The Resilient Brain: Epigenetics Stress and Lifecourse Early Life Deprivation Bruce McEwen

(digital whooshing) (digital beeping) (playful piano music) – [Narrator] We are the paradoxical ape, bipedal, naked, large-brained. Long the master of fire,
tools, and language but still trying to understand ourselves. Aware that death is inevitable. Yet filled with optimism, we grow up slowly, we hand down knowledge, we empathize, and deceive. We shape the future from our shared understanding of the past. Carta brings together experts
from diverse disciplines to exchange insights on who
we are and how we got here. An exploration made possible by the generosity of humans like you. (bouncy digital music) (energetic digital music) – [Bruce] I very much regret that I can’t be there in
person to give this talk and I certainly send my best to everyone. The starting point for this talk is the notion that the
human mind has evolved to be able to anticipate
and plan into the future. The downside is that we
sometimes stress ourselves out and get caught up in fear and anxiety by imagining and
anticipating negative things that will never happen. This was depicted by Robert Sapolsky in his book, “Why Zebras
Don’t Get Ulcers.” But what goes on in our brains and bodies when this is happening? So I’m going to speak to
you via this PowerPoint about a new way of looking not only at stress but at
experiences in general, whether or not we call them stressful, and how they affect both
the brain and the body, and shape the human mind. This involves epigenetics,
referring to mechanisms that express what is in our DNA to shape us as individuals
over our lifecourse and hopefully instill in us
the capacity for resilience. So what is stress? There is positive stress,
exhilaration from a challenge that has a satisfying outcome after giving a talk, or passing an exam. There’s tolerable stress
when bad things happen and yet we can show resilience and move on in our lives. For both of these, we need
to have good self-esteem, good sense of mastery
and control in our lives. But then there’s toxic
stress where there is a lack of this sense of mastery and control, and one can feel helpless. Poor self-esteem is probably a factor, lack of social and emotional support from friends and family but also there may be what we can call compromised brain architecture due to the effects of
early life adversity. Not everything is called stress and experiences related
to social isolation, circadian disruption as
in jet lag, shift work, just simply being deprived of sleep, living in ugly, noisy,
polluted neighborhood with a lack of green space, and of course, our health damaging
behaviors, diet, exercise, and alcohol, and smoking. All of these get under the skin and dysregulate our physiology. This slide highlights a
term called the exposome which is really the sum total of our experiences and environment that provide opportunities but also limit what we can do. It also points out that the brain is the central organ of stress and adaptation to it determines
those health behaviors, influences physiology, enables us to adapt or to become dysregulated and what is we refer
to as allostatic load, and reflects the experiences
over our entire lives. Allostatic overload
refers to the fact that the same mediators like
cortisol, and adrenaline, and anabolic hormones in the immune system that allow us to adapt and survive can also cause damage
when they are overused and out of balance with each other. The metaphor of heavyweights
on the seesaw illustrates that the system may maintain
it’s balance for awhile keep homeostasis but eventually
there is a breakdown, a wear and tear, a disorder. So we often talk about an inverted U-shaped dose response curve describing both the beneficial and the deleterious effects
of the same mediators. As a heads up for later on, this slide again points out the importance of individual differences early in life. Especially adverse
experiences early in life that can determine a
trajectory for our entire lives that may increase our
vulnerability to various disorders. Now we come to epigenetics
which speaks to how genes are regulated by experiences
that are mediated in part by hormones and
other chemical mediators in the brain and body. Epigenetics shapes individuals and it does so through
a number of mechanisms including transcription
factors, non-coding RNAs, the phenomenon of RNA editing, the methylation of cytosine
residues in the DNA, and modifications of histones. The genes that we have
determine what is possible. Let’s look at what happens
to a pair of identical twins because of what are called
non-shared experiences. Early in life children the
twins show very similar patterns of methylation of DNA as shown on the left but when twins are in their 50s there are considerable differences because of the fact that they haven’t always experienced the same things and certainly not at the same time. This is a reflection of how
experiences shape individuals even individuals that
have exactly the same DNA. Experiences via epigenetic mechanisms cause ongoing remodeling of
the developing and adult brain that involve not only
changes in gene expression but also structural changes
that are seen in dendrites, synapses, and limited
amounts of neurogenesis in the hippocampo region of
the adult and developing. Hormones and other systemic mediators of the metabolic immune system play a mediating role in
this brain plasticity. Stress, sex, and thyroid
hormones enter the brain and they bind to receptors,
and influence neural activity, gene expression, and
alter neural architecture. To do this, metabolic
hormones like leptin, ghrelin, IGF-1, and insulin have largely procognitive
and protective effects. Yet as we’ll see when there
is resistance to these actions because of a disease processes then other things not
so good things happen. The brain also contains
cells called microglia related to the immune
