Feeling stressed at times is of course a normal part of life and not necessarily a bad thing. It can focus how we react to dealing with specific problems or tasks, or can motivate a course of action to completion. But unchecked chronic stress is different. It can result in emotional, psychological, and even physical effects that interfere with life. The connection between exposure to significant amounts of stress early in life with chronic stress later in life is well established. Early life stress can lead to a three-fold increase in the susceptibility to chronic stress induced depression and other psychiatric disorders during adulthood in response to stressful triggers, depending on the severity and timing.

But what happens in the brain that is responsible for this connection has remained largely a mystery, until now. A new study published in Nature Neuroscience has identified a molecular mechanism responsible for a series of gene changes that link early life stress with chronic stress later on. Importantly, in proof of concept experiments in the same paper, the authors show how these gene changes can be reversed using a small molecule drug.

This work is particularly timely given the unknown effects that the Covid-19 pandemic will have on children years and even decades from now.

What Happens in the Brain Following Early Life Stress

The human brain is built in a way that mirrors its evolutionary and developmental history. Biology tends not to replace things that are working, it builds on top of them. Instead of fixing what isn’t broken just use what works and make it better, is biology’s Moto.

In the case of the brain, while the cortex gets all the attention for being responsible for higher cognitive processes, it is the youngest part of the brain in terms of the evolutionary timeline. The comparatively older parts of the brain that sit below the cortex deeper down support the fundamental functions necessary to support life. To ensure the survival of the organism and species, these more primitive functions had to precede cognition and the ability to contemplate the meaning of life. Things like appetite, sex drive, thirst, and breathing. Emotions, the reward circuits that drive pleasure from external stimuli, and how we respond to stress are also complex neural functions in these deep brain structures.

One of these important deep-brain structures is an area called the nucleus accumbens, a group of neurons that integrates information from different brain regions to fine-tune how we respond to stress. It is what drives us towards positive stimuli and away from negative or damaging ones. So it is critical in regulating how susceptible one might be to depression and related challenges in the face of stressful conditions.

Experiencing stress during early life does not necessarily mean that chronic adulthood stress and its effects on mental and physical health are inevitable, but it does prime the brain to respond in a way that makes chronic anxiety or mood disorders more likely if the individual is exposed to a major stressor later on in their lives. It is what the researchers describe as an increased sensitivity to a ‘second hit’ of stress.

Catherine J. Peña, Assistant Professor in the Princeton Neuroscience Institute at Princeton University and one of the two senior authors of the paper, explained how early life stress in the form of “deprivation and neglect can have distinct effects from abuse. For a long time they were lumped together. But recent studies over the last ten years have started to tease them apart. Timing is key. The type and timing of stress changes what symptoms occur later.”

A Domino Effect of Molecular Changes

Intense stress in early life can lead to transcriptional changes that affect the neurons in the nucleus accumbens. Transcription is the first step in gene expression and the production of proteins. An RNA copy is made of a gene’s DNA that encodes the target protein to be synthesized. Disruptions to transcription can result in serious affects downstream on the physiology and functions of the brain and, indeed, the entire body.

An increased susceptibility to adulthood chronic stress as a result of exposure to early life stress is mediated by transcriptional changes occurring in the nucleus accumbens. This effect is what scientists refer to epigenetics – the study of how heritable traits and the environment affect what genes get turned on and off. Unlike mutations though, epigenetic effects are not mediated by any changes to the underlying sequence of DNA, just the selection of genes that get activated.

Uncovering the molecular details responsible for these changes though required a bit of scientific detective work. Eric J. Nestler, Professor and Dean for Academic and Scientific Affairs at the Icahn School of Medicine at Mount Sinai and the paper’s other senior author, pointed out that “epigenetic modifications over fifteen years ago were suspected as a possible mechanism by which behavioral experiences produce long term changes”. But what gene and molecular modifications were in fact the link has not been clear.

