Tracking toxic stress caused by adverse events has emerged as one of the new metrics that Rhode Island Kids Count is using to measure health and wellness of children in Rhode Island. 

And, neuroscience research focused on early life stress has developed new collaborative partnerships here in Rhode Island to explore how it may change brain development. 

Researchers at Brown University, led by Kevin Bath, an assistant professor in the Department of Cognitive, Linguistic and Psychological Sciences, are in the process of resubmitting their work to be published in the Journal of Neuroscience that details their findings on the ways that stress changes neurotrophins – proteins involved in promoting the survival, development and function of neurons. In particular, it will show that stress is accelerating the maturation of the brain on multiple levels. 

In addition, the research by Bath and his collaborators has just been selected as a “hot topic” at the Society of Neuroscience conference this fall.

The new paper, Bath explained, shows that stress is accelerating the maturation of the brain on multiple levels. “That is a really novel idea,” Bath told ConvergenceRI. “It’s always been thought that stress suppresses growth to impact brain development and function.”

At the suggestion of Christopher Moore, the Brown University neuroscientist involved with the development of bioluminescent optogenetics, ConvergenceRI sat down with Bath to talk about his latest research findings. It is a conversation that does not necessarily translate easily into an everyday vernacular.

But it is an important part of the conversation/convergence around toxic stress that ConvergenceRI is planning to hold this fall, tentatively scheduled for Oct. 28. Stay tuned for more details.

ConvergenceRI: Tell me about your latest research, what are you doing?
BATH: I’ve always been interested in stress, and stress-related development, and its impact on brain development, and how the brain works.

But, for a number of years, I kind of got pulled away from that.

Much of the work that I’ve been doing in my post-doctorate [years] was looking at the role of neurotrophins and their role in brain development and brain functioning, and the ways that they impact emotional development and pathological outcomes, such as anxiety.

I was in the emotional arena, but away from my love and my interest in stress, and how stress impacts the brain. 

Since coming to Brown, I was involved in the developoment of a behavioral testing facility for rodents. But just in the last year, I was appointed to a new faculty position in the Department of Cognitive, Linguistic and Psychological Sciences.

It’s an independent faculty position, where I can now pursue wholeheartedly my own program of research. So, this is where a lot of my previous work in stress and brain development is coming back into the central focus of my research.

I’m interested in how real life stress impacts brain development and its contribution to outcomes such as depression and anxiety. I also wanted to draw from my previous work and understand the role of neurotrophins in these outcomes. 

ConvergenceRI: For my readers who are not scientists, could you define what neurotrophins are?
BATH: Neuro is having to do with the central nervous system, and trophins are related to growth and development. 

Neurotrophins are a class of genes within the brain that are important for promoting the growth and development of neuronal cells. 

ConvergenceRI: Are there particular names, categories, or labels for neurotrophins?
BATH: The one that comes up most often is known as BDNF, or brain derived neutrophic factor.

BDNF levels have been shown to be decreased in depressed patients. Most anti-depressants elevate BDNF levels, and the degree to which BDNF goes up, predicts success of the treatment. In addition, mutations in the BDNF gene have been associated with increased risk for depression.

There are four neurotrophins – BDNF, NGF, NT3 and NT4. BDNF is the one that is most heavily expressed in the brain and most intimately involved in the regulation of brain development.

Importantly, the levels of BDNF change over the course of development. Peaks in BDNF have been associated with the opening and closure of sensitive periods in development (times that are critical for the development of such systems as vision and emotion). Disturbances in the peaks and troughs of BDNF have the potential to alter the development of these basic circuits with implications for lifelong functioning.

When we think about many neuropsychiatric disorders, they tend to peak during defined periods in development: for example, autism and communications disorders often emerge between two and four years of age; depression peaks during late adolescence and early adulthood; schizophrenia during the transition into early adulthood.

If we think about the timing of those various disorders, and begin to think about what’s happening in terms of the underlying neural development, and look for differences in onset and completion of these developmental events, we may begin to get a toe hold on the mechanisms that may underlie these disorders.

In my lab, we study the effects of early life stress on brain and behavioral development, and track these developmental events.

To do this, we use a mouse model. Our mouse model of toxic stress involves maternal bedding restriction.

ConvergenceRI: Can you describe it?

BATH: Typically, what happens, is that a mouse builds a nest, gives birth to her pups, sits on the nest, and takes care of her pups. During this time, the mother makes very few exits from the nest, just leaving to drink, get some food, and then goes back.

