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Epigenetics and serotonin (amygdala threat response)?

Epigenetics and serotonin (amygdala threat response)?


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In this article it states that:

Increased promoter methylation of the serotonin transporter gene predicted increased threat related amygdala activity.

I'm finding this somewhat difficult to understand. Increased promoter methylation would imply that the serotonin transporter gene is less expressed, so less serotonin is taken up by the presynaptic neuron, leading to increased serotonin levels in the synaptic cleft. Surely the increased serotonin levels would lead to decreased amygdala response to threat? After all, selective serotonin reputable inhibitors (SSRIs) are used to treat anxiety disorders and depression by reducing uptake of serotonin and increasing serotonin levels as well.

It seems like these two are suggesting two contrasting effects for the same cause? Have I misunderstood something?


From my limited understanding…

First off, you're definitely interpreting this correctly. The authors note:

[… ] methylation of the proximal promoter of human SLC6A4 predicts threat-related amygdala reactivity, possibly reflecting decreased serotonin transporter gene expression and, consequently, reduced regional serotonin reuptake.

However, it's definitely true that increased serotonin signaling is associated with increased amygdala reactivity (e.g., Fakra et al., 2009).

Moreover, SSRI administration in neurotic (Simplicio et al., 2013) and healthy (Bigos et al., 2008) adults seems to initially increase amydgala reactivity to threatening faces. Simplicio et al. interpret this as facilitating "a process of decreasing emotional avoidance," which would be adaptive in the long-term through greater exposure (and habituation to) "benign 'threat' cues" like faces.

Both Fakra et al. (2009) and Bigos et al. (2008) suggest that acute effects of increased 5HT on amygdala reactivity may have to do with delayed effects on prefrontal cortex, which would otherwise exhibit control over amygdala reactivity. More specifically, Bigos et al. argue:

While acute 5-HT reuptake blockade may potentiate stimulus-dependent amygdala reactivity, likely through stimulation of excitatory postsynaptic 5-HT receptors located on apical dendrites of glutamatergic neurons (McDonald and Mascagni, 2007), chronic blockade may lead to a more general increase in 5-HT neurotransmission via downregulation of negative feedback 5-HT autoreceptors (Blier and de Montigny, 1999). This shift toward generally increased neurotransmission after chronic reuptake blockade may allow 5-HT to potentiate the response of pyramidal neurons in prefrontal circuits, via volume transmission at excitatory 5-HT receptors localized extrasynaptically (Jansson et al, 2001; Sharp et al, 2007), thereby mediating top-down regulation of the amygdala (Hariri and Holmes, 2006).

So SSRIs might have long-term adaptive consequences via effects on prefrontal cortex, otherwise not seen acutely.


Sounding the alarm

The stress response begins in the brain (see illustration). When someone confronts an oncoming car or other danger, the eyes or ears (or both) send the information to the amygdala, an area of the brain that contributes to emotional processing. The amygdala interprets the images and sounds. When it perceives danger, it instantly sends a distress signal to the hypothalamus.

Command center

When someone experiences a stressful event, the amygdala, an area of the brain that contributes to emotional processing, sends a distress signal to the hypothalamus. This area of the brain functions like a command center, communicating with the rest of the body through the nervous system so that the person has the energy to fight or flee.

The hypothalamus is a bit like a command center. This area of the brain communicates with the rest of the body through the autonomic nervous system, which controls such involuntary body functions as breathing, blood pressure, heartbeat, and the dilation or constriction of key blood vessels and small airways in the lungs called bronchioles. The autonomic nervous system has two components, the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system functions like a gas pedal in a car. It triggers the fight-or-flight response, providing the body with a burst of energy so that it can respond to perceived dangers. The parasympathetic nervous system acts like a brake. It promotes the "rest and digest" response that calms the body down after the danger has passed.

After the amygdala sends a distress signal, the hypothalamus activates the sympathetic nervous system by sending signals through the autonomic nerves to the adrenal glands. These glands respond by pumping the hormone epinephrine (also known as adrenaline) into the bloodstream. As epinephrine circulates through the body, it brings on a number of physiological changes. The heart beats faster than normal, pushing blood to the muscles, heart, and other vital organs. Pulse rate and blood pressure go up. The person undergoing these changes also starts to breathe more rapidly. Small airways in the lungs open wide. This way, the lungs can take in as much oxygen as possible with each breath. Extra oxygen is sent to the brain, increasing alertness. Sight, hearing, and other senses become sharper. Meanwhile, epinephrine triggers the release of blood sugar (glucose) and fats from temporary storage sites in the body. These nutrients flood into the bloodstream, supplying energy to all parts of the body.

All of these changes happen so quickly that people aren't aware of them. In fact, the wiring is so efficient that the amygdala and hypothalamus start this cascade even before the brain's visual centers have had a chance to fully process what is happening. That's why people are able to jump out of the path of an oncoming car even before they think about what they are doing.

As the initial surge of epinephrine subsides, the hypothalamus activates the second component of the stress response system — known as the HPA axis. This network consists of the hypothalamus, the pituitary gland, and the adrenal glands.

The HPA axis relies on a series of hormonal signals to keep the sympathetic nervous system — the "gas pedal" — pressed down. If the brain continues to perceive something as dangerous, the hypothalamus releases corticotropin-releasing hormone (CRH), which travels to the pituitary gland, triggering the release of adrenocorticotropic hormone (ACTH). This hormone travels to the adrenal glands, prompting them to release cortisol. The body thus stays revved up and on high alert. When the threat passes, cortisol levels fall. The parasympathetic nervous system — the "brake" — then dampens the stress response.


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Keywords: epigenetics (MeSH), work stress, daily life stress, socioeconomic status (MeSH), susceptibility, resilience (psychological), candidate risk variants, epigenome wide association

Citation: Gottschalk MG, Domschke K and Schiele MA (2020) Epigenetics Underlying Susceptibility and Resilience Relating to Daily Life Stress, Work Stress, and Socioeconomic Status. Front. Psychiatry 11:163. doi: 10.3389/fpsyt.2020.00163

Received: 06 November 2019 Accepted: 20 February 2020
Published: 20 March 2020.

Christine Allwang, Technical University of Munich, Germany

Livio Provenzi, Neurological Institute Foundation Casimiro Mondino (IRCCS), Italy
Michael Deuschle, Central Institute for Mental Health, Germany

Copyright © 2020 Gottschalk, Domschke and Schiele. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


Serotonin study explains why some people are more prone to anxiety

New research untangles anxiety's roots in the brain and points to improved treatment.

Anxiety is not a one size fits all experience. When faced with the same situation or stressor, some people remain calm, while others panic. Now, due to a strange new study on marmosets, researchers are one step closer to understanding why an event might cause some individual's anxiety to skyrocket while others remain chill.

According to research published Monday in the Journal of Neuroscience, trait anxiety — a general tendency to respond with anxiety to perceived threats in the environment — is tied to serotonin transporters operating in the brain’s emotion-processing center, the amygdala.

If the findings translate to humans, scientists may eventually be able to create faster and more effective anti-anxiety medications by targeting these brain regions.

People vary in their vulnerability to anxiety, and based on this research, there is a “clear neurological basis for this vulnerability,” co-author Shaun Quah, a neuroscience researcher at the University of Cambridge, tells Inverse.

“It is important for people to be more compassionate and understand that not everyone will react to the same stressor the same way some people are predisposed to be more sensitive to feelings of anxiety.”

Serotonin systems — Previous research suggests serotonin, the so-called "happy chemical," plays a pivotal role in regulating mood and contributing to mental well-being. The brain's serotonin levels are partly controlled by proteins on the surface of brain cells - the serotonin transporter. When transporter levels are high, serotonin levels are lower, Quah explains.

Common anti-anxiety and anti-depression drugs called selective serotonin reuptake inhibitors (SSRIs) target these serotonin transporters, and can sometimes successfully relieve symptoms in humans and animals. Because these oral drugs do not work for everyone, researchers — like this team — endeavor to make more effective treatments.

Previously, scientists didn't exactly know how serotonin systems in particular brain regions influence individual differences in trait anxiety.

To explore this question, researchers examined marmosets — small monkeys whose brains share “large similarities” to the human brain, Quah explains. These monkeys also show similar trait anxiety-like behavior to humans that is sensitive to SSRIs.

The team set up two experiments: In the first, researchers placed each monkey alone in a cage and exposed the animals to an unknown human wearing a mask. The human stood 40 centimeters from the cage and maintained eye contact with the monkey for two minutes.

They observed how the monkeys reacted before, during, and after encountering the human intruder. The researchers tracked how and where animals moved around the cage, shifts indicative of their level of avoidance. The team also documented if the animals bobbed their bodies or made vocalizations — behavioral shifts that indicate their level of anxiety.

The scientists used these behavioral cues to create anxiety scores for each animal. The animals with the highest anxiety scores spent the majority of their time towards the back of the cage, high up, remaining relatively still, and making head and body bobs and calls, the study reports.

Then, the researchers humanely euthanized the animals and analyzed various brain regions including the prefrontal cortex, amygdala, the dorsal anterior cingulate cortex, and raphe nuclei. They examined levels of expression for the serotonin transporter gene in these specific areas as they were involved in the brain's serotonin and emotion regulation circuit.

This revealed that monkeys with heightened reactivity (those that were the most anxious) had high levels of gene expression for serotonin transporters in their amygdala. This finding suggests serotonin signaling may be driving anxious behavior.

"As non-human primate's brains share large similarities to the human brain, our findings suggest that decreased serotonin signaling in the amygdala may, in part, underlie people's heightened reactivity to a perceived threat," Quah says.

The team conducted a second experiment to see if they could modulate this serotonin signaling. They selected six monkeys who exhibited trait anxiety. Then, they implanted thin metal tubes directly into their brains while they were under anesthesia. The team subsequently directly infused SSRI medication to the anxious monkeys' amygdalae.

Researchers then repeated the first experiment — exposed the monkeys to an unknown human and tracked their reaction. After the direct infusion, monkeys experienced immediate symptom relief and expressed reduced levels of anxiety-related behaviors.

Directly infusing SSRIs to the amygdalae caused a much faster anti-anxiety effect in the monkeys than typically seen with oral SSRI's medications. Symptom relief normally takes several weeks to appear if the drug is taken orally.

The research needs to be replicated in humans before it can be said with confidence that this version of SSRI treatment would work for people. Currently, implanting tubes specifically for anti-anxiety drug delivery into the human brain isn't a viable option, Quah says.

But these findings do suggest that targeting the amygdalae may speed up effective treatment for animals and people with trait anxiety.

"If you find yourself to be prone to feeling anxious, you should not consider it a personal failing," Quah says. "It is likely due to a natural disposition."

Quah suggests discussing methods of managing these feelings with a mental health counselor or therapist.


DISCUSSION

It should be pointed that that the aforementioned studies are faced with some limitations. Firstly, the smaller-scale sample size of the cohort warrants no well-clarified discoveries [ 78 ]. Secondly, because various variants and markers were not replicated well among independent datasets, it makes us to wonder whether the novel findings are well-evaluated [ 79 ]. Thirdly, it is crucial to probe possible variants and markers among numerous ethnic populations due to the fact that various populations may draw distinctive conclusions [ 37 ].

In order to weigh GxE interactions, future studies might take advantage of utilizing new artificial intelligence and machine learning techniques such as deep learning artificial neural network algorithms [ 80 , 81 ]. In order to assess GxE interactions, feasible artificial intelligence and machine learning algorithms encompass a wide spectrum of models such as artificial neural networks, Bayesian networks, decision trees, generative adversarial networks, support vector machines, and regression models [ 82 ]. Furthermore, future research can contribute to identify genetic and epigenetic markers by using whole genome sequencing [ 83 ] or exome sequencing [ 84 ]. Whole genome sequencing serves as an overall approach in genomic research and provides a wide variety of genetic variants in an individual subject due to the reduced cost and expanded throughput from next-generation sequencing techniques [ 85 ]. Exome sequencing, which selectively sequences the nucleotides of protein-coding exons in an individual subject, has been employed as an alternative and efficient approach for Mendelian disorders and common diseases [ 84 ]. All in all, combining whole genome sequencing or exome sequencing with innovative artificial intelligence and machine learning algorithms might likely accomplish a comprehensive understanding of GxE interactions in depression in future research.

In future work, artificial intelligence and machine learning pipelines can be used to provide a thorough validation and evaluate whether we are able to replicate the current findings in predictive and diagnostic research studies. Additionally, we should explore possible genetic and epigenetic markers by utilizing custom artificial intelligence and machine learning pipelines thereby, genetic and epigenetic networks would be interpreted at the genome level. In order to precisely understand pathogenesis and therapy in depression, future work must ultimately figure out how to integrate multiple markers and multi-omics, such as clinical data, genetics, transcriptomics, metabolomics, proteomics, epigenetics, and imaging data [ 79 ]. In additional, artificial intelligence and machine learning techniques (such as deep learning, computer vision, and natural language processing) may play a pivotal role in eliminating the false positive candidate variants and genes that were observed in the previous association studies with meta-analysis, GxE interaction analysis, epigenetic analysis, and pathway models [ 82 ]. Artificial intelligence and machine learning models involving with multi-omics data not only will achieve better results when dealing with incomplete data from any single data source, but also will bridge the gap among various phenotypes, genomic mechanisms, and biological regulation models [ 86 ]. Although forecast testing for disease status and treatment responses in depression are now nonexistent ahead of diagnosis, it is anticipated that artificial intelligence and machine learning approaches will be leveraged to predict the tendency of drug efficacy and to contribute meaningful guidance for clinicians on determining personalized medications in future research [ 87 ].


