HDAC Inhibitor Facilitates Extinction of Fear Memories in the Reconsolidation Window

February 5, 2014 · Posted in Potential Treatments · Comment 

mouse in its hole

Unwanted recall and re-experiencing of traumatic memories is thought to be a crucial mechanism leading to the onset of post-traumatic stress disorder (PTSD). The inability to diminish (extinguish) those memories contributes to the persistence  of PTSD. A new study suggests that the extinction of fear memories can be enhanced by a drug that acts epigenetically to alter the structure of DNA and subsequent gene expression.

DNA is wound around structures called histones, and chemical changes can affect how loosely or tightly the DNA is wound. Johannes Graff et al. reported in the journal Cell in 2014 that application of a histone deacetylase (HDAC) inhibitor, which keeps acetyl groups on histones, ensuring that DNA is wrapped more loosely and is easier to activate (or transcribe), helps rodents revise both new and old fear memories after they have been actively recalled.

When a memory is actively recalled, the trace of that memory in the brain becomes more amenable to revision over the proceeding five minutes to one hour (a period known as the reconsolidation window). New learning and extinction training (to get rid of the memory) lasts much longer when it takes place during the reconsolidation window than when the same procedures are performed 6 hours later (after the reconsolidation window has closed) or if the procedures are performed in the absence of active recall of the memory (when the reconsolidation window is never opened).

We have previously described the 2013 work of Xue et al. published in the journal Science, which showed that this specific procedure could yield long-lasting extinction of a patient’s craving for cocaine or heroin, and could reduce amygdala activation (as observed via functional magnetic resonance imaging) in response to an experiment that produces conditioned fear (Agren et al. Science, 2013).

Editor’s Note: This new work by Graff et al. adds another twist.  Older long-term memories are more stable and less amenable to new learning than more recent (but still long-term) memories.  The application of an HDAC inhibitor changes this and makes even very old memories amenable to lasting revision. The HDAC inhibitor that Graff et al. used was a specific inhibitor for HDAC type II.  However, the anticonvulsant valproate (Depakote) is a potent although nonspecific HDAC inhibitor, and presumably could have the same facilitating effect as the more selective drug.

EMDR (Eye Movement Desensitization and Reprocessing), which has been widely used for the treatment of PTSD, includes active memory recall, immediately followed by an attempt to re-interpret and construct new memories of the trauma.  These elements could open the reconsolidation window. However, EMDR works less well with older memories compared to more recent traumatic memories.

The Graff et al. data would suggest that adding an HDAC inhibitor such as valproate to EMDR-like work might make it more effective in revising more remote memories. Graff et al. encourage controlled clinical trials with a type II inhibitor to confirm that their findings in rodents would generalize to humans. While awaiting such validation through controlled clinical trials, it would not be surprising if clinicians started trying out the paradigm on their own using valproate.

Epigenetic Regulation of Social Attachment: Genes May Dictate Partner Preference

January 15, 2014 · Posted in Genetics, Neurobiology · Comment 

prairie voles

Prairie voles, which form monogamous bonds for life, are often studied as a source of information about social attachment. New findings indicate that these mating choices are regulated by epigenetics.

Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Environmental events such as stress or exposure to chemicals can bring about epigenetic changes by adding or subtracting acetyl or methyl groups from strands of DNA or the histones around which it is wound.

When prairie voles mate naturally, levels of oxytocin, often thought of as the “bonding hormone,” increase in the reward area of the brain, the nucleus accumbens. When voles are given a drug that increases histone acetylation, their behavior mimics natural partner preference. The drug, known as a histone deacetylase (HDAC) inhibitor, blocks the removal of acetyl groups, and researchers Wang et al. reported in the journal Nature Neuroscience in 2013 that oxytocin levels increase in the nucleus accumbens. The voles receive the drug and mate for life, suggesting that social bonding is epigenetically regulated.