system that also responds to immune system cells and chemicals in a way that are just now being revealed. We discovered a number of years ago, that the hippocampus brain
region involved in memory and we now know mood regulation has receptors for
glucocorticoids like cortisol. This discovery actually provided
a gateway into discoveries by us and by many other laboratories that the hippocampus
and other brain regions for higher brain functions
like the amygdala, the prefrontal cortex,
the nuclei accumbens have receptors and respond to sex, stress, and metabolic hormones, and immune system chemicals, and also hormones even from
the bone and the muscle. Stress induces the
secretion of glucocorticoids and the of excitatory amino
acid neurotransmitters and these have biphasic
effects on the hippocampus. That is they promote, as we’ll
see, structural remodeling which as is not damage but in the extreme seizures cause irreversible
damage and neuronal loss to these CA3 pyramidal cells. Well as I said, repeated stress
actually leads to reversible debranching of apical dendrites that we think is actually
a protective response against permanent irreversible damage. A bit of evidence for this
is that hibernating hamsters that are low on energy resources show a rapid dendrite shrinkage of the CA3 neurons within hours and an equally rapid
regrowth when aroused. Which is an important ability in order to protect them from danger. Translational studies
on the human hippocampus have shown shrinkage of the hippocampus with major depression, also in diabetes, in post-traumatic stress disorder, and in Cushing’s disease, and
also of course in dementia. Of course, the hippocampus also changes without disease processes in
chronic stress over many years, in chronic jet jag, as for air crews who have regular international flights, with lack of exercise, and
also with chronic inflammation which is a common denominator
of many of the disorders like depression, and diabetes, and PSD, and Cushing’s disease. The good news is that when
people even in their 60s and 70s walk an hour a day five
out of seven days a week as in this study from the
University of Illinois over the six months to a year the hippocampus actually gets larger, cognitive function
improves, mood improves. Regular exercise is a
well-recognized antidepressant for mild and moderate depression. And what’s remarkable
based on animal studies is that the increase in neurogenesis which would be one of the factors that enlarges the hippocampus actually requires a hormone
from the liver, namely IGF-1. In animal studies blockade of that hormone by putting in immuno neutralizing it actually prevents exercise
from stimulating neurogenesis and there are other systemic factors that also appear to be involved
required, shall we say, for exercise to increase neurogenesis. I mentioned the metabolic hormones before, I’ll just remind you again
that in states of, for example, insulin resistance or leptin resistance the brain begins to malfunction. Insulin resistance is
associated with diabetes, it’s also associated with a specific form of depressive illness and people with these conditions have an increased likelihood
of developing dementia because of this dysregulation
that also affects the overflow of excitatory amino acids that can alternately
cause irreversible damage. So here we have the inverted
U-shaped dose response curve in which we have on the
upside the enhancement by moderate levels of cortisol and these excitatory
amino acid transmitters that are so important in the brain. Enhancement of cognitive function
but more intense activity can actually impair these same functions. As we sometimes say,
“Stress makes you stupid.” There is the adaptive
plasticity I’ve referred to, described already. There is the damage potentiation with seizures, stroke, and
head trauma which are very real and part of the downside
of the inverted U. And of course, brain aging is associated with extra glutamate and inflammation and degeneration of brain structures. And then the loss of
ability to show resilience and recovery after a challenge. For example, after a stressful experience, instead of spontaneous recovery if the state of anxiety pertains then one has an anxiety disorder and there needs to be
external intervention, either pharmacologically,
or behaviorally, or both. The hippocampus is not
the only brain structure that is effected by these
stressful and other experiences. The amygdala actually
turns on stress hormones and increases heart rate, it’s the nexus of anxiety and fear. And neurons in the amygdala actually grow and become more active, even while neurons in the
hippocampus are shrinking. In the prefrontal cortex, which is important for self
regulation of our behavior, mood, and impulse regulation, decision making, working memory, the prefrontal cortex also
shuts off the stress response. And so these brain structures are involved both in the systemic
responses to stressors as well as in cognitive
and in other functions and there is rearrangement of
their architecture as well. So far, we haven’t considered whether males and females differ. And indeed they do in many of
the things I have discussed. Sex differences involve not
only hormonal programming but also genes on the X and Y chromosomes and the mitochondrial DNA which
we inherit from our mothers. In fact, the entire brain has
receptors for sex hormones in both the male and female,
both types of sex hormones, androgens and estrogens
in both males and females. Many of these receptors
mediate what we call non-genomic effects that
change the cytoskeleton, modulate neurotransmitter release, effect how mitochondria
buffer calcium ions which is very important
to maintain free radicals at a moderate level, and also
there are cell nuclear effects that is genomic effects
in inhibitory interneurons that regulate excitatory neuron activity. One example of how males
and females differ in a part of the brain that we never suspected would be affected differently has to do with the stress