An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents

Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals.


Behavioral Epigenetics and Attachment

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&ldquo&hellipthe perception of safety is the turning point in the development of relationships&hellip&rdquo Stephen Porges, 2011

&ldquoThe reality of the functional genome does not admit to main effects of either gene or environment, but rather to a constant interaction between the DNA and its environment&rdquo Michael Meaney, 2010

Introduction

One of the hottest areas of neuroscience is the study of how life experience affects patterns of gene expression in the brain, what some call behavioral epigenetics (Weaver, 2004 McEwen, 2012). Of great relevance to therapists interested in attachment, this fast growing body of research is revealing how early life experience can channel brain development towards either social engagement or self defense. Researchers are uncovering experience-dependent effects on the development of the brain during the sensitive period for attachment-based learning in animals, work that has now been extended to humans. Furthermore, epigenetic research is exploring the potential for reversing the effects of poor parental care by altering patterns of gene expression in the brain after the sensitive period for attachment has passed (Landers and Sullivan, 2012). Clearly, this research has huge implications for the whole field of mental health.

Epigenetic Effects of Early Care On the Child&rsquos Stress Systems

Groundbreaking studies by Michael Meaney and his colleagues (Kaffman and Meaney, 2007) Meaney, 2010) laid the foundation for studying the effects of differences in the quality of early maternal care on patterns of gene expression in the brains of offspring. This seminal work showed that naturally occurring differences in the quality of maternal care within the first week of a rat pup&rsquos life trigger different patterns of gene expression in the regions of the brain that support both self defense and social engagement. Young rats who are licked a lot and nursed in a certain position show a different pattern of gene expression in their hippocampus, prefrontal cortex, and amygdala than pups who don&rsquot get as much of this &ldquoenriched&rdquo kind of stimulation. These differences in gene expression enable well cared for rats to be more social, less fearful, and faster to approach and explore new things than their less well cared for peers.

In the well licked babies, the gene for the receptor for the stress hormone, corticosterone, called the GR, is more highly expressed (or in technical terms, less methylated) in the hippocampus than it is in the less licked rats. This means that the well cared for pups acquire more GRs in their hippocampus. These hippocampal GRs are an essential component of the stress response system because they help to turn off the stress response after a stressful experience is over. In the low licked offspring, the stress response system stays active longer, facilitating self defense, but at the cost of growth and social connectedness.

Epigenetic research that began with rodent studies has since been extended both to non-human primates and to humans. Maternal licking in the rat is a form of tactile stimulation similar to grooming behavior in primates and to all forms of &ldquogood touch&rdquo in humans. Studies in humans show that certain qualities of touch activate the insula, ACC, and orbitol regions of the brain while calming the amygdala in ways that promote well being, trust, and social engagement, very much like licking does in Meaney&rsquos rat pups. While studying gene expression patterns in human brains is more difficult than it is with rodents where brain tissues from different regions can be readily examined, methods for behavioral epigenetic studies in humans are being developed.

An intriguing study by Meaney&rsquos group (McGowen et al, 2009) used postmortem brain tissue to explore patterns of gene expression associated with childhood abuse in a group of suicide victims (McGowan et al., 2009). The pattern of gene expression seen in the brains of those individuals who had experienced abuse in early childhood matched the pattern of methylation in the rat studies, showing gene suppression in the equivalent promoter region of the GR gene. In other words, the pattern of gene expression was consistent with epigenetic programming of the human brain by early life adversity.

In addition to showing that early life experiences with attachment figures activate different patterns of gene expression (and therefore, protein synthesis and brain structure) during the initial period for attachment-based learning, epigenetic research is exploring the potential for reversing early life patterns of gene suppression associated with separation, early abuse, and neglect. This research includes both environmental interventions- Environmental Enrichment- and pharmacological methods such as administration of demethylating drugs to unblock methylated promoter regions of genes in animals exposed to poor care early in life. Both types of interventions have shown some capacity to alter the effects of early life adversity on gene expression in brain regions, including the hippocampus. While epigenetic effects triggered by social experiences are strongest during the sensitive period for attachment-based learning, experience-dependent gene expression continues throughout life (Weaver et al, 2004). This exciting line of research has strong implications both for psychotherapy and psychopharmacology.

Gene Expression, Trust, and Mistrust

The social engagement and social defense systems are under development early in life and both are affected by the nature of caregiving that infants of various mammalian species receive. Epigenetic research is showing that differences in the quality of early care have differential impact on the patterns of gene expression in these two systems, channeling brain structure and functioning along different trajectories. In effect, epigenetic mechanisms by which the environment impacts brain development is nature&rsquos way of helping to ensure that the young adapt to life in the specific kind of social world they are likely to be living in. If this first &ldquoenvironment of care&rdquo is safe, the young brain will be sculpted or &ldquoprogrammed&rdquo for living in connection with other people. If the early environment exposes the young to harsh, insensitive treatment by attachment figures, the young brain will be epigenetically sculpted for surviving (and reproducing) in a world in which it is vital to be hypervigilant, slow to trust, and quick to deploy one&rsquos defenses. While both of these developmental scenarios of &ldquobiological embedding of early experience&rdquo(Hertzman,2012 ) are initially adaptive, a wealth of research on attachment formation shows that early experiences with sensitive, nurturing caregivers promotes a pattern of brain development supportive of emotional resilience, empathy, and cognitive flexibility (National Scientific Council on the Developing Child, 2008).

Children who are forced to adapt to high levels of adversity very early in life when the brain systems for social engagement and self defense are under construction are at risk for developmental stress disorders, including depression, social anxiety, and PTSD (Heim and Nemeroff, 2002). In brain terms, this means that the development of the circuit that connects the prefrontal cortex to subcortical regions, especially to the amygdala, may be compromised by over activation of the child&rsquos stress response system early in life. The development of the fronto limbic system connecting the lower regions of the prefrontal cortex, including the orbitol region and the ventral anterior cingulate cortex (ACC,) to the amgydala forms the core neural substrate for self regulation throughout the lifespan. When the initial development of this circuit is suppressed for any reason, it is more difficult later in life to regulate emotions, behavior, cognitions, and attention. As a result of these regulatory difficulties, it is harder for the individual to learn from new experiences and to change one&rsquos mind about the meaning of old experiences. Children who have to adopt an early life survival strategy of premature self reliance and defensiveness are vulnerable later in life to all kinds of health problems because of their chronic exposure to high levels of stress hormones. In the brain, chronic activation of the stress response systems can have toxic effects, especially on the hippocampus and the prefrontal cortex (McEwen, 2012), while promoting chronic hyper-activation of the amygdala.

This developmental scenario of chronic stress is a common one for children exposed to abuse and neglect early in life. Having an underdeveloped fronto limbic system biases these children towards hyper-reactivity to aspects of their environment that they perceive as threatening. This includes a strong tendency to perceive other people as untrustworthy, based on prior learning that has become the basis for habitual ways of responding to attachment figures. In common parlance, these kids are more prone to flipping their lids and either blowing up or freezing in fright when they detect signs of negative intentions or rejection, especially in other people&rsquos facial expressions and voices.

Appraising Safety and Threat: A Two Level System

The process of shifting between social engagement and defensive states depends heavily on the way we appraise the level of safety or threat posed by other people in our environment (Porges, 2011) . This appraisal process occurs on two basic levels: 1) an unconscious or implicit, ultra rapid level based heavily on the functioning of the amgydala and its ability to activate approach and avoidance responses to other people and 2) a conscious, slower appraisal system based on prefrontal regions of the brain that can modulate and inhibit the implicit, fast acting &ldquofirst pass&rdquo appraisal system. Porges calls the implicit, subcortical appraisal of safety and threat &ldquoneuroception&rdquo. The ability of the prefrontal regions to modulate the neuroceptive process typically increases with age and brain maturation into adulthood however, this process of developing a robust fronto-limbic system is also significantly affected by early life experiences with attachment figures, i.e., by epigenetic processes.

The amygdala is functional very early in life, providing infants with a rough and ready, implicit way of detecting threats in the social environment. However, nurturing, responsive parenting buffers the defensive reactions from the amygdala, in part by decreasing the release of stress hormones such as cortisol and norepinephrine while promoting the release of calming chemicals such as oxytocin in this region. Social engagement involves eye contact, the ability to read other people&rsquos facial expressions, ability to extract emotional meaning in other people&rsquos voices, ability to put emotion into one&rsquos own voice. Different types of social stimuli all pass through the amygdala early in the sequence of sensory processing in the brain. How the amygdala responds to this information biases the young child towards either social approach or social avoidance. The role of the amygdala as a switching mechanism between attachment learning and avoidance learning is beautifully described by Landers and Sullivan (2012) and there is a wealth of data that strongly indicates a similar process in humans (Caldji et al, 2003).

The amygdala is a creature of proximity in the sense that the closer something comes to us, either in space or time, the stronger the potential reaction of the amygdala, especially to something perceived as threatening or stressful. This helps to understand why mistrustful children are likely to become more defensive the closer we try to get to them. This has a lot to do neurobiologically with why some children with attachment problems often respond dramatically differently to strangers or people who are more distant from them than to attachment figures who try to come very close. The amygdala appears to be part of the brain system that monitors &ldquopersonal space&rdquo at about an arm&rsquos length from our bodies, basically treating this space as an extension of ourselves.

If a caregiver is being neglectful or causing pain, the child&rsquos amygdala starts to react to the caregiver as, in part at least, a source of pain and fear, setting up the potential for chronic conflict between approach and avoidance tendencies. The amygdala is strongly connected to the stress response system, or HPA axis, that activates the endocrine circuitry and ultimately engages the adrenal glands in producing stress hormones such as cortisol. It is also strongly connected to the brain&rsquos vigilance system that is based on the release of norepinephrine (NE) from the locus coeruleus (LC). When the amygdala detects a potential threat, it triggers the release of NE from the LC, ramping up attention to the possible threatening object or person. Through back projections to all sensory processing regions, the amygdala can intensify sensory experiences if it detects something as emotionally relevant, ramping up attention to that thing or person. Through its connections with the stress/defense systems- the HPA axis that produces stress hormones and the sympathetic and parasympathetic defense systems that support fight, flight, and freeze reactions- the amygdala can orchestrate the process of keeping the brain and body on high alert, promoting self defense over social engagement.

A number of genes are now known to be targets for epigenetic effects in the amygdala. These include GABA receptor genes, the gene for the oxytocin receptor, genes that express proteins involved in the growth of connections between the amygdala and other brain regions, and genes for CRH, the chemical that triggers the neuroendocrine stress response system. Research has begun to target the GABA system in the amygdala as an extremely important mechanism for epigenetic effects of early experience on emotional resilience and vulnerability (Cadji, Diorio, & Meaney, 2003 Diorio and Meaney, 2007).

The GABA-A Receptor in the Amygdala

In the amygdala of well cared for rats, the gene for the GABA-A receptor shows different patterns of expression than in the less well cared for peers. This is important because GABA is the main inhibitory chemical in the brain. The action of GABA in the amygdala makes it possible to modulate defensive reactivity that otherwise can set off the fight, flight, or freeze responses within milliseconds of detecting a potential threat. The amygdala specializes in avoidance learning, orchestrating the process of learning to associate social stimuli with pain, danger, or distress. By having more sensitive GABA-A receptors in their amygdala, the well licked rats have more power to &ldquoveto&rdquo output from the central region of the amygdala to the stress/defense systems.

The GABA-A receptor is composed of several different subunits and the genes for these subunits are targets for epigenetic programming by maternal care (Caldji, Diori, and Meaney, 2003). In the first week of a rats life, maternal care is associated with differences in GABA-A receptor subunit expression and these differences are intriguingly related to fearful behavior throughout the life of these animals. According to this research, &ldquothe adult offspring of high licking-grooming mothers show significantly higher levels of GABAA/Benzodiazepine receptor binding in the basolateral and central nuclei of the amygdala and the locus coeruleus. These findgings provide a mechanism for increased GABAergic inhibition of amygdala-locus coeruleus activity&rdquo (Caldji et al, 2003,p.1957).

In poorly nurtured rats, suppression of the gene for GABA-A receptor subunits in the amygdala leads to less sensitive GABA receptors, which, in turn, makes the amygdala more highly reactive to perceived threats. Also, because higher brain regions in the prefrontal cortex modulate the amygdala by activating GABA receptors in the amygdala, the lower sensitivity of the GABA system in the amygdala lessens the capacity of the prefrontal regions to inhibit amygdala reactivity.