Similar epigenetic alterations may play a role in human social bonding and vulnerability to depression. Depressed mothers and their offspring have low levels of oxytocin in their blood, and maternal depression is a risk factor for depression in the offspring, as reported by Apter-Levy et al. in the American Journal of Psychiatry in 2013.

Editor’s Note: Perhaps depressed moms who show reduced physical and verbal interactions with their newborns should receive special training in holding, cuddling, cooing, and other social bonding activities that could increase their infants’ oxytocin levels and potentially also decrease their own anxiety and depression.

Types of Epigenetic Modifications

January 3, 2014 · Posted in Genetics, Theory · Comment 

DNA strandWe sometimes refer to epigenetics, a process by which the environment impacts not your inherited genes (based on the DNA nucleotides that encode amino acids to be sequenced in the production of proteins), but how easy it is to activate gene transcription or repress gene transcription.

There are various epigenetic modifications that can occur. Sometimes acetyl or methyl groups are added to DNA or the histones around which DNA is wound.

1. DNA Methylation (usually repressive)

2. Histone Methylation (usually repressive)

3. Histone Acetylation (usually activating)

4. DNA hydroxymethylation

5. Micro RNAs (si-mRNA) (repressing or activating)

6. Nucleosome remodeling by chromatin regulatory enzymes. If the histone spools around which DNA is wrapped are moved further apart, this is activating. If the histones are moved closer together, this is repressing.

Transgenerational Transmission of PTSD

January 2, 2014 · Posted in Risk Factors, Theory · Comment 

mother with newborn

At a recent scientific meeting, Rachael Yehada showed that PTSD-like traits could be passed transgenerationally. Mothers in New York City who were pregnant on September 11, 2001 and developed post-traumatic stress disorder (PTSD) produced children with low cortisol in their blood (a sign of PTSD). If the fathers had PTSD during the mother’s pregnancy, the children had high cortisol.

These gender-related findings have some parallels in studies of rodents. When a rat pup is separated from its mother for 15 minutes, the mother is overjoyed to see the pup return and licks and grooms it excessively. This maternal overprotection yields an animal with lifelong low cortisol through an epigenetic process. The glucocorticoid receptor gives a feedback message to suppress cortisol, and glucocorticoid receptors are increased in the pups’ brains because of lower methylation of the DNA promoter for glucocorticoid receptors.

If a father has PTSD, there is more methylation of the promoter for glucocorticoid receptors and less expression of them in the forebrain. There is also less feedback suppression of cortisol and the baby exhibits high cortisol.

The methylation of the glucocorticoid receptors in the offspring’s white blood cells is highly correlated (r=0.57, p<0.005, n=23) with methylation in the parent’s white blood cells.

Information from Environmental Experiences Can Be Passed on in Dad’s Sperm

December 30, 2013 · Posted in Theory · Comment 

lab mouse

Contrary to all common sense, researcher Brian Dias showed that when rats that were future fathers learned to associate an odor with a shock, this learning could be passed on to the next generation when the father mated with a female rat that had not learned the same association.

It turns out that the next generation of rat pups shows increased behavioral reactivity to the odor in a process different from the fear conditioning they might exhibit if they learned to avoid the odor through their own experiences.

Presumably, the pup is somehow programmed through an epigenetic modification of the father’s sperm to grow more neurons from the nose to the olfactory bulb that specifically react to the odor its father feared, and not to other odors. Miraculously, when the second generation pup grows up and fathers a third generation pup, the new pup also shows increased behavioral sensitivity to that specific odor. How the odor information from the first generation is represented in the fathers’ sperm and passed on to their descendants is still a complete mystery.

There are also new data that a father rat fed a diet deficient in folic acid (vitamin B9) will sire offspring with more congenital malformations. Additionally, an obese father rat fed a diet that includes extra fat calories will sire pups that become obese as adults even when fed a normal milk diet from a svelte mother before weaning and then fed a normal diet after weaning.

Mothers’ behavior usually gets most of the credit and/or blame for her children’s behavior, but now it looks like fathers’ diet or behavior (even before they have children) may have lasting consequences for their offspring.