In the fragmented version [developed by a lab at UC Irvine], we take away the mother’s bedding, and we only give her limited access to materials. She builds a makeshift nest, but she doesn’t have the resources to make a full nest. She is stressed out about this; and leaves the nest much more often, running around to look for nesting materials.

Basically, what you have is a single parent who doesn’t have the resources to take care of the young, and gets stressed out, and then the stress gets transmitted to the young pups.

The research looks at what happens to the pups as they grow, compared to the control group, where the animals were reared with unlimited access to bedding material. In particular, what happens in terms of brain development.

In most stress models, stress results in a shrinkage of many portions of the brain (e.g. the hippocampus). They observe that the neurons shrink, losing branches and connections with other cells. These effects have been associated with impairments in learning and memory as well as the development of anxiety and depression. In humans exposed to significant stress early in development, you can use MRI to study the effects of stress on brain size, and see similar effects, with smaller hippocampi in stressed children compared with controls.

Based upon such observations, it has become doctrine that stress suppresses growth or causing the loss of connections needed for brain development.

But, that is not necessarily the whole story.

ConvergenceRI: What do you mean?

BATH: There have been a few studies that have shown opposing effects. Girls experiencing significant stress early in life have been show to have earlier menarche [first period].

What we’ve found in our mice is that, in response to stress, the pups brains are maturing faster. To show this, we looked at several measures of neuronal development, including the process of myelination (the fatty wrapping around axons of neurons that insulates them and helps them communicate more rapidly). We also found that some late developing types of neurons (Parvalbumin cells) arrived earlier in the brains of these animals. 

[Bath shows a slide on his laptop that captures the results of his research, looking at the impacts on stress on maturation.] 

ConvergenceRI: How does this translate into potential applications in making us think differently about toxic stress in early human development?
BATH: When you think about stress in adults, when you think about depression in adults, what is the typical course of treatment? You give them anti-depressants. As I mentioned earlier, antidepressants increase BDNF to help grow connections between cells in the adult. 

However, in early development, if the negative outcomes are related to the premature maturation of the brain, giving anti-depressants may exacerbate this acceleration. It's possible that these treatments may be making it all that much worse when used early in development. This may be contributing to some of the paradoxical effects seen in kids treated with antidepressants (worsening of symptoms). However, studies of the interaction between stress and antidepressant treatment in the developing brain still need to be done.

We should also be thinking of other ways to intervene to mitigate the effects of stress, rather than simply using pharmacological approaches.

ConvergenceRI: With toxic stress, are there applications for the use of bioluminescent optogenetics, which is a platform technology, that could be useful to help slow down the maturing process of those cells as a result of stress?

BATH: Yes, it may be very useful to quiet down some of those early maturing cells during early development. 

ConvergenceRI: There’s a pilot program now underway to develop a diagnosis and treatment guidelines for toxic stress in pediatrics. How could the research that you’re doing potentially influence their diagnostic work to make it more complete?
BATH: Based upon our work, we are identifying potential biomarkers of adverse stress effects on the brain (including measures of maturation) that can be compared against population norms. 

In addition, we are identifying potential pathways through which stress is impacting brain development, and peripheral measures of those genes or mutations in those genes may be useful in identifying individuals at risk for adverse outcomes. 

ConvergenceRI: Are you familiar with the work being done by Audrey Tyrka and changes in mitochrondial DNA related to stress?
BATH: Yes, we have had a running dialogue for the past several years and have been working to develop mouse to human translational studies.    

ConvergenceRI: What kinds of potential applications are there for your work in terms of addiction?
BATH: There’s a significant amount of work on stress related to cocaine addiction and smoking addiction. Stress has been implicated in altering the expression of genes associated with tagging events as positive versus negative outcomes.

Many of those studies have also identified changes in neurotrophin expression as a critical factor mediating negative outcomes. With stress, many of the positive signals resulting from drugs of abuse becomes more potent for the animal, and possibly humans as well, driving a higher risk of addiction and abuse. 

ConvergenceRI: What role might calcium ions play in strengthening or modifying such signals?

BATH: Calcium is a major player in many of the basic events regulating cellular excitability and plasticity.  I believe there is strong reason to believe that changes in calcium signaling are also related to many of the negative outcomes that we (and others) are observing.

ConvergenceRI: Will you be willing to participate in the planned conservation/convergence around toxic stress this fall?
BATH: Absolutely.