This is a structural and functional set up for making a person more highly reactive to stress and more vulnerable to stress-induced disorders of all kinds, including PTSD, depression, and social anxiety. In essence, people with reduced GABA activity in the amygdala are more &ldquoamygdaloid&rdquo in their reactions to all kinds of stressors, meaning that they have difficulty regulating negative emotions, actions, and thoughts. These individuals are likely to have a negative reaction to novelty, being more at the mercy of their rapid appraisal system that is biased towards avoidance of new things in a seemingly &ldquobetter safe than sorry&rdquo approach to life. With less ability to inhibit the activity of the amygdala, it is harder for these people to &ldquoget above&rdquo their quick reactions to things and to other people. This makes it harder for them to change their behavior in the light of new experiences.

The Oxytocin Receptor in the Amygdala

Oxytocin (OT) plays several roles in humans and other mammals: 1) promotes social approach behavior 2) facilitates formation of social memories 3) enhances the ability to read other people&rsquos minds, facilitating empathy and &ldquomindsight&rdquo and 4) reduces stress reactivity and self defensiveness (Carter, 2007). All of these functions are made possible by the presence of the oxytocin receptor (OTR) in a wide variety of brain regions that are involved in social and emotional aspects of functioning. The gene for the OTR is a known target for epigenetic effects, meaning that early life experiences affect the level of expression of the OTR gene in the brain. Furthermore, researchers have found a significant relationship between the density of OTR receptors in key brain regions in the limbic system, and individual differences in social affiliation, empathy, and &ldquomindreading&rdquo ability in humans (Andari et al, 2010 Kumsta et al, 2013).

The amygdala is a key region of the brain for oxytocin activity at OTRs . Combining the findings from studies dealing with both animals and humans, it is clear that there is an important process of environmental tuning of the structure and functioning of the amgydala involving epigenetic effects on expression of the OTR gene in the amygdala. This research is extremely interesting in terms of understanding how good care buffers the child&rsquos stress systems and promotes the development of secure attachments and prosocial behavior. By activating the oxytocin system, sensitive parenting helps to quiet the amygdala and facilitate bonding and trust.

Based on this research, we can see how early experiences with attachment figures can promote either secure attachment based on deep safety being close to an adult or insecure attachment that depends upon a certain level of vigilance or at least ambivalence about being close to others. For children who are exposed early in life to abusive and/or neglectful attachment figures, it would be maladaptive to have a high level of gene expression of the OTR gene in the amgydala because this would promote prosocial behavior and a tendency to approach unreliable attachment figures in a trusting, relaxed manner, something which would not be very safe to do. It would be adaptive for these children if their brains produced fewer OTRs and GABA receptors, making it easier neurobiologically to &ldquoplay defense&rdquo around others.

Targeting The Neuroceptive System: An Epigenetic Model of Attachment-based Intervention

Since the amygdala is a major switching station in the brain between the social engagement system and the self defense system, it makes evolutionary sense that this region is a major target for epigenetic effects of good and poor relationships. The question for intervention then becomes what kinds of relational processes have the power to alter early patterns of gene expression in the amygdala so as to shift its functioning towards social engagement and away from reflexive defensiveness. This shifting of the neuroceptive system can be seen as the key to helping defensive children (and adults) shift from core defensiveness and mistrust towards social engagement and trust.

Reversal of Early Epigenetic Effects

The task for a model of therapeutic intervention is to determine what kinds of new experiences beyond the sensitive period for attachment formation can alter the early patterns of gene activity that supported self defensive living. In animal research, there is a line of recent research that is studying this very question, exploring the kinds of later life experiences that can shift patterns of gene expression in the direction of less defensive, more pro- social behavior. This research deals with so called Environmental Enrichment.

Environmental Enrichment and the Re Opening of Attachment-based Learning

The key to helping mistrustful children learn to trust is to somehow re-engage them in attachment learning when they have passed the sensitive period for this process. Environmental Enrichment involves creating opportunities for novel social experiences which can jiggle the brain into a state of alertness, surprise and curiosity and launch a process of renewed social learning that can alter old learning that is no longer adaptive. This involves surprising a mistrusting child with openness rather than responding in a predictably defensive way to mistrusting behavior.

Re-engaging the child&rsquos brain in new attachment-based learning requires that the child experience an immediate disparity or incongruity between the caregiver&rsquos behavior in the moment and the kind of reactions predicted by the child in a &ldquomindless&rdquo state of mistrustfulness. Novel experiences with caregivers can trigger the process of tagging brain cells for further gene expression, a process involving what are called Immediate Early Genes or IEGs. Brains are in the business of making sense of experiences by comparing new experiences to old experiences, determining rapidly if there is &ldquonews of a difference&rdquo and if so, starting a process of trying to resolve the disparity. So creating disparity, surprising the brain, presenting the brain with a mystery, would appear to be essential to altering patterns of gene expression in a therapeutic direction.

The neuroscience literature on sensitive periods and post sensitive period learning shows that different brain processes are involved during these different periods. During a sensitive period, learning is highly efficient because the brain is in a state of high arousal and receptivity, making it easy to learn simply from continued exposure to recurring experiences with an attachment figure. Sensitive periods are a time in brain development when there are high levels of neurotransmitter activity in the brain, including high levels of dopamine and serotonin and norepinephrine. This high level of arousal facilitates all kinds of learning. The sensitive period for attachment in humans is probably the time between birth and around 18 to 24 months. Once this period has passed, attachment learning probably requires intensive, highly arousing, attention-demanding experiences to re open the &ldquogate&rdquo for engaging the brain in this kind of learning and for facilitating the unlearning of old patterns of relating to unreliable caregivers. The new attachment figure has to somehow co-create with the child experiences that are novel, surprising, beyond the &ldquosame old, same old&rdquo, triggering unpredictable reactions in the child. While all kinds of learning are more difficult after a sensitive period for that type of learning has been closed, the neuroscience on sensitive periods and later life learning suggests that post sensitive period learning is quite possible given the necessary kinds of experiences and stimulation.

PACE: A Formula for Epigenetic Reprogramming of the Child&rsquos Neuroceptive System

PACE, playfulness, acceptance, curiosity, empathy,(Hughes, 2009) appears to be a formula for re engaging the child&rsquos brain in attachment based learning, based on a growing body of evidence from attachment-focused treatment around the world. From a brain based perspective, PACE can be seen as a formula for promoting the kinds of epigenetic changes in a child&rsquos brain that would facilitate the shift from defensiveness to openness. Clearly from the research described earlier, the important brain targets for these changes would be selected genes in the amygdala, the hippocampus, and the PFC. How might PACE trigger changes in gene expression in these key brain regions?

PACE has the potential to do two important things that could promote epigenetic changes in a child&rsquos brain: 1) dampen the reflexive defense system by promoting oxytocin flow into the amygdala and 2) turn on excitatory neurochemistry, especially dopamine, to support new learning, engaging what Panksepp calls the &ldquoseeking system&rdquo, a state of curiosity about the new attachment figure that reopens the child&rsquos mind to attachment-based learning.

PACE and the Amygdala: Shifting From Self Defense to Openness

A major goal of a brain based approach to helping defensive children form secure attachments to trustworthy caregivers would be to alter the pattern of activity in the children&rsquos defensive brain circuitry. Since the amygdala plays a leading part in orchestrating this defensive way of relating, it is essential to target the amygdala for therapeutic modulation, for shifting the amygdala&rsquos bias towards self defensive behavior towards social engagement. By being playful, accepting, curious, and empathic, the adult may be able to de-activate the child&rsquos defense system, at least transiently. This transient buffering of the child&rsquos defense system would very likely activate the immediate early gene system to tag brain cells in the amygdala, alerting them, in a sense, that there is &ldquonews of a difference&rdquo, that this adult seems different from other adults who presented a threat in the past. This news of a difference, would, in turn, probably activate the hippocampus to help compare the present experience to the past the lower region of the prefrontal cortex, the orbitol region, which specializes in learning and remembering social contingencies and in &ldquoreversal learning&rdquo and the anterior cingulate cortex (ACC) that is vitally involved in fear &ldquoextinction&rdquo and in resolving conflicts between old, habitual ways of reacting and new ways of behaving. This sequence of brain activity would very likely create a state of mind conducive to altering patterns of gene expression in the fronto-limbic regions that are the foundational system for social and emotional functioning.

In sum, the rapidly growing field of behavioral epigenetics of early life experience, combined with research on processes for reversing adverse epigenetic effects, provides a new window into the neurobiology of relationships and the underlying mechanisms of therapeutic change. Furthermore, beyond the social processes discussed here, epigenetic processes are now known to be associated with a wide range activities, including exercise, the sleep/wake cycle, and, intriguingly, certain mindfulness practices that promote expansion in a region of the brain associated with self reflection and compassion (Davidson et al, 2003). Combining the research on various kinds of epigenetic processes, we begin to see an emergent integration of relational processes, intrapersonal processes, and pharmacology that could be the foundation for a more effective model of mental health interventions. With a deeper understanding of how experience gets embedded in our brains and bodies, we can learn to target epigenetic changes that promote greater resilience and capacity for human connection.

References and Resources for Further Reading

Andari,E., Duhamel,J., Zulla,T., Herbrecht,E., Lebayer,M., and Sirigu,A. (2010). Promotingh social behavior with oxytocin in high-functioning autism spectrum disorders. Published online before print February 16, 2010, doi:10,1073/pnas. 0910249107 PNAS February 16,2010.

Avishai-Eliner,S., Gilles,E.E., Eghal-Ahmadi,M.,Bar-El,Y., and Baram,T.Z. (2001). Altered regulation of gene and protein expression of hypothalamic-pituitary-adrenal axis components in an immature rat model of chronic stress. Journal of Neuroendocrinology, 15, 114-119.

Caldji,C., Diorio, J., and Meaney, M.J. (2003). Variations in maternal care alter GABA(a) receptor subunit expression in brain regions associated with fear. Neuropsychopharmacology, 28, 1950-1959.

Canli,T., Qui,M.,Omura,K., Congdon,E., Haas,B.W., Amin,Z. et al (2006). Neural correlates of epigenesis. Proceedings of the National Academy of Sciences, 103,16033-16038.

Carter,C.S. (2007). Neuropeptides and the protective effects of social bonds. In E.Harmon-Jones and P.Winkielman (Eds.), Social Neuroscience (pp. 425-438). New York,NY: Guilford Press.

Champagne,F. (2008). Maternal influence on offspring reproductive behavior: Implications for transgenerational effects. In R.Bridges (Ed.), Neurobiology of the parental brain (pp. 307-318). San Diego,CA: Academic Press.

Cushing,B.S. & Kramer,K.M. (2005). Mechanisms underlying epigenetic effects of early social experience: The role of neuropeptides and steroids. Neuroscience and Biobehavioral Reviews, 29,1089-1105.

Davidson,R.J., Kabat-Zinn,J., Schumacher,J., Rosenkranz,M., Muller,D., Santorelli,S.F., et al (2003). Alterations in brain and immune function produced by mindfulness meditation. Psychosomatic Medicine, 65, 564-570.

Diroio, J. & Meaney, M.J. (2007). Maternal programming of defensive responses through sustained effects on gene expression. Journal of Psychiatry and Neuroscience, 32, 275-284.

Domes,G., Heinrichs,M., Glascher,J., Buchel,C., Braus,D.F., and Herpetz,S.C. (2007). Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biological Psychiatry,10,1187-1190.

Drevets,W.C. (2000). Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Progree in Brain Research, 126, 413-431.

Eluvathingal,J., Chugani,H., Behen,M., Juhasz,C., Muzik,O., Maqbool,M., et al (2006). Abnormal brain connectivity in children after severe socioemotional deprivation: A diffusion tensor imaging study. Pediatrics, 117 (6), 2093-2100.

Feldman,R., Gordon,I., and Zagoory-Sharon,O. (2010). The cross-generation transmission of oxytocin in humans. Hormones and Behavior, 58, 669-676.

Francis,D.D., Champagne,F., and Meaney,M.J. (2000). Variations in maternal behavior are associated with differences in oxytocin receptor levels in the rat. Journal of Neuroendocrinology, 12, 1145-1148.

Guastella,A.J., Mitchell,P.B., and Dadds,M.R. (2008). Oxytocin enhances the encoding of positive social memories in humans. Biological Psychiatry, 64, 256-258.

Heim,C. & Nemeroff,C.B. (2002 ) Neurobiology of early life stress: Clinical studie. Seminars in Clinical Neuropsychiatry, 7, 147-159.

Hertzman,C. (2012). Putting the concept of biological embedding in historical perspective. Proceedings of the National Academy of Sciences USA, 109,17160-17167.

Hughes,D. (2009). Attachment-focused parenting. New York, NY: Norton.

Kaffman,A. & Meaney,M.J. (2007). Neurodevelopmental sequalae of postnatal maternal care in rodent: Clinical and research implications of molecular insights. Journal of Child Psychology and Psychiatry, 48, 224-244.