Conditioned Fear Can Be Transmitted Transgenerationally in Rodents

December 27, 2013 · Posted in Theory · Comment 

rat and its pups

Scientists often use fear conditioning to study rodents’ learning and behavior. If a particular stimulus (such as a light, a sound, or an odor) is presented paired with the delivery of a mild shock, the animal begins to associate the stimulus with the shock and will freeze when it is presented and avoid the stimulus.

New research shows that if a pregnant rat (known as a dam) goes through fear conditioning that pairs an odor with a shock, the rat’s offspring will also avoid that odor into adolescence. Even if the pups are raised by a different mother who never went through the fear conditioning, they still avoid the odor into adolescence, showing that they do not learn the behavior through watching their mother.

The conditioning is specific to the particular odor, such that a different odor not used in the fear conditioning does not evoke a heightened reaction from the pups. It appears that the pup learns the fear through chemical signals, such as alarm pheromones that can pass through the placenta.

Malnutrition Early in Life Has Lasting Effects

November 25, 2013 · Posted in Risk Factors · Comment 

hungry child

Severe malnutrition in the first year of life even when corrected for the rest of a person’s life leaves a legacy of permanent cognitive deficits, marked deficits in attention, and increases in depression, conduct disorders, and medical disorders compared to carefully matched controls. Jamina Galler, a researcher at Harvard Medical School, gave a plenary talk at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry on the long-term effects of even short-term childhood malnutrition, including marasmus (calorie deficiency) and kwashiorkor (protein deficiency).

Galler’s studies followed three generations of people born in Barbados and observed the consequences of prior malnutrition, which was completely eliminated in Barbados by 1980. The consequences of malnutrition in the first year of life not only affected the first (G1) generation, but subsequently their offspring in the G2 generation who also suffered an excess of attention-deficit hyperactivity disorder, low IQ, and low annual income into adulthood. That is, the early malnutrition had transgenerational effects.

Malnutrition is a huge problem worldwide and is especially bad in sub-Saharan Africa and some parts of Asia. Globally, malnutrition accounts for 50% of the deaths of children under age five. However, even in the US hunger is a problem for one in four children, or about 16 million individuals, and the long-term consequences of hunger remain to be further studied.

Studies in animals indicate that early malnutrition has epigenetic effects that can be passed on to four future generations before they are reversed. Epigenetic effects refer to environmental factors that cannot change the sequence of DNA, but change how easily it is transcribed by adding or taking away acetyl and methyl groups on DNA and histones, the structures around which DNA is wound. Malnutrition (defined as 6–8% casein, a type of protein, in the diet instead of the normal 25%) in rodents affects cognitive abilities and blood pressure and can lead to diabetes, obesity, and other metabolic abnormalities. The next generation is also affected because a previously malnourished mother huddles too much with her offspring, and they become obese as a result of these poor parenting skills. The second generation also exhibits epigenetic changes in the prefrontal cortex (such as too few glucocorticoid receptors due to methylation of the glucocorticoid promoter) and fewer neurons in the hippocampus.

Editor’s Note: Other data indicate similar long-lasting epigenetic and transgenerational effects of other types of childhood adversity, such as verbal, physical, or sexual abuse. These findings in humans are also paralleled by findings in animals, and give strong credence to the idea that the environment can have long-lasting effects on neurobiology and behavior via epigenetic effects that can be superimposed on whatever genetic effects are inherited.

Data from this editor (Robert Post) and colleagues on verbal abuse in childhood is striking; this supposedly less severe form of abuse is still associated with a more difficult course of bipolar disorder and an increase in medical comorbidities. Thus, the experience of early abuse, even just verbal abuse, appears to have long-lasting consequences for psychiatric and medical health into adulthood.