induced debranching of dendrites in the male of neurons in the prefrontal cortex that project to other cortical regions. They shrink with repeated
stress in the male but in the female brain
under the same chronic stress these neurons do not shrink. But then there are neurons
from the prefrontal cortex which project to the amygdala
and these don’t change with chronic stress in the male but the dendrites of those
neurons in the female that project the amygdala
actually expand their dendrites under chronic stress but only when there
are estrogens on board. Because this is so surprising
and because there are sex hormone receptors in
many parts of the brain we suspect that there are many
other subtle sex differences that are yet to be discovered. And indeed males and females
handle many of the same things with similar outcomes but
looking at how the human brain, human male and female
brain handles challenges it turns out that they use
somewhat different circuitry probably related to the
underlying sex differences some of which I have just
described in this slide. Another aspect of
plasticity and resilience is that when dendrites
shrink with repeated stress in the middle and then
recover on the right, the shrinkage has occurred
from the more distal parts of the dendrites further out but the recovery occurs more
proximately to the cell body. So these are different neurons
than they were before stress and yet functionally they appear to do many of the same things. So the brain is continually
changing and that’s. We haven’t addressed, so far, the effects of early life adversity on brain development,
brain body interactions. I promised you earlier that
I would talk about this and indeed a major focus of
ongoing work in our laboratory has to do with the effects
of early life deprivation and my participation in the National Scientific
Council on the Developing Child. Also it means that I’m involved in thinking about this
in human terms as well. An experiment on this next slide where the mother in this case mouse also rat is deprived
somewhat of the bedding so that she becomes less attentive and irregular in caring for her pups. They develop a behavioral alterations, increased levels of anxiety,
and if one looks as we did here at how the hippocampus
responds epigenetically, gene expression responses, it turns out that animals
subjected to early life stress have a more restricted response that to experiences later in life. This has implications
then there are studies, as many of you know, in the
human with early life stress having effects to alter the
ability of the human brain to respond in the same way. And of course then we come
to the developmental issues where children experience adversity. And this involves abuse,
neglect, the living in chaos and uncertainty, and also
the effects of poverty. Many of these things
overlap with each other. The consequences of which
include greater helplessness and distress, and poor
self-regulatory behaviors that can lead to such
things as substance abuse, mood anxiety disorders, and
in terms of brain development, indications are that out of
these various forms of adversity can alter the development
of the prefrontal cortex, have poverty leading to
smaller amounts of gray matter, a smaller hippocampus, and
the neglect of children. Lack of stimulation by
their parents results in development of a smaller vocabulary which has implications for their ability to function in society and education. And then there are systemic effects such as elevated blood pressure,
cardiovascular reactivity, and later on cardiovascular
disease, depression, diabetes, of substance abuse, and
antisocial behavior. So that when the brain is
programmed for uncertainty there is increase vigilance,
amygdala reactivity and the reduced capacity for what we call proactive planning. The question is, can this
be changed later in life? And the answer is we hope so. That the capacity for showing plasticity, brain plasticity combined
with, particular windows of opportunity such as adolescences the early life including also the mother, the pregnant mother,
transition to adulthood, family formation, and even retirement. These are opportunities for
interventions that can improve the trajectory towards a healthier life. So to summarize what I have told you, first I’ve told you that
experiences shape individuals epigenetically within
what our genes will allow. That there is something
called adaptive plasticity of the healthy brain that requires ongoing interactions with the body. Allostasis and allostatic
load and overload reflect the biphasic
nature of the mediators which epigenetic mediators that
is which can help us adapt. On the other hand, when
overused and dysregulated they can cause problems. It’s very important, of course, that there are sex differences which permeate the entire brain allowing males and females
to use different strategies but often with similar
outcomes in problem solving throughout life. Also there is the
continuity of the lifecourse including transgenerational
epigenetic effects that I’ve mentioned and in
particular early life adversity redirects and limits the
responses to experiences but because of ongoing adaptive plasticity windows of opportunity are
present throughout the lifecourse that allow interventions specific for that stage of the lifecourse in many cases to have beneficial effects. Collaborators and
colleagues are shown here, an enormous number. I can’t possibly go through all the names but obviously they’re the
ones who deserve all credit for many of the things
that I’ve talked about. I also want to acknowledge
the MacArthur Network for Socioeconomic Status and Health, the National Scientific Council for the Developing Child
which is ongoing now, and the Hope for Depression
Research Foundation that supports some of our
ongoing current research. Thank you very much. (audience applauding) (bouncy digital music)

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