Kosfeld,M., Heinrichs,M., Fischbacker,U., and Fehr,E. (2006). Oxytocin increases trust in humans. Nature, 435, 673-676.

Kumsta,R., Hummel,E.,Chen,F., and Heinrichs,M. (2013). Epigenetic regulation of the oxytocin receptor gene: Implications for behavioral neuroscience. Frontiers in Neuroscience, 7, 1-6.

Landers,M.S., & Sullivan,R.M. (2012). The development and neurobiology of infant attachment and fear. Developmental Neuroscience, 34, 101-114. Doi: 10.1159/000336732.

McEwen,B.S. (2012) Brain on stress: How the social environment gets under the skin. PNAS, 109, 17180-17185. doi: 10.1073/pnas.1121254109.

McGowan,P.O., Sasaki,A., D&rsquoAlessio, A.C., Dymov,S., Labonte,B. et al (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342-348. doi: 10.1038/nn2270.

Meaney,M.J. (2010). Epigenetics and the biological definition of gene x environment interactions. Child Development, 81, 41-79.

Moriceau,S., Raineki,C., Holman, J.D., Holman, J.G., Sullivan, R.M., and Young,L. (2009). Enduring neurobehavioral effects of early life trauma mediated through learning and corticosterone suppression. Special issue on Long Term Consequences of Early Life Experience. Front Behav Neuroscience, 22

National Scientific Council on the Developing Child (2008). The timing and quality of early experiences combine to shape brain architecture. Center on the Developing Child, Harvard University, Working Paper 5.

Panksepp,J. (2007). Neuroevolutionary sources of laughter and social joy: Modeling primal human laughter in laboratory rats. Behavioral Brain Research, 182,231-244.

Porges,S. ( 2011). The polyvagal theory: Neurophysiological foundations of emotions, attachment, communication, and self-regulation. New York, NY: Norton.

Raineki, C., Moriceau, S., and Sullivan, R.M. (2010). Developing a neurobehavioral animal model of infant attachment to an abusive caregiver. Biological Psychiatry, 67, 1137-1145 (Pub Med: 20163787).

Roth,T.L., Lubin,F.D., Funk,A.J. and Sweatt,J.D. (2009). Lasting epigenetic influence of early-life adversity on the BDNF gene. Biological Psychiatry, 65, 760-769.

Sabatini,M., Ebert,P., Lewis,D., Levitt,P., Cameron,J., and Mirnics,K. (2007). Amygdala gene expression correlates of social behavior in monkeys experiencing maternal separation. The Journal of Neuroscience, 27(12), 3295-3304.

Sevelinges,Y., Mouly,M.A., Moriceau,S., Raineki,C., Forest,C., and Sullivan, R.M. (2011). Adult depression-like behavior and amygdala dysfunction rescued by odor previously paired with shock in infancy. Developmental Cognitive Neuroscience, 1, 77-87.

Suomi,S.J. (2003). Gene-environment interactions and the neurobiology of social conflict. Annals of the New York Academy of Science, 1008, 132-139.

Unternaehrer,E., Luers, P., Mill, J., Dempster,E., Meyer,A., Staehli,S., et al. (2012). Dynamic changes in DNA methylation of stress associated genes (OXTR,BDNF) after acute psychosocial stress. Transl. Psychiatry e 150.

Weaver,I., Meaney,M., & Szy,M. (2006) Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. PNAS, 103, 3480-3485. Doi: 10.1073/pnas.0507526103.


Serotonin and Violence

Serotonin and Violence

Levels of neurotransmitters in the brain can influence behaviour, so it’s plausible to think that in the criminal brain there may be some abnormalities in neurotransmitter levels.

Numerous research studies have shown that violent criminals do in fact tend to have low levels of serotonin (e.g. Moi and Jessel, 1995 Scerbo and Raine, 1993). Studies have also shown that serotonin is associated with controlling impulsive behaviour (Krakowski, 2003)

One method of investigating biological correlates of behaviour is to use animals in the laboratory, like rats and mice. There have been numerous studies that show a correlation between serotonin levels in rats and aggression. That is to say, low levels of serotonin are correlated with high levels of aggression. (Chiara, et al, 1971) But because of the complex nature of the serotonin system in the brain and the difficulty of manipulating aggression in a lab, it’s been difficult to explain how serotonin affects violence.

With modern technology, researchers can now investigate the relationship between areas of the brain and neurotransmitter levels in ways they couldn’t before. The following study provides one possible answer for explaining the relationship between neurotransmission (serotonin levels) and violent behaviour.

Passamonti et al, 2012 (Full Study Link)

Healthy volunteer samples serotonin levels were manipulated by altering their diet. A repeated measures design was used where on one day they were given a diet that lacked tryptophan, which is an important amino acid that helps build serotonin. A lack of tryptophan in the diet will reduce levels of serotonin available in the brain. In the control condition they were given a placebo diet, which was the same mixture but had normal amounts of tryptophan.

The participants were put in fMRIs and their brain activity was measured while they were seeing images of happy, angry or neutral faces. The researchers could see the activation of different areas of the brain as the different faces were shown.

The results showed that there was reduced activity in the frontal lobe during the low serotonin conditions when the participant was viewing the angry face. Moreover, communication between the amygdala and the frontal lobe was weaker in this condition.

By applying what we know about the frontal lobe and its role in regulating impulsive behaviour, as well as the amygdala in emotion and the stress response, this provides plausible clues as to why low serotonin might lead to acts of aggression or violence. If an individual is threatened and they have low levels of serotonin, they may not be able to perform top-down control that is to say, the lack of activity in the PFC may affect their ability to regulate the stress response as triggered by the amygala’s reactivity towards the threat. This might increase their emotional level and increase chances of a highly emotion reaction to the threat. The reduced activity in their PFC as a result of the low serotonin may also affect their ability to inhibit impulsive reactions and think through their actions, so if someone has a tendency towards violence they may not be able to reduce an impulsive reaction towards an individual who is threatening them.

This study might not make heaps of sense to you unless you have first learned about the role of the PFC in impulse control and the amygdala in emotion, social threat and the stress response. In the themantic unit on Criminology, these concepts are covered first before going into the role of serotonin on aggression and violence.

Guiding Question

Dr Molly Crockett was a co-author of this study and you can watch her TED Talk below. In this talk she addresses the requirement for people to beware of the media’s tendency to oversimplify scientific findings.


Epigenetics Might Help Us Predict How the Brain Responds to Threats

If you could predict how well your clients might be able to deal with stress, just based on a blood or saliva
sample, would that change your treatment approach?

There’s a specific gene that’s been getting a lot of attention lately because it affects how the brain processes serotonin – a chemical created inside the body believed to be responsible for maintaining mood balance.

The serotonin transporter gene codes for a molecule that regulates the amount of serotonin signaling between brain cells, and it’s a key target for the treatment of mood disorders. It’s also well known for its involvement in clinical depression and posttraumatic stress disorder (PTSD).

And recent discoveries in epigenetics are indicating that changes to how the serotonin transporter gene gets expressed might be involved in a person’s brain response to threats.

Now, I’ve talked a little about what epigenetics is before, but here it is in a nutshell: There are tiny molecules called ‘methyl groups’ that can attach themselves to our DNA, and when this happens, they can change how a gene is expressed. Essentially, the methyl groups will regulate where and when a gene is active.

What makes epigenetics different from ‘classical genetics’ is that, while the genetic code of your DNA doesn’t get changed structurally, stress or other factors in the environment can cause chemical changes in your body. The environmental signals can trigger those methyl groups to park themselves on your DNA, affecting the way your genetic code gets read.

Researchers at Duke University knew that differences in the DNA sequence of the serotonin transporter gene seemed to give some folks exaggerated responses to stress (and seemed to play a role in depression). But they wanted to look at how epigenetics might be at work here.

Led by Ahmad Hariri, PhD, the researchers recruited 80 college-aged participants who are part of the ongoing Duke Neurogenetics Study (DNS) – a collaborative study that’s working to link genes, brain activity, and other biological markers that could indicate a risk for mental illness in young adults.

First they used non-invasive brain imaging to look at the amygdala of each participant while showing them pictures of angry or fearful faces and watching their responses. The amygdala governs how we respond to threat or stress.

Next, they measured the amount of methylation (how many methyl groups were present) on serotonin transporter DNA that they isolated from the participants’ saliva.

And they found a strong correlation between the amount of methylation and the amount of reactivity they saw in the amygdala. Plus, they found that the amount of methylation seemed to be a better predictor of amygdala activity than any other variation in the serotonin transporter gene.

But the researchers wanted to make sure that what they were seeing wasn’t a one-time thing.
They took a look at a different set of participants, this time 96 adolescents participating in the Teen Alcohol Outcomes Study (TAOS) at the University of Texas Health Science Center at San Antonio. Using the same methods as before, the group found an even stronger link between methylation and amygdala reactivity.

So, epigenetics could be playing an important role in whether or not we’re getting enough serotonin to the brain, and in turn, that could be affecting our moods or how we respond to trauma.

Now we do need to be cautious – this work is strictly correlative, and it’s all just getting started. The next step will be to find out how methylation directly affects the brain.

If you’d like to read more about the work of Dr. Hariri and his team, you can find the full study published in Nature Neuroscience, volume 17, pp. 1153-1155.

Eventually this work might help us predict mental illness, using saliva or blood samples to show us whether or
not genes for specific disorders are, or are not, expressed.

You can learn more about how epigenetics is involved in trauma and what that could mean for the way you approach treatment – click here for our courses on trauma.

. . . if a tiny sample of saliva could help you better detect a client’s risk for something like posttraumatic

stress disorder, would you incorporate that into your treatment? And what sort of benefits do you think there might be from this? You can let me know what you think in the space below.


Small DNA modifications predict brain's threat response

An artist's conception shows how molecules called methyl groups attach to a specific stretch of DNA, changing expression of the serotonin transporter gene in a way that ultimately shapes individual differences in the brain's reactivity to threat. The methyl groups in this diagram are overlaid on the amygdala of the brain, where threat perception occurs. Credit: Annchen Knodt, Duke University

The tiny addition of a chemical mark atop a gene that is well known for its involvement in clinical depression and posttraumatic stress disorder can affect the way a person's brain responds to threats, according to a new study by Duke University researchers.

The results, which appear online August 3 in Nature Neuroscience, go beyond genetics to help explain why some individuals may be more vulnerable than others to stress and stress-related psychiatric disorders.

The study focused on the serotonin transporter, a molecule that regulates the amount of serotonin signaling between brain cells and is a major target for treatment of depression and mood disorders. In the 1990s, scientists discovered that differences in the DNA sequence of the serotonin transporter gene seemed to give some individuals exaggerated responses to stress, including the development of depression.

Sitting on top of the serotonin transporter's DNA (and studding the entire genome), are chemical marks called methyl groups that help regulate where and when a gene is active, or expressed. DNA methylation is one form of epigenetic modification being studied by scientists trying to understand how the same genetic code can produce so many different cells and tissues as well as differences between individuals as closely related as twins.

In looking for methylation differences, "we decided to start with the serotonin transporter because we know a lot about it biologically, pharmacologically, behaviorally, and it's one of the best characterized genes in neuroscience," said senior author Ahmad Hariri, a professor of psychology and neuroscience and member of the Duke Institute for Brain Sciences.

"If we're going to make claims about the importance of epigenetics in the human brain, we wanted to start with a gene that we have a fairly good understanding of," Hariri said.

This work is part of the ongoing Duke Neurogenetics Study (DNS), a comprehensive study linking genes, brain activity and other biological markers to risk for mental illness in young adults.

The group performed non-invasive brain imaging in the first 80 college-aged participants of the DNS, showing them pictures of angry or fearful faces and watching the responses of a deep brain region called the amygdala, which helps shape our behavioral and biological responses to threat and stress.

The team also measured the amount of methylation on serotonin transporter DNA isolated from the participants' saliva, in collaboration with Karestan Koenen at Columbia University's Mailman School of Public Health in New York.

The greater the methylation of an individual's serotonin transporter gene, the greater the reactivity of the amygdala, the study found. Increased amygdala reactivity may in turn contribute to an exaggerated stress response and vulnerability to stress-related disorders.

To the group's surprise, even small methylation variations between individuals were sufficient to create differences between individuals' amygdala reactivity, said lead author Yuliya Nikolova, a graduate student in Hariri's group. The amount of methylation was a better predictor of amygdala activity than DNA sequence variation, which had previously been associated with risk for depression and anxiety.

The team was excited about the discovery but also cautious, Hariri said, because there have been many findings in genetics that were never replicated.

That's why they jumped at the chance to look for the same pattern in a different set of participants, this time in the Teen Alcohol Outcomes Study (TAOS) at the University of Texas Health Science Center at San Antonio.

Working with TAOS director, Douglas Williamson, the group again measured amygdala reactivity to angry and fearful faces as well as methylation of the serotonin transporter gene isolated from blood in 96 adolescents between 11 and 15 years old. The analyses revealed an even stronger link between methylation and amygdala reactivity.