Childhood Adversity and Epigenetic Pockmarks

August 19, 2013 · Posted in Risk Factors · Comment 

Neglected lonely childMaltreatment in childhood may have a lasting impact on health through epigenetics. Epigenetics refers to the idea that events and substances in the environment can affect the structure of DNA by adding chemicals (often methyl or acetyl groups) onto DNA and histones (structures around which DNA is wound) in such a way that the DNA is more or less likely to be transcribed and activated to produce new proteins. Thus our DNA is shaped not only by the genetic inheritance we receive from our parents, but also by events in the environment (which do not alter the sequence of DNA but can influence how easily the DNA gets turned on to produce proteins in our bodies.)

A 2013 study by Divya Mehta et al. published in the Proceedings of the National Academy of Sciences analyzed the childhood backgrounds of adult patients with PTSD and found that patients’ profiles of disease-related gene expression and DNA methylation in blood differed greatly depending on whether or not they had experienced abuse in childhood. Adults who had been abused as children were about twice as likely to show patterns of DNA methylation accompanying their PTSD-related changes in gene expression.

The implication of this research is that childhood trauma can leave a kind of epigenetic pockmark on a person’s DNA, affecting the way the DNA produces proteins, potentially for the rest of that person’s life.

Rats Exposed to Jet Fuel Pass Epigenetic Changes on to Third Generation

April 8, 2013 · Posted in Risk Factors · Comment 

rat

A recent study of rats showed that exposure to hydrocarbons (jet fuel JP-8) can bring about disease not just in the rats who were exposed, but also in subsequent generations. Epigenetics is the study of how environmental events or biochemical changes can affect the structure of DNA, e.g. by attaching extra methyl groups. (These kinds of “epimutations” are separate from the inherited genetic makeup we receive from our parents, but new evidence suggests that some can be passed on to future generations.)

When first generation female rats were exposed to jet fuel, third generation rats showed 33 different examples of DNA methylation as well as obesity.

Previous research has shown similar signs of transgenerational transmission of disease resulting from first generation exposure to chemicals such as bisphenol A, phthalates, dioxins, and pesticide mixtures.

Study of Twins Sheds Light on Epigenetic Mechanisms Implicated In Bipolar Disorder

March 26, 2013 · Posted in Risk Factors · Comment 

twins

At the 5th Biennial Conference of the International Society for Bipolar Disorders, H. Sugawara and colleagues reported on a particular example of epigenetics, an emerging field that studies ways that events and substances in the environment affect the structure of DNA. Often methyl or acetyl groups attach to DNA, making it easier or more difficult to transcribe. Sugawara’s group discussed hypermethylation of the serotonin transporter gene in bipolar disorder in an analysis of monozygotic twins discordant for bipolar disorder.

Monozygotic (identical) twins are highly concordant for bipolar disorder, meaning if one has the illness the other is likely to, but this does not occur 100% of the time. Thus, environmental or epigenetic mechanisms could account for the lack of genetic transmission of the illness in the odd cases in which one twin does not develop the illness.

Sugawara’s research group found that DNA hypermethylation of the allele encoding the serotonin transporter occurred in the twins with bipolar illness but not in those without. Once the expression of this particular gene had been identified as a difference between twins with and without bipolar disorder, the researchers examined the gene in non-twin patients with bipolar disorder compared to healthy controls and confirmed that people with bipolar disorder were more likely to have the hypermethylated allele.

The researchers believed that carrying a short form of the serotonin transporter was associated with DNA hypermethylation, and they went on to study the expression of mRNA for the transporter in bipolar patients carrying the short form of the allele. They found that DNA methylation was also higher at the serotonin transporter site in postmortem brains of bipolar patients.

Editor’s Note: This study provides one of the first insights into possible environmental mechanisms that explain why some people at risk for bipolar disorder develop the illness and others do not. Another possible mechanism for differential expression of the illness has been suggested by E.F. Torrey and colleagues, who believe that a viral infection may enter an individual’s genome and directly alter DNA sequences. The current data from Sugawara’s research group suggest the importance of further study of the serotonin transporter site in bipolar disorder and the mechanistic reasons for the DNA hypermethylation that occurs there.

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