The researchers eventually zeroed in on two key enzymes that affect the structure and, as a consequence, function of chromatin. Chromatin is the material that chromosomes are made from – a combination of DNA and proteins that help keep the DNA tightly coiled inside a cell. The set of chromosomes in the cells of our bodies, including neurons, are the carriers of our genetic information.

They knew that modifications to chromatin could cause changes in gene expression long after the perturbation that causes the modification in the first place. In the case of early life stress, the culprits turned out to be transcriptional alterations to two enzymes that regulate a particular biochemical reaction responsible for how chromatin is made.

During normal development, this biochemical reaction (a dimethylation reaction of a DNA packaging protein called Histone H3) is tightly regulated by these two enzymes, but is dysregulated when alterations to the enzymes occur. What is responsible for the transcriptional changes to these enzymes? Physiological effects induced by intense stress during critical developmental periods in early life.

From Molecules to Neurons to Potential Treatments

Adding further weight to their argument is the fact that the researchers were able to show that these molecular changes predominantly occurred in a subpopulation of neurons that were previously shown to be associated with an increased susceptibility to depression. Another major subpopulation of neurons, known to induce resilience to chronic stress, were less affected.

Encouragingly though, they were able to at least partially reverse the increased susceptibility to chronic stress by treating the mice in their study with a small molecule that inhibits the function of one of the two modified enzymes. And while these studies were carried out in a mouse model of stress, meaning that much more work needs to be done before any of these results can be clinically translated into a drug that can treat chronic stress in humans, it is an important pre-clinical proof-of-concept step.

As Dr. Nestler explained, the test drug was given to the mice as adults while they were experiencing stress. “The next step is to see if it is equally effective after stress.”

Implications for the Covid-19 Generation

Much has been written (and speculated) over this past year about the potential economic, societal, mental health, and educational impacts of Covid-19 on children and young adults. The Centers for Disease Control (CDC) reported that starting in April of last year, the number of pediatric mental health related visits to emergency departments across the country relative to the total number of pediatric emergency visits went up significantly compared to 2019. For children 5 to 11 years of age the increase was about 24%, while for the 12 to 17 age range it was 31%. Furthermore, the numbers remained at these levels through at least October of 2020 – the period covered by the study.

The authors concluded that “Monitoring indicators of children’s mental health, promoting coping and resilience, and expanding access to services to support children’s mental health are critical during the Covid-19 pandemic.”

A number of peer-reviewed clinical studies have documented the psychological, social, and mental health implications of the pandemic on children and adolescents, along with guidelines for doctors and parents on how best to provide support tailored to the age range and needs of the child. A number of experts have also been suggested that the effects on children from the Covid-19 pandemic are on par with other natural disaster and life changing traumatic events experienced by younger individuals. Presumably, this implies that both short and long term effects might mirror what has been observed in children exposed to such other events.

Clearly, intense and traumatic levels of stress have been and continue to be experienced by at least a significant percentage of children due to Covid-19 worldwide. If, and to what degree, this translates into an increased susceptibility for chronic stress and associated clinical disorders in the later years of life of remains to be determined.

As Dr. Peña explained, the loss of a parent “is roughly equivalent to the level of trauma” they modeled in their study. But in some cases, extreme stress experienced by the parents could be passed on to children second hand. Such situations could arise, for example, trying to balance work and family life during the Covid-19 lockdown, as a result of the loss of a job and income, or if a parent cannot be there for their child emotionally. Of course, these considerations are not just limited to this past year, and are of broader significance than just the pandemic, relevant to any situation that causes extreme stress in a child.

Luckily though, it is not all bad news. Dr. Peña also pointed out that parents, care givers, and communities are generally able to do a good job of buffering a child’s stress response.

Still, continued research into understanding and mitigating the neurobiological link between early life stress and chronic stress may be more important than ever given the number of individuals potentially affected. Such research is not only foundational for potential future clinical treatments for depression, anxiety and other related disorders, but also provides a scientific grounding to support broader economic, social and policy considerations.