"Now over 10 percent of the differences in amygdala function mapped onto these small differences in methylation," Hariri said. The DNS study had found just under 7 percent.

Taking the study one step further, the group also analyzed patterns of methylation in the brains of dead people in collaboration with Etienne Sibille at the University of Pittsburgh, now at the Centre for Addiction and Mental Health in Toronto.

Once again, they saw that methylation of a single spot in the serotonin transporter gene was associated with lower levels of serotonin transporter expression in the amygdala.

"That's when we thought, 'Alright, this is pretty awesome,'" Hariri said.

Hariri said the work reveals a compelling mechanistic link: Higher methylation is generally associated with less reading of the gene, and that's what they saw. He said methylation dampens expression of the gene, which then affects amygdala reactivity, presumably by altering serotonin signaling.

The researchers would now like to see how methylation of this specific bit of DNA affects the brain. In particular, this region of the gene might serve as a landing place for cellular machinery that binds to the DNA and reads it, Nikolova said.

The group also plans to look at methylation patterns of other genes in the serotonin system that may contribute to the brain's response to threatening stimuli.

The fact that serotonin transporter methylation patterns were similar in saliva, blood and brain also suggests that these patterns may be passed down through generations rather than acquired by individuals based on their own experiences.

Hariri said he hopes that other researchers looking for biomarkers of mental illness will begin to consider methylation above and beyond DNA sequence-based variation and across different tissues.


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Keywords: epigenetics (MeSH), work stress, daily life stress, socioeconomic status (MeSH), susceptibility, resilience (psychological), candidate risk variants, epigenome wide association

Citation: Gottschalk MG, Domschke K and Schiele MA (2020) Epigenetics Underlying Susceptibility and Resilience Relating to Daily Life Stress, Work Stress, and Socioeconomic Status. Front. Psychiatry 11:163. doi: 10.3389/fpsyt.2020.00163

Received: 06 November 2019 Accepted: 20 February 2020
Published: 20 March 2020.

Christine Allwang, Technical University of Munich, Germany

Livio Provenzi, Neurological Institute Foundation Casimiro Mondino (IRCCS), Italy
Michael Deuschle, Central Institute for Mental Health, Germany

Copyright © 2020 Gottschalk, Domschke and Schiele. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


Serotonin and Violence

Serotonin and Violence

Levels of neurotransmitters in the brain can influence behaviour, so it’s plausible to think that in the criminal brain there may be some abnormalities in neurotransmitter levels.

Numerous research studies have shown that violent criminals do in fact tend to have low levels of serotonin (e.g. Moi and Jessel, 1995 Scerbo and Raine, 1993). Studies have also shown that serotonin is associated with controlling impulsive behaviour (Krakowski, 2003)

One method of investigating biological correlates of behaviour is to use animals in the laboratory, like rats and mice. There have been numerous studies that show a correlation between serotonin levels in rats and aggression. That is to say, low levels of serotonin are correlated with high levels of aggression. (Chiara, et al, 1971) But because of the complex nature of the serotonin system in the brain and the difficulty of manipulating aggression in a lab, it’s been difficult to explain how serotonin affects violence.

With modern technology, researchers can now investigate the relationship between areas of the brain and neurotransmitter levels in ways they couldn’t before. The following study provides one possible answer for explaining the relationship between neurotransmission (serotonin levels) and violent behaviour.

Passamonti et al, 2012 (Full Study Link)

Healthy volunteer samples serotonin levels were manipulated by altering their diet. A repeated measures design was used where on one day they were given a diet that lacked tryptophan, which is an important amino acid that helps build serotonin. A lack of tryptophan in the diet will reduce levels of serotonin available in the brain. In the control condition they were given a placebo diet, which was the same mixture but had normal amounts of tryptophan.

The participants were put in fMRIs and their brain activity was measured while they were seeing images of happy, angry or neutral faces. The researchers could see the activation of different areas of the brain as the different faces were shown.

The results showed that there was reduced activity in the frontal lobe during the low serotonin conditions when the participant was viewing the angry face. Moreover, communication between the amygdala and the frontal lobe was weaker in this condition.

By applying what we know about the frontal lobe and its role in regulating impulsive behaviour, as well as the amygdala in emotion and the stress response, this provides plausible clues as to why low serotonin might lead to acts of aggression or violence. If an individual is threatened and they have low levels of serotonin, they may not be able to perform top-down control that is to say, the lack of activity in the PFC may affect their ability to regulate the stress response as triggered by the amygala’s reactivity towards the threat. This might increase their emotional level and increase chances of a highly emotion reaction to the threat. The reduced activity in their PFC as a result of the low serotonin may also affect their ability to inhibit impulsive reactions and think through their actions, so if someone has a tendency towards violence they may not be able to reduce an impulsive reaction towards an individual who is threatening them.

This study might not make heaps of sense to you unless you have first learned about the role of the PFC in impulse control and the amygdala in emotion, social threat and the stress response. In the themantic unit on Criminology, these concepts are covered first before going into the role of serotonin on aggression and violence.

Guiding Question

Dr Molly Crockett was a co-author of this study and you can watch her TED Talk below. In this talk she addresses the requirement for people to beware of the media’s tendency to oversimplify scientific findings.


An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents

Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals.


Behavioral Epigenetics and Attachment

Download the articles here: [wlm_private &ldquoNPT Basic|3 Year Subscription|Standard Membership|Staff|NPT Premium|Standard Monthly|2 Year Subscription&rdquo] Members use this link to get the downloads for free. [/wlm_private]

&ldquo&hellipthe perception of safety is the turning point in the development of relationships&hellip&rdquo Stephen Porges, 2011

&ldquoThe reality of the functional genome does not admit to main effects of either gene or environment, but rather to a constant interaction between the DNA and its environment&rdquo Michael Meaney, 2010

Introduction

One of the hottest areas of neuroscience is the study of how life experience affects patterns of gene expression in the brain, what some call behavioral epigenetics (Weaver, 2004 McEwen, 2012). Of great relevance to therapists interested in attachment, this fast growing body of research is revealing how early life experience can channel brain development towards either social engagement or self defense. Researchers are uncovering experience-dependent effects on the development of the brain during the sensitive period for attachment-based learning in animals, work that has now been extended to humans. Furthermore, epigenetic research is exploring the potential for reversing the effects of poor parental care by altering patterns of gene expression in the brain after the sensitive period for attachment has passed (Landers and Sullivan, 2012). Clearly, this research has huge implications for the whole field of mental health.

Epigenetic Effects of Early Care On the Child&rsquos Stress Systems

Groundbreaking studies by Michael Meaney and his colleagues (Kaffman and Meaney, 2007) Meaney, 2010) laid the foundation for studying the effects of differences in the quality of early maternal care on patterns of gene expression in the brains of offspring. This seminal work showed that naturally occurring differences in the quality of maternal care within the first week of a rat pup&rsquos life trigger different patterns of gene expression in the regions of the brain that support both self defense and social engagement. Young rats who are licked a lot and nursed in a certain position show a different pattern of gene expression in their hippocampus, prefrontal cortex, and amygdala than pups who don&rsquot get as much of this &ldquoenriched&rdquo kind of stimulation. These differences in gene expression enable well cared for rats to be more social, less fearful, and faster to approach and explore new things than their less well cared for peers.

In the well licked babies, the gene for the receptor for the stress hormone, corticosterone, called the GR, is more highly expressed (or in technical terms, less methylated) in the hippocampus than it is in the less licked rats. This means that the well cared for pups acquire more GRs in their hippocampus. These hippocampal GRs are an essential component of the stress response system because they help to turn off the stress response after a stressful experience is over. In the low licked offspring, the stress response system stays active longer, facilitating self defense, but at the cost of growth and social connectedness.

Epigenetic research that began with rodent studies has since been extended both to non-human primates and to humans. Maternal licking in the rat is a form of tactile stimulation similar to grooming behavior in primates and to all forms of &ldquogood touch&rdquo in humans. Studies in humans show that certain qualities of touch activate the insula, ACC, and orbitol regions of the brain while calming the amygdala in ways that promote well being, trust, and social engagement, very much like licking does in Meaney&rsquos rat pups. While studying gene expression patterns in human brains is more difficult than it is with rodents where brain tissues from different regions can be readily examined, methods for behavioral epigenetic studies in humans are being developed.

An intriguing study by Meaney&rsquos group (McGowen et al, 2009) used postmortem brain tissue to explore patterns of gene expression associated with childhood abuse in a group of suicide victims (McGowan et al., 2009). The pattern of gene expression seen in the brains of those individuals who had experienced abuse in early childhood matched the pattern of methylation in the rat studies, showing gene suppression in the equivalent promoter region of the GR gene. In other words, the pattern of gene expression was consistent with epigenetic programming of the human brain by early life adversity.

In addition to showing that early life experiences with attachment figures activate different patterns of gene expression (and therefore, protein synthesis and brain structure) during the initial period for attachment-based learning, epigenetic research is exploring the potential for reversing early life patterns of gene suppression associated with separation, early abuse, and neglect. This research includes both environmental interventions- Environmental Enrichment- and pharmacological methods such as administration of demethylating drugs to unblock methylated promoter regions of genes in animals exposed to poor care early in life. Both types of interventions have shown some capacity to alter the effects of early life adversity on gene expression in brain regions, including the hippocampus. While epigenetic effects triggered by social experiences are strongest during the sensitive period for attachment-based learning, experience-dependent gene expression continues throughout life (Weaver et al, 2004). This exciting line of research has strong implications both for psychotherapy and psychopharmacology.

Gene Expression, Trust, and Mistrust

The social engagement and social defense systems are under development early in life and both are affected by the nature of caregiving that infants of various mammalian species receive. Epigenetic research is showing that differences in the quality of early care have differential impact on the patterns of gene expression in these two systems, channeling brain structure and functioning along different trajectories. In effect, epigenetic mechanisms by which the environment impacts brain development is nature&rsquos way of helping to ensure that the young adapt to life in the specific kind of social world they are likely to be living in. If this first &ldquoenvironment of care&rdquo is safe, the young brain will be sculpted or &ldquoprogrammed&rdquo for living in connection with other people. If the early environment exposes the young to harsh, insensitive treatment by attachment figures, the young brain will be epigenetically sculpted for surviving (and reproducing) in a world in which it is vital to be hypervigilant, slow to trust, and quick to deploy one&rsquos defenses. While both of these developmental scenarios of &ldquobiological embedding of early experience&rdquo(Hertzman,2012 ) are initially adaptive, a wealth of research on attachment formation shows that early experiences with sensitive, nurturing caregivers promotes a pattern of brain development supportive of emotional resilience, empathy, and cognitive flexibility (National Scientific Council on the Developing Child, 2008).

Children who are forced to adapt to high levels of adversity very early in life when the brain systems for social engagement and self defense are under construction are at risk for developmental stress disorders, including depression, social anxiety, and PTSD (Heim and Nemeroff, 2002). In brain terms, this means that the development of the circuit that connects the prefrontal cortex to subcortical regions, especially to the amygdala, may be compromised by over activation of the child&rsquos stress response system early in life. The development of the fronto limbic system connecting the lower regions of the prefrontal cortex, including the orbitol region and the ventral anterior cingulate cortex (ACC,) to the amgydala forms the core neural substrate for self regulation throughout the lifespan. When the initial development of this circuit is suppressed for any reason, it is more difficult later in life to regulate emotions, behavior, cognitions, and attention. As a result of these regulatory difficulties, it is harder for the individual to learn from new experiences and to change one&rsquos mind about the meaning of old experiences. Children who have to adopt an early life survival strategy of premature self reliance and defensiveness are vulnerable later in life to all kinds of health problems because of their chronic exposure to high levels of stress hormones. In the brain, chronic activation of the stress response systems can have toxic effects, especially on the hippocampus and the prefrontal cortex (McEwen, 2012), while promoting chronic hyper-activation of the amygdala.

This developmental scenario of chronic stress is a common one for children exposed to abuse and neglect early in life. Having an underdeveloped fronto limbic system biases these children towards hyper-reactivity to aspects of their environment that they perceive as threatening. This includes a strong tendency to perceive other people as untrustworthy, based on prior learning that has become the basis for habitual ways of responding to attachment figures. In common parlance, these kids are more prone to flipping their lids and either blowing up or freezing in fright when they detect signs of negative intentions or rejection, especially in other people&rsquos facial expressions and voices.

Appraising Safety and Threat: A Two Level System

The process of shifting between social engagement and defensive states depends heavily on the way we appraise the level of safety or threat posed by other people in our environment (Porges, 2011) . This appraisal process occurs on two basic levels: 1) an unconscious or implicit, ultra rapid level based heavily on the functioning of the amgydala and its ability to activate approach and avoidance responses to other people and 2) a conscious, slower appraisal system based on prefrontal regions of the brain that can modulate and inhibit the implicit, fast acting &ldquofirst pass&rdquo appraisal system. Porges calls the implicit, subcortical appraisal of safety and threat &ldquoneuroception&rdquo. The ability of the prefrontal regions to modulate the neuroceptive process typically increases with age and brain maturation into adulthood however, this process of developing a robust fronto-limbic system is also significantly affected by early life experiences with attachment figures, i.e., by epigenetic processes.

