profile that resembles human depression. When Chiu and colleagues pretreated these stressed mice with sub-therapeutic doses of lithium (600 mg/L) in their drinking water for several weeks, a sub-therapeutic dose of ketamine (2.5 mg/kg of body weight) was enough to produce robust antidepressant effects in the mice, while neither drug alone was effective at these doses.

The combination of ketamine and lithium also restored the density of spines on the dendrites of neurons in the medial prefrontal cortex. Post-treatment with lithium (1200 mg/L) for several weeks was also successful in extending the effects of a single (50 mg/kg) ketamine injection.

Both lithium and ketamine affect the intracellular signaling pathway mTOR. Ketamine activates the pathway, increasing levels of synaptic proteins and dendritic spine density. It also increases brain-derived neurotrophic factor (BDNF) and the BDNF receptor TrkB. BDNF is important for learning and memory.

When lithium was added to the treatment of the mice with ketamine, the mTOR and BNDF pathways were further activated. Lithium also inhibits the receptor GSK-3, supporting ketamine’s rapid-acting antidepressant effects.

Ketamine treatment can produce oxidative stress, in which toxic free radicals can endanger cells, and the addition of low doses of lithium also completely prevented this neurochemical side effect.

Chiu and colleagues hope that the findings of this study in mice can eventually be applied to research in humans in the hopes of finding a clinical option that would sustain the rapid-onset antidepressant effects of ketamine for the long term.

Methamphetamine Kills Dopamine Neurons in the Midbrain of Mice

December 29, 2014 · Posted in Risk Factors · Comment 

rat

Epidemiological studies have linked methamphetamine use to risk of Parkinson’s disease, and animal studies of the illicit drug have shown that it harms dopamine neurons. A 2014 study by Sara Ares-Santos et al. in the journal Neuropsychopharmacology compared the effects of repeated low or medium doses to those of a single high dose on mice. Loss of dopaminergic terminals, where dopamine is released, was greatest after three injections of 10mg/kg given at three-hour intervals, followed by three injections of 5 mg/kg at three-hour intervals, and a one-time dose of 30mg/kg. All of the dosages produced similar rates of degeneration of dopamine neurons via necrosis (cell destruction) and apoptosis (cell suicide) in the substantia nigra pars compacta (the part of the brain that degenerates in Parkinson’s disease) and the striatum.

Antidepressants and Ketamine Reverse Animal Models of Anhedonia and Learned Helplessness

October 20, 2014 · Posted in Neurobiology · Comment 

rat

Researcher Tony Pitts presented a study at the 2014 meeting of the International College of Neuropsychopharmacology (CINP) that described the neurobiology of an animal model of depression in rodents. In animal models, researchers provoke depression-like symptoms in animals with the hopes of finding neurobiological clues to human depression. Pitts’ studies explored the effects of acute stressors as well as more chronic long-term stressors such as learned helplessness.

In the rodents, acute stressors caused increased cell firing in the hippocampus, which caused increases in burst firing and an increase in the number of cells firing in the ventral tegmental area, which then led to increased activity in the nucleus accumbens (the brain’s reward center). However, after the stressor was over, there was an opponent process that resulted in a much more prolonged period of inhibition in the nucleus accumbens, with associated decreases in psychomotor activity and reward seeking. The rodents lost their preference for sucrose and engaged in less intracranial self-stimulation, pressing a bar to stimulate the brain pleasurably. These and other effects suggest an analogy to anhedonia (loss of pleasure in activities that were previously enjoyed), which is a key component of human depression.

In related studies, after experiencing periods of inescapable shocks, rodents developed learned helplessness, failing to avoid the area where shocks were delivered even when an exit was readily available. Rodents who had learned helplessness showed inhibited firing of cells in the ventral tegmental area, less activity in the nucleus accumbens, and apparent anhedonia. This inhibition was mediated via messages from the infralimbic prefrontal cortex (the equivalent to the subgenual cingulate cortex in humans, important for motivation) to the amygdala and then the GABAergic ventral pallidum, which decreased the number of dopaminergic cells firing in the ventral tegmental area. Blocking the amygdala input to this inhibitory pathway reversed the low dopamine firing and the anhedonia-like behaviors.

The anesthetic ketamine (which has rapid-acting antidepressant effects in humans) produces an immediate reversal of the learned helpless behavior in the rodents and increases the number of dopamine cells firing in the ventral tegmental area. Ketamine administered directly into the nucleus accumbens induces long-term potentiation (enhanced synaptic responsivity) and reverses helpless behavior and the long-term depression of neural firing that is associated with it.

Thus, when an acute stressor is over and the opponent process emerges, or following long-term chronic stressors such as learned helplessness, the excitatory path to the ventral tegmental area is absent, while the inhibitory path to the ventral tegmental area (via the infralimbic prefrontal cortex, amygdala, and ventral pallidum) predominates. Ketamine is able to re-activate the activating pathway and increase activity in the ventral tegmental area and the nucleus accumbens, changes that are associated with the reversal of learned helplessness and anhedonia.

Editor’s Note: In the previous BNN, we reported researcher Scott Russo’s findings that input from the intralaminar nucleus of the thalamus was critical to the depression-like behaviors seen in a different animal model of depression, social defeat stress, where repeated exposure to defeat by a larger, more aggressive animal produces behaviors that resemble human depression. Here in Pitts’ research, learned helplessness is induced by inescapable shocks. Both models share the finding that firing decreases in the reward area of the brain (the nucleus accumbens). However, the key part of the brain driving the low levels of activity in the nucleus accumbens and the associated depression-like behavior appear to be different in these two different models. The intralaminar nucleus of the thalamus plays a key role in the social defeat stress model, while the infralimbic cortex and the amygdala play key roles in the learned helplessness model. These data together suggest that part of the reason depression differs from person to person may be because the illness can be driven by different brain areas as a result of different kinds of stressors.

Antidepressants and Ketamine Induce Resilience in Animals Susceptible to Depression-Like Behavior

October 14, 2014 · Posted in Neurobiology · Comment 

ratTo study depression in humans, researchers look to rodents to learn more about behavior. Rodents who are repeatedly defeated by more aggressive animals often begin to exhibit behavior that resembles depression. At the 2014 meeting of the International College of Neuropsychopharmacology (CINP), researcher Andre Der-Avakian reported that in a recent study, repeated experiences of social defeat led to depressive behavior in a subgroup of animals (which he calls susceptible), but not in others (which he calls resilient). Among many biological differences, the resilient animals showed increases in neurogenesis in the dentate gyrus of the hippocampus.

Chronic treatment of the susceptible animals with the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine or the tricyclic antidepressant desipramine, which both increase neurogenesis, also reversed the depressive behavior in about half of the animals. A single injection of the anesthetic ketamine (which has rapid-acting antidepressant effects in humans) reversed social avoidance behavior in about 25% of the animals. One depression-like symptom was anhedonia (loss of pleasure from previously enjoyed activities), which researchers measured by observing to what extent the animals engaged in intracranial self-stimulation, pressing a bar to stimulate the brain pleasurably. The effectiveness of the drugs in inducing resilient behavior was related to the degree of anhedonia seen in the animals. The drugs worked less well in the more anhedonic animals (those who gave up the intracranial stimulation more easily, indicating that they experienced less reward from it.)

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