The amygdala is functional very early in life, providing infants with a rough and ready, implicit way of detecting threats in the social environment. However, nurturing, responsive parenting buffers the defensive reactions from the amygdala, in part by decreasing the release of stress hormones such as cortisol and norepinephrine while promoting the release of calming chemicals such as oxytocin in this region. Social engagement involves eye contact, the ability to read other people&rsquos facial expressions, ability to extract emotional meaning in other people&rsquos voices, ability to put emotion into one&rsquos own voice. Different types of social stimuli all pass through the amygdala early in the sequence of sensory processing in the brain. How the amygdala responds to this information biases the young child towards either social approach or social avoidance. The role of the amygdala as a switching mechanism between attachment learning and avoidance learning is beautifully described by Landers and Sullivan (2012) and there is a wealth of data that strongly indicates a similar process in humans (Caldji et al, 2003).

The amygdala is a creature of proximity in the sense that the closer something comes to us, either in space or time, the stronger the potential reaction of the amygdala, especially to something perceived as threatening or stressful. This helps to understand why mistrustful children are likely to become more defensive the closer we try to get to them. This has a lot to do neurobiologically with why some children with attachment problems often respond dramatically differently to strangers or people who are more distant from them than to attachment figures who try to come very close. The amygdala appears to be part of the brain system that monitors &ldquopersonal space&rdquo at about an arm&rsquos length from our bodies, basically treating this space as an extension of ourselves.

If a caregiver is being neglectful or causing pain, the child&rsquos amygdala starts to react to the caregiver as, in part at least, a source of pain and fear, setting up the potential for chronic conflict between approach and avoidance tendencies. The amygdala is strongly connected to the stress response system, or HPA axis, that activates the endocrine circuitry and ultimately engages the adrenal glands in producing stress hormones such as cortisol. It is also strongly connected to the brain&rsquos vigilance system that is based on the release of norepinephrine (NE) from the locus coeruleus (LC). When the amygdala detects a potential threat, it triggers the release of NE from the LC, ramping up attention to the possible threatening object or person. Through back projections to all sensory processing regions, the amygdala can intensify sensory experiences if it detects something as emotionally relevant, ramping up attention to that thing or person. Through its connections with the stress/defense systems- the HPA axis that produces stress hormones and the sympathetic and parasympathetic defense systems that support fight, flight, and freeze reactions- the amygdala can orchestrate the process of keeping the brain and body on high alert, promoting self defense over social engagement.

A number of genes are now known to be targets for epigenetic effects in the amygdala. These include GABA receptor genes, the gene for the oxytocin receptor, genes that express proteins involved in the growth of connections between the amygdala and other brain regions, and genes for CRH, the chemical that triggers the neuroendocrine stress response system. Research has begun to target the GABA system in the amygdala as an extremely important mechanism for epigenetic effects of early experience on emotional resilience and vulnerability (Cadji, Diorio, & Meaney, 2003 Diorio and Meaney, 2007).

The GABA-A Receptor in the Amygdala

In the amygdala of well cared for rats, the gene for the GABA-A receptor shows different patterns of expression than in the less well cared for peers. This is important because GABA is the main inhibitory chemical in the brain. The action of GABA in the amygdala makes it possible to modulate defensive reactivity that otherwise can set off the fight, flight, or freeze responses within milliseconds of detecting a potential threat. The amygdala specializes in avoidance learning, orchestrating the process of learning to associate social stimuli with pain, danger, or distress. By having more sensitive GABA-A receptors in their amygdala, the well licked rats have more power to &ldquoveto&rdquo output from the central region of the amygdala to the stress/defense systems.

The GABA-A receptor is composed of several different subunits and the genes for these subunits are targets for epigenetic programming by maternal care (Caldji, Diori, and Meaney, 2003). In the first week of a rats life, maternal care is associated with differences in GABA-A receptor subunit expression and these differences are intriguingly related to fearful behavior throughout the life of these animals. According to this research, &ldquothe adult offspring of high licking-grooming mothers show significantly higher levels of GABAA/Benzodiazepine receptor binding in the basolateral and central nuclei of the amygdala and the locus coeruleus. These findgings provide a mechanism for increased GABAergic inhibition of amygdala-locus coeruleus activity&rdquo (Caldji et al, 2003,p.1957).

In poorly nurtured rats, suppression of the gene for GABA-A receptor subunits in the amygdala leads to less sensitive GABA receptors, which, in turn, makes the amygdala more highly reactive to perceived threats. Also, because higher brain regions in the prefrontal cortex modulate the amygdala by activating GABA receptors in the amygdala, the lower sensitivity of the GABA system in the amygdala lessens the capacity of the prefrontal regions to inhibit amygdala reactivity.

This is a structural and functional set up for making a person more highly reactive to stress and more vulnerable to stress-induced disorders of all kinds, including PTSD, depression, and social anxiety. In essence, people with reduced GABA activity in the amygdala are more &ldquoamygdaloid&rdquo in their reactions to all kinds of stressors, meaning that they have difficulty regulating negative emotions, actions, and thoughts. These individuals are likely to have a negative reaction to novelty, being more at the mercy of their rapid appraisal system that is biased towards avoidance of new things in a seemingly &ldquobetter safe than sorry&rdquo approach to life. With less ability to inhibit the activity of the amygdala, it is harder for these people to &ldquoget above&rdquo their quick reactions to things and to other people. This makes it harder for them to change their behavior in the light of new experiences.

The Oxytocin Receptor in the Amygdala

Oxytocin (OT) plays several roles in humans and other mammals: 1) promotes social approach behavior 2) facilitates formation of social memories 3) enhances the ability to read other people&rsquos minds, facilitating empathy and &ldquomindsight&rdquo and 4) reduces stress reactivity and self defensiveness (Carter, 2007). All of these functions are made possible by the presence of the oxytocin receptor (OTR) in a wide variety of brain regions that are involved in social and emotional aspects of functioning. The gene for the OTR is a known target for epigenetic effects, meaning that early life experiences affect the level of expression of the OTR gene in the brain. Furthermore, researchers have found a significant relationship between the density of OTR receptors in key brain regions in the limbic system, and individual differences in social affiliation, empathy, and &ldquomindreading&rdquo ability in humans (Andari et al, 2010 Kumsta et al, 2013).

The amygdala is a key region of the brain for oxytocin activity at OTRs . Combining the findings from studies dealing with both animals and humans, it is clear that there is an important process of environmental tuning of the structure and functioning of the amgydala involving epigenetic effects on expression of the OTR gene in the amygdala. This research is extremely interesting in terms of understanding how good care buffers the child&rsquos stress systems and promotes the development of secure attachments and prosocial behavior. By activating the oxytocin system, sensitive parenting helps to quiet the amygdala and facilitate bonding and trust.

Based on this research, we can see how early experiences with attachment figures can promote either secure attachment based on deep safety being close to an adult or insecure attachment that depends upon a certain level of vigilance or at least ambivalence about being close to others. For children who are exposed early in life to abusive and/or neglectful attachment figures, it would be maladaptive to have a high level of gene expression of the OTR gene in the amgydala because this would promote prosocial behavior and a tendency to approach unreliable attachment figures in a trusting, relaxed manner, something which would not be very safe to do. It would be adaptive for these children if their brains produced fewer OTRs and GABA receptors, making it easier neurobiologically to &ldquoplay defense&rdquo around others.

Targeting The Neuroceptive System: An Epigenetic Model of Attachment-based Intervention

Since the amygdala is a major switching station in the brain between the social engagement system and the self defense system, it makes evolutionary sense that this region is a major target for epigenetic effects of good and poor relationships. The question for intervention then becomes what kinds of relational processes have the power to alter early patterns of gene expression in the amygdala so as to shift its functioning towards social engagement and away from reflexive defensiveness. This shifting of the neuroceptive system can be seen as the key to helping defensive children (and adults) shift from core defensiveness and mistrust towards social engagement and trust.

Reversal of Early Epigenetic Effects

The task for a model of therapeutic intervention is to determine what kinds of new experiences beyond the sensitive period for attachment formation can alter the early patterns of gene activity that supported self defensive living. In animal research, there is a line of recent research that is studying this very question, exploring the kinds of later life experiences that can shift patterns of gene expression in the direction of less defensive, more pro- social behavior. This research deals with so called Environmental Enrichment.

Environmental Enrichment and the Re Opening of Attachment-based Learning

The key to helping mistrustful children learn to trust is to somehow re-engage them in attachment learning when they have passed the sensitive period for this process. Environmental Enrichment involves creating opportunities for novel social experiences which can jiggle the brain into a state of alertness, surprise and curiosity and launch a process of renewed social learning that can alter old learning that is no longer adaptive. This involves surprising a mistrusting child with openness rather than responding in a predictably defensive way to mistrusting behavior.

Re-engaging the child&rsquos brain in new attachment-based learning requires that the child experience an immediate disparity or incongruity between the caregiver&rsquos behavior in the moment and the kind of reactions predicted by the child in a &ldquomindless&rdquo state of mistrustfulness. Novel experiences with caregivers can trigger the process of tagging brain cells for further gene expression, a process involving what are called Immediate Early Genes or IEGs. Brains are in the business of making sense of experiences by comparing new experiences to old experiences, determining rapidly if there is &ldquonews of a difference&rdquo and if so, starting a process of trying to resolve the disparity. So creating disparity, surprising the brain, presenting the brain with a mystery, would appear to be essential to altering patterns of gene expression in a therapeutic direction.

The neuroscience literature on sensitive periods and post sensitive period learning shows that different brain processes are involved during these different periods. During a sensitive period, learning is highly efficient because the brain is in a state of high arousal and receptivity, making it easy to learn simply from continued exposure to recurring experiences with an attachment figure. Sensitive periods are a time in brain development when there are high levels of neurotransmitter activity in the brain, including high levels of dopamine and serotonin and norepinephrine. This high level of arousal facilitates all kinds of learning. The sensitive period for attachment in humans is probably the time between birth and around 18 to 24 months. Once this period has passed, attachment learning probably requires intensive, highly arousing, attention-demanding experiences to re open the &ldquogate&rdquo for engaging the brain in this kind of learning and for facilitating the unlearning of old patterns of relating to unreliable caregivers. The new attachment figure has to somehow co-create with the child experiences that are novel, surprising, beyond the &ldquosame old, same old&rdquo, triggering unpredictable reactions in the child. While all kinds of learning are more difficult after a sensitive period for that type of learning has been closed, the neuroscience on sensitive periods and later life learning suggests that post sensitive period learning is quite possible given the necessary kinds of experiences and stimulation.

PACE: A Formula for Epigenetic Reprogramming of the Child&rsquos Neuroceptive System

PACE, playfulness, acceptance, curiosity, empathy,(Hughes, 2009) appears to be a formula for re engaging the child&rsquos brain in attachment based learning, based on a growing body of evidence from attachment-focused treatment around the world. From a brain based perspective, PACE can be seen as a formula for promoting the kinds of epigenetic changes in a child&rsquos brain that would facilitate the shift from defensiveness to openness. Clearly from the research described earlier, the important brain targets for these changes would be selected genes in the amygdala, the hippocampus, and the PFC. How might PACE trigger changes in gene expression in these key brain regions?

PACE has the potential to do two important things that could promote epigenetic changes in a child&rsquos brain: 1) dampen the reflexive defense system by promoting oxytocin flow into the amygdala and 2) turn on excitatory neurochemistry, especially dopamine, to support new learning, engaging what Panksepp calls the &ldquoseeking system&rdquo, a state of curiosity about the new attachment figure that reopens the child&rsquos mind to attachment-based learning.

PACE and the Amygdala: Shifting From Self Defense to Openness

A major goal of a brain based approach to helping defensive children form secure attachments to trustworthy caregivers would be to alter the pattern of activity in the children&rsquos defensive brain circuitry. Since the amygdala plays a leading part in orchestrating this defensive way of relating, it is essential to target the amygdala for therapeutic modulation, for shifting the amygdala&rsquos bias towards self defensive behavior towards social engagement. By being playful, accepting, curious, and empathic, the adult may be able to de-activate the child&rsquos defense system, at least transiently. This transient buffering of the child&rsquos defense system would very likely activate the immediate early gene system to tag brain cells in the amygdala, alerting them, in a sense, that there is &ldquonews of a difference&rdquo, that this adult seems different from other adults who presented a threat in the past. This news of a difference, would, in turn, probably activate the hippocampus to help compare the present experience to the past the lower region of the prefrontal cortex, the orbitol region, which specializes in learning and remembering social contingencies and in &ldquoreversal learning&rdquo and the anterior cingulate cortex (ACC) that is vitally involved in fear &ldquoextinction&rdquo and in resolving conflicts between old, habitual ways of reacting and new ways of behaving. This sequence of brain activity would very likely create a state of mind conducive to altering patterns of gene expression in the fronto-limbic regions that are the foundational system for social and emotional functioning.

In sum, the rapidly growing field of behavioral epigenetics of early life experience, combined with research on processes for reversing adverse epigenetic effects, provides a new window into the neurobiology of relationships and the underlying mechanisms of therapeutic change. Furthermore, beyond the social processes discussed here, epigenetic processes are now known to be associated with a wide range activities, including exercise, the sleep/wake cycle, and, intriguingly, certain mindfulness practices that promote expansion in a region of the brain associated with self reflection and compassion (Davidson et al, 2003). Combining the research on various kinds of epigenetic processes, we begin to see an emergent integration of relational processes, intrapersonal processes, and pharmacology that could be the foundation for a more effective model of mental health interventions. With a deeper understanding of how experience gets embedded in our brains and bodies, we can learn to target epigenetic changes that promote greater resilience and capacity for human connection.

References and Resources for Further Reading

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Avishai-Eliner,S., Gilles,E.E., Eghal-Ahmadi,M.,Bar-El,Y., and Baram,T.Z. (2001). Altered regulation of gene and protein expression of hypothalamic-pituitary-adrenal axis components in an immature rat model of chronic stress. Journal of Neuroendocrinology, 15, 114-119.

Caldji,C., Diorio, J., and Meaney, M.J. (2003). Variations in maternal care alter GABA(a) receptor subunit expression in brain regions associated with fear. Neuropsychopharmacology, 28, 1950-1959.

Canli,T., Qui,M.,Omura,K., Congdon,E., Haas,B.W., Amin,Z. et al (2006). Neural correlates of epigenesis. Proceedings of the National Academy of Sciences, 103,16033-16038.

Carter,C.S. (2007). Neuropeptides and the protective effects of social bonds. In E.Harmon-Jones and P.Winkielman (Eds.), Social Neuroscience (pp. 425-438). New York,NY: Guilford Press.

Champagne,F. (2008). Maternal influence on offspring reproductive behavior: Implications for transgenerational effects. In R.Bridges (Ed.), Neurobiology of the parental brain (pp. 307-318). San Diego,CA: Academic Press.

Cushing,B.S. & Kramer,K.M. (2005). Mechanisms underlying epigenetic effects of early social experience: The role of neuropeptides and steroids. Neuroscience and Biobehavioral Reviews, 29,1089-1105.

Davidson,R.J., Kabat-Zinn,J., Schumacher,J., Rosenkranz,M., Muller,D., Santorelli,S.F., et al (2003). Alterations in brain and immune function produced by mindfulness meditation. Psychosomatic Medicine, 65, 564-570.

Diroio, J. & Meaney, M.J. (2007). Maternal programming of defensive responses through sustained effects on gene expression. Journal of Psychiatry and Neuroscience, 32, 275-284.

Domes,G., Heinrichs,M., Glascher,J., Buchel,C., Braus,D.F., and Herpetz,S.C. (2007). Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biological Psychiatry,10,1187-1190.

Drevets,W.C. (2000). Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Progree in Brain Research, 126, 413-431.

Eluvathingal,J., Chugani,H., Behen,M., Juhasz,C., Muzik,O., Maqbool,M., et al (2006). Abnormal brain connectivity in children after severe socioemotional deprivation: A diffusion tensor imaging study. Pediatrics, 117 (6), 2093-2100.

Feldman,R., Gordon,I., and Zagoory-Sharon,O. (2010). The cross-generation transmission of oxytocin in humans. Hormones and Behavior, 58, 669-676.

Francis,D.D., Champagne,F., and Meaney,M.J. (2000). Variations in maternal behavior are associated with differences in oxytocin receptor levels in the rat. Journal of Neuroendocrinology, 12, 1145-1148.

Guastella,A.J., Mitchell,P.B., and Dadds,M.R. (2008). Oxytocin enhances the encoding of positive social memories in humans. Biological Psychiatry, 64, 256-258.

Heim,C. & Nemeroff,C.B. (2002 ) Neurobiology of early life stress: Clinical studie. Seminars in Clinical Neuropsychiatry, 7, 147-159.

Hertzman,C. (2012). Putting the concept of biological embedding in historical perspective. Proceedings of the National Academy of Sciences USA, 109,17160-17167.

Hughes,D. (2009). Attachment-focused parenting. New York, NY: Norton.

Kaffman,A. & Meaney,M.J. (2007). Neurodevelopmental sequalae of postnatal maternal care in rodent: Clinical and research implications of molecular insights. Journal of Child Psychology and Psychiatry, 48, 224-244.

Kosfeld,M., Heinrichs,M., Fischbacker,U., and Fehr,E. (2006). Oxytocin increases trust in humans. Nature, 435, 673-676.

Kumsta,R., Hummel,E.,Chen,F., and Heinrichs,M. (2013). Epigenetic regulation of the oxytocin receptor gene: Implications for behavioral neuroscience. Frontiers in Neuroscience, 7, 1-6.

Landers,M.S., & Sullivan,R.M. (2012). The development and neurobiology of infant attachment and fear. Developmental Neuroscience, 34, 101-114. Doi: 10.1159/000336732.

McEwen,B.S. (2012) Brain on stress: How the social environment gets under the skin. PNAS, 109, 17180-17185. doi: 10.1073/pnas.1121254109.

McGowan,P.O., Sasaki,A., D&rsquoAlessio, A.C., Dymov,S., Labonte,B. et al (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342-348. doi: 10.1038/nn2270.

Meaney,M.J. (2010). Epigenetics and the biological definition of gene x environment interactions. Child Development, 81, 41-79.

Moriceau,S., Raineki,C., Holman, J.D., Holman, J.G., Sullivan, R.M., and Young,L. (2009). Enduring neurobehavioral effects of early life trauma mediated through learning and corticosterone suppression. Special issue on Long Term Consequences of Early Life Experience. Front Behav Neuroscience, 22

National Scientific Council on the Developing Child (2008). The timing and quality of early experiences combine to shape brain architecture. Center on the Developing Child, Harvard University, Working Paper 5.

Panksepp,J. (2007). Neuroevolutionary sources of laughter and social joy: Modeling primal human laughter in laboratory rats. Behavioral Brain Research, 182,231-244.

Porges,S. ( 2011). The polyvagal theory: Neurophysiological foundations of emotions, attachment, communication, and self-regulation. New York, NY: Norton.

Raineki, C., Moriceau, S., and Sullivan, R.M. (2010). Developing a neurobehavioral animal model of infant attachment to an abusive caregiver. Biological Psychiatry, 67, 1137-1145 (Pub Med: 20163787).

Roth,T.L., Lubin,F.D., Funk,A.J. and Sweatt,J.D. (2009). Lasting epigenetic influence of early-life adversity on the BDNF gene. Biological Psychiatry, 65, 760-769.

Sabatini,M., Ebert,P., Lewis,D., Levitt,P., Cameron,J., and Mirnics,K. (2007). Amygdala gene expression correlates of social behavior in monkeys experiencing maternal separation. The Journal of Neuroscience, 27(12), 3295-3304.

Sevelinges,Y., Mouly,M.A., Moriceau,S., Raineki,C., Forest,C., and Sullivan, R.M. (2011). Adult depression-like behavior and amygdala dysfunction rescued by odor previously paired with shock in infancy. Developmental Cognitive Neuroscience, 1, 77-87.

Suomi,S.J. (2003). Gene-environment interactions and the neurobiology of social conflict. Annals of the New York Academy of Science, 1008, 132-139.

Unternaehrer,E., Luers, P., Mill, J., Dempster,E., Meyer,A., Staehli,S., et al. (2012). Dynamic changes in DNA methylation of stress associated genes (OXTR,BDNF) after acute psychosocial stress. Transl. Psychiatry e 150.

Weaver,I., Meaney,M., & Szy,M. (2006) Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. PNAS, 103, 3480-3485. Doi: 10.1073/pnas.0507526103.


DISCUSSION

It should be pointed that that the aforementioned studies are faced with some limitations. Firstly, the smaller-scale sample size of the cohort warrants no well-clarified discoveries [ 78 ]. Secondly, because various variants and markers were not replicated well among independent datasets, it makes us to wonder whether the novel findings are well-evaluated [ 79 ]. Thirdly, it is crucial to probe possible variants and markers among numerous ethnic populations due to the fact that various populations may draw distinctive conclusions [ 37 ].

In order to weigh GxE interactions, future studies might take advantage of utilizing new artificial intelligence and machine learning techniques such as deep learning artificial neural network algorithms [ 80 , 81 ]. In order to assess GxE interactions, feasible artificial intelligence and machine learning algorithms encompass a wide spectrum of models such as artificial neural networks, Bayesian networks, decision trees, generative adversarial networks, support vector machines, and regression models [ 82 ]. Furthermore, future research can contribute to identify genetic and epigenetic markers by using whole genome sequencing [ 83 ] or exome sequencing [ 84 ]. Whole genome sequencing serves as an overall approach in genomic research and provides a wide variety of genetic variants in an individual subject due to the reduced cost and expanded throughput from next-generation sequencing techniques [ 85 ]. Exome sequencing, which selectively sequences the nucleotides of protein-coding exons in an individual subject, has been employed as an alternative and efficient approach for Mendelian disorders and common diseases [ 84 ]. All in all, combining whole genome sequencing or exome sequencing with innovative artificial intelligence and machine learning algorithms might likely accomplish a comprehensive understanding of GxE interactions in depression in future research.

In future work, artificial intelligence and machine learning pipelines can be used to provide a thorough validation and evaluate whether we are able to replicate the current findings in predictive and diagnostic research studies. Additionally, we should explore possible genetic and epigenetic markers by utilizing custom artificial intelligence and machine learning pipelines thereby, genetic and epigenetic networks would be interpreted at the genome level. In order to precisely understand pathogenesis and therapy in depression, future work must ultimately figure out how to integrate multiple markers and multi-omics, such as clinical data, genetics, transcriptomics, metabolomics, proteomics, epigenetics, and imaging data [ 79 ]. In additional, artificial intelligence and machine learning techniques (such as deep learning, computer vision, and natural language processing) may play a pivotal role in eliminating the false positive candidate variants and genes that were observed in the previous association studies with meta-analysis, GxE interaction analysis, epigenetic analysis, and pathway models [ 82 ]. Artificial intelligence and machine learning models involving with multi-omics data not only will achieve better results when dealing with incomplete data from any single data source, but also will bridge the gap among various phenotypes, genomic mechanisms, and biological regulation models [ 86 ]. Although forecast testing for disease status and treatment responses in depression are now nonexistent ahead of diagnosis, it is anticipated that artificial intelligence and machine learning approaches will be leveraged to predict the tendency of drug efficacy and to contribute meaningful guidance for clinicians on determining personalized medications in future research [ 87 ].


Small DNA modifications predict brain's threat response

An artist's conception shows how molecules called methyl groups attach to a specific stretch of DNA, changing expression of the serotonin transporter gene in a way that ultimately shapes individual differences in the brain's reactivity to threat. The methyl groups in this diagram are overlaid on the amygdala of the brain, where threat perception occurs. Credit: Annchen Knodt, Duke University

The tiny addition of a chemical mark atop a gene that is well known for its involvement in clinical depression and posttraumatic stress disorder can affect the way a person's brain responds to threats, according to a new study by Duke University researchers.

The results, which appear online August 3 in Nature Neuroscience, go beyond genetics to help explain why some individuals may be more vulnerable than others to stress and stress-related psychiatric disorders.

The study focused on the serotonin transporter, a molecule that regulates the amount of serotonin signaling between brain cells and is a major target for treatment of depression and mood disorders. In the 1990s, scientists discovered that differences in the DNA sequence of the serotonin transporter gene seemed to give some individuals exaggerated responses to stress, including the development of depression.

Sitting on top of the serotonin transporter's DNA (and studding the entire genome), are chemical marks called methyl groups that help regulate where and when a gene is active, or expressed. DNA methylation is one form of epigenetic modification being studied by scientists trying to understand how the same genetic code can produce so many different cells and tissues as well as differences between individuals as closely related as twins.

In looking for methylation differences, "we decided to start with the serotonin transporter because we know a lot about it biologically, pharmacologically, behaviorally, and it's one of the best characterized genes in neuroscience," said senior author Ahmad Hariri, a professor of psychology and neuroscience and member of the Duke Institute for Brain Sciences.

"If we're going to make claims about the importance of epigenetics in the human brain, we wanted to start with a gene that we have a fairly good understanding of," Hariri said.

This work is part of the ongoing Duke Neurogenetics Study (DNS), a comprehensive study linking genes, brain activity and other biological markers to risk for mental illness in young adults.

The group performed non-invasive brain imaging in the first 80 college-aged participants of the DNS, showing them pictures of angry or fearful faces and watching the responses of a deep brain region called the amygdala, which helps shape our behavioral and biological responses to threat and stress.

The team also measured the amount of methylation on serotonin transporter DNA isolated from the participants' saliva, in collaboration with Karestan Koenen at Columbia University's Mailman School of Public Health in New York.

The greater the methylation of an individual's serotonin transporter gene, the greater the reactivity of the amygdala, the study found. Increased amygdala reactivity may in turn contribute to an exaggerated stress response and vulnerability to stress-related disorders.

To the group's surprise, even small methylation variations between individuals were sufficient to create differences between individuals' amygdala reactivity, said lead author Yuliya Nikolova, a graduate student in Hariri's group. The amount of methylation was a better predictor of amygdala activity than DNA sequence variation, which had previously been associated with risk for depression and anxiety.

The team was excited about the discovery but also cautious, Hariri said, because there have been many findings in genetics that were never replicated.

That's why they jumped at the chance to look for the same pattern in a different set of participants, this time in the Teen Alcohol Outcomes Study (TAOS) at the University of Texas Health Science Center at San Antonio.

Working with TAOS director, Douglas Williamson, the group again measured amygdala reactivity to angry and fearful faces as well as methylation of the serotonin transporter gene isolated from blood in 96 adolescents between 11 and 15 years old. The analyses revealed an even stronger link between methylation and amygdala reactivity.

"Now over 10 percent of the differences in amygdala function mapped onto these small differences in methylation," Hariri said. The DNS study had found just under 7 percent.

Taking the study one step further, the group also analyzed patterns of methylation in the brains of dead people in collaboration with Etienne Sibille at the University of Pittsburgh, now at the Centre for Addiction and Mental Health in Toronto.

Once again, they saw that methylation of a single spot in the serotonin transporter gene was associated with lower levels of serotonin transporter expression in the amygdala.

"That's when we thought, 'Alright, this is pretty awesome,'" Hariri said.

Hariri said the work reveals a compelling mechanistic link: Higher methylation is generally associated with less reading of the gene, and that's what they saw. He said methylation dampens expression of the gene, which then affects amygdala reactivity, presumably by altering serotonin signaling.

The researchers would now like to see how methylation of this specific bit of DNA affects the brain. In particular, this region of the gene might serve as a landing place for cellular machinery that binds to the DNA and reads it, Nikolova said.

The group also plans to look at methylation patterns of other genes in the serotonin system that may contribute to the brain's response to threatening stimuli.

The fact that serotonin transporter methylation patterns were similar in saliva, blood and brain also suggests that these patterns may be passed down through generations rather than acquired by individuals based on their own experiences.

Hariri said he hopes that other researchers looking for biomarkers of mental illness will begin to consider methylation above and beyond DNA sequence-based variation and across different tissues.


Serotonin study explains why some people are more prone to anxiety

New research untangles anxiety's roots in the brain and points to improved treatment.

Anxiety is not a one size fits all experience. When faced with the same situation or stressor, some people remain calm, while others panic. Now, due to a strange new study on marmosets, researchers are one step closer to understanding why an event might cause some individual's anxiety to skyrocket while others remain chill.

According to research published Monday in the Journal of Neuroscience, trait anxiety — a general tendency to respond with anxiety to perceived threats in the environment — is tied to serotonin transporters operating in the brain’s emotion-processing center, the amygdala.

If the findings translate to humans, scientists may eventually be able to create faster and more effective anti-anxiety medications by targeting these brain regions.

People vary in their vulnerability to anxiety, and based on this research, there is a “clear neurological basis for this vulnerability,” co-author Shaun Quah, a neuroscience researcher at the University of Cambridge, tells Inverse.

“It is important for people to be more compassionate and understand that not everyone will react to the same stressor the same way some people are predisposed to be more sensitive to feelings of anxiety.”

Serotonin systems — Previous research suggests serotonin, the so-called "happy chemical," plays a pivotal role in regulating mood and contributing to mental well-being. The brain's serotonin levels are partly controlled by proteins on the surface of brain cells - the serotonin transporter. When transporter levels are high, serotonin levels are lower, Quah explains.

Common anti-anxiety and anti-depression drugs called selective serotonin reuptake inhibitors (SSRIs) target these serotonin transporters, and can sometimes successfully relieve symptoms in humans and animals. Because these oral drugs do not work for everyone, researchers — like this team — endeavor to make more effective treatments.

Previously, scientists didn't exactly know how serotonin systems in particular brain regions influence individual differences in trait anxiety.

To explore this question, researchers examined marmosets — small monkeys whose brains share “large similarities” to the human brain, Quah explains. These monkeys also show similar trait anxiety-like behavior to humans that is sensitive to SSRIs.

The team set up two experiments: In the first, researchers placed each monkey alone in a cage and exposed the animals to an unknown human wearing a mask. The human stood 40 centimeters from the cage and maintained eye contact with the monkey for two minutes.

They observed how the monkeys reacted before, during, and after encountering the human intruder. The researchers tracked how and where animals moved around the cage, shifts indicative of their level of avoidance. The team also documented if the animals bobbed their bodies or made vocalizations — behavioral shifts that indicate their level of anxiety.

The scientists used these behavioral cues to create anxiety scores for each animal. The animals with the highest anxiety scores spent the majority of their time towards the back of the cage, high up, remaining relatively still, and making head and body bobs and calls, the study reports.

Then, the researchers humanely euthanized the animals and analyzed various brain regions including the prefrontal cortex, amygdala, the dorsal anterior cingulate cortex, and raphe nuclei. They examined levels of expression for the serotonin transporter gene in these specific areas as they were involved in the brain's serotonin and emotion regulation circuit.

This revealed that monkeys with heightened reactivity (those that were the most anxious) had high levels of gene expression for serotonin transporters in their amygdala. This finding suggests serotonin signaling may be driving anxious behavior.

"As non-human primate's brains share large similarities to the human brain, our findings suggest that decreased serotonin signaling in the amygdala may, in part, underlie people's heightened reactivity to a perceived threat," Quah says.

The team conducted a second experiment to see if they could modulate this serotonin signaling. They selected six monkeys who exhibited trait anxiety. Then, they implanted thin metal tubes directly into their brains while they were under anesthesia. The team subsequently directly infused SSRI medication to the anxious monkeys' amygdalae.

Researchers then repeated the first experiment — exposed the monkeys to an unknown human and tracked their reaction. After the direct infusion, monkeys experienced immediate symptom relief and expressed reduced levels of anxiety-related behaviors.

Directly infusing SSRIs to the amygdalae caused a much faster anti-anxiety effect in the monkeys than typically seen with oral SSRI's medications. Symptom relief normally takes several weeks to appear if the drug is taken orally.

The research needs to be replicated in humans before it can be said with confidence that this version of SSRI treatment would work for people. Currently, implanting tubes specifically for anti-anxiety drug delivery into the human brain isn't a viable option, Quah says.

But these findings do suggest that targeting the amygdalae may speed up effective treatment for animals and people with trait anxiety.

"If you find yourself to be prone to feeling anxious, you should not consider it a personal failing," Quah says. "It is likely due to a natural disposition."

Quah suggests discussing methods of managing these feelings with a mental health counselor or therapist.


Epigenetics Might Help Us Predict How the Brain Responds to Threats

If you could predict how well your clients might be able to deal with stress, just based on a blood or saliva
sample, would that change your treatment approach?

There’s a specific gene that’s been getting a lot of attention lately because it affects how the brain processes serotonin – a chemical created inside the body believed to be responsible for maintaining mood balance.

The serotonin transporter gene codes for a molecule that regulates the amount of serotonin signaling between brain cells, and it’s a key target for the treatment of mood disorders. It’s also well known for its involvement in clinical depression and posttraumatic stress disorder (PTSD).

And recent discoveries in epigenetics are indicating that changes to how the serotonin transporter gene gets expressed might be involved in a person’s brain response to threats.

Now, I’ve talked a little about what epigenetics is before, but here it is in a nutshell: There are tiny molecules called ‘methyl groups’ that can attach themselves to our DNA, and when this happens, they can change how a gene is expressed. Essentially, the methyl groups will regulate where and when a gene is active.

What makes epigenetics different from ‘classical genetics’ is that, while the genetic code of your DNA doesn’t get changed structurally, stress or other factors in the environment can cause chemical changes in your body. The environmental signals can trigger those methyl groups to park themselves on your DNA, affecting the way your genetic code gets read.

Researchers at Duke University knew that differences in the DNA sequence of the serotonin transporter gene seemed to give some folks exaggerated responses to stress (and seemed to play a role in depression). But they wanted to look at how epigenetics might be at work here.

Led by Ahmad Hariri, PhD, the researchers recruited 80 college-aged participants who are part of the ongoing Duke Neurogenetics Study (DNS) – a collaborative study that’s working to link genes, brain activity, and other biological markers that could indicate a risk for mental illness in young adults.

First they used non-invasive brain imaging to look at the amygdala of each participant while showing them pictures of angry or fearful faces and watching their responses. The amygdala governs how we respond to threat or stress.

Next, they measured the amount of methylation (how many methyl groups were present) on serotonin transporter DNA that they isolated from the participants’ saliva.

And they found a strong correlation between the amount of methylation and the amount of reactivity they saw in the amygdala. Plus, they found that the amount of methylation seemed to be a better predictor of amygdala activity than any other variation in the serotonin transporter gene.

But the researchers wanted to make sure that what they were seeing wasn’t a one-time thing.
They took a look at a different set of participants, this time 96 adolescents participating in the Teen Alcohol Outcomes Study (TAOS) at the University of Texas Health Science Center at San Antonio. Using the same methods as before, the group found an even stronger link between methylation and amygdala reactivity.

So, epigenetics could be playing an important role in whether or not we’re getting enough serotonin to the brain, and in turn, that could be affecting our moods or how we respond to trauma.

Now we do need to be cautious – this work is strictly correlative, and it’s all just getting started. The next step will be to find out how methylation directly affects the brain.

If you’d like to read more about the work of Dr. Hariri and his team, you can find the full study published in Nature Neuroscience, volume 17, pp. 1153-1155.

Eventually this work might help us predict mental illness, using saliva or blood samples to show us whether or
not genes for specific disorders are, or are not, expressed.

You can learn more about how epigenetics is involved in trauma and what that could mean for the way you approach treatment – click here for our courses on trauma.

. . . if a tiny sample of saliva could help you better detect a client’s risk for something like posttraumatic

stress disorder, would you incorporate that into your treatment? And what sort of benefits do you think there might be from this? You can let me know what you think in the space below.


Sounding the alarm

The stress response begins in the brain (see illustration). When someone confronts an oncoming car or other danger, the eyes or ears (or both) send the information to the amygdala, an area of the brain that contributes to emotional processing. The amygdala interprets the images and sounds. When it perceives danger, it instantly sends a distress signal to the hypothalamus.

Command center

When someone experiences a stressful event, the amygdala, an area of the brain that contributes to emotional processing, sends a distress signal to the hypothalamus. This area of the brain functions like a command center, communicating with the rest of the body through the nervous system so that the person has the energy to fight or flee.

The hypothalamus is a bit like a command center. This area of the brain communicates with the rest of the body through the autonomic nervous system, which controls such involuntary body functions as breathing, blood pressure, heartbeat, and the dilation or constriction of key blood vessels and small airways in the lungs called bronchioles. The autonomic nervous system has two components, the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system functions like a gas pedal in a car. It triggers the fight-or-flight response, providing the body with a burst of energy so that it can respond to perceived dangers. The parasympathetic nervous system acts like a brake. It promotes the "rest and digest" response that calms the body down after the danger has passed.

After the amygdala sends a distress signal, the hypothalamus activates the sympathetic nervous system by sending signals through the autonomic nerves to the adrenal glands. These glands respond by pumping the hormone epinephrine (also known as adrenaline) into the bloodstream. As epinephrine circulates through the body, it brings on a number of physiological changes. The heart beats faster than normal, pushing blood to the muscles, heart, and other vital organs. Pulse rate and blood pressure go up. The person undergoing these changes also starts to breathe more rapidly. Small airways in the lungs open wide. This way, the lungs can take in as much oxygen as possible with each breath. Extra oxygen is sent to the brain, increasing alertness. Sight, hearing, and other senses become sharper. Meanwhile, epinephrine triggers the release of blood sugar (glucose) and fats from temporary storage sites in the body. These nutrients flood into the bloodstream, supplying energy to all parts of the body.

All of these changes happen so quickly that people aren't aware of them. In fact, the wiring is so efficient that the amygdala and hypothalamus start this cascade even before the brain's visual centers have had a chance to fully process what is happening. That's why people are able to jump out of the path of an oncoming car even before they think about what they are doing.

As the initial surge of epinephrine subsides, the hypothalamus activates the second component of the stress response system — known as the HPA axis. This network consists of the hypothalamus, the pituitary gland, and the adrenal glands.

The HPA axis relies on a series of hormonal signals to keep the sympathetic nervous system — the "gas pedal" — pressed down. If the brain continues to perceive something as dangerous, the hypothalamus releases corticotropin-releasing hormone (CRH), which travels to the pituitary gland, triggering the release of adrenocorticotropic hormone (ACTH). This hormone travels to the adrenal glands, prompting them to release cortisol. The body thus stays revved up and on high alert. When the threat passes, cortisol levels fall. The parasympathetic nervous system — the "brake" — then dampens the stress response.



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