Impact of Early Life Deprivation Danielle Stolzenberg Marcus Pembrey Bruce McEwen

(cheerful piano music) – [Narrator] We are the paradoxical ape. Bipedal, naked, large brain. 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. (electronic music) (light electronic music) – So I’ve spent my research career focusing on the phenomenon of mothering, and I’d like to start with a video that I think does a good job illustrating why I find mothering to be so phenomenal. The maternal instinct is sometimes greater than the instinct for one’s own survival. And you can see this wild rat was caught chasing a predator, attacking this predator, so
that it would release her baby, or pup, as we call it. And my favorite part is the last part, where after the snake releases the pup, she actually continues
to run after the snake and continue to attack it, just to make sure that it gets the point to stay away from her nest. So certainly, this behavior
is not limited to wild rats, but we can see these kinds of behaviors in the laboratory, as well. This is a rat from my lab, and we were weighing her pups one morning, she’s rearing them in a
semi-natural environment, so this is outdoors, and you can see, she wasn’t having any of it, and she retrieved each one of her pups back into her nest box. So rats aren’t the only
ones that care for infants. Maternal care is a defining characteristic of mammalian behavior. And this behavior is really motivated, and it’s also unconditional,
so as we saw in these videos, moms care for infants
across multiple contexts, even when those contexts
are quite challenging. So it’s not escaped my attention that not all mothers are committed to the survival of their
infants, unfortunately, and this is quite predominant in humans. So we’ve already heard a little bit about this earlier today, but the statistics are
really quite staggering. So three million annual reports of child abuse in the United States. Many of these incidents go without report, so I think this is probably
a conservative estimate. Five children die every single day, due to abuse, maltreatment, or neglect. And actually, a large portion
of abuse or maltreatment is neglect, failing to care for infants, failing to provide basic food, water, shelter, protection from harm, as well as, of course, emotional support. Every 10 seconds is how
often abuse gets reported. So these statistics, for me, were really staggering when I read them. And I think what I find most outrageous is that despite the prevalence of neglect, we know almost nothing about dysfunction in the maternal brain. And to me, this is a huge
gap in our literature that we really need to focus on. So today, I want to
propose, first and foremost, that studying mothers has merit. If we want to understand how
to prevent child neglect, I think it’s important to understand what causes a neglectful parenting
style in the first place. And with respect to this, I want to talk about my hypothesis for one of the ways that I think neglect might emerge, and that’s related to disruption in experience-dependent plasticity within the maternal brain. And specifically, on
talking about neural systems that have been identified in rodent models that we know are important for the onset of mothering behavior. And these systems are changed during this transition to motherhood, to both increase the likelihood that positive responses are
displayed towards infants, but also, and importantly,
to reduce the likelihood that some negative,
fearful, defensive type of response occurs when moms
are interacting with infants. So my laboratory has
addressed these issues using rodent models, and
I think it’s important to take a moment and
talk about why I think that studying rodents can tell
us something about humans. So first and foremost, what we know about the neurobiology of parental care actually comes from work
that was conducted in rats, so rats have been a really
important model organism for studying caregiving behavior. They reproduce well in the laboratory, they have short gestations. But what’s, really, I think,
most important is that they don’t form selective
attachments with their young. And so when we talk about
selective attachment, I’m talking about this idea that a mother would recognize its own infants, and distinguish its own
infant from other infants, and provide care and support
only to its own infant, while actually actively avoiding or rejecting the advances
of any other infant. I’m not really interested in mechanisms that underlie infant recognition, and that’s why I think it’s important that rats allow us to study questions about motivation to interact
infants, more generally. And we can therefore use foster infants when we conduct studies
with rats and with mice to ask questions about the
capacity an animal might have to show caregiving behavior, regardless of whether or not
it’s actually appropriate for that animal to show
caregiving behavior at all. We don’t have to worry about lactation, variability in the health of
offspring, any of those things. We can ask questions about, how does this animal respond to infants, how can we turn caregiving behavior on? In this regard, I think
one of the greatest things about using rodent models
is we can ask questions about turning caregiving
behavior on in males. So rodents are uniparental. Like most mammalian
species, it’s the mother that provides the sole care, but because we can use foster pups, we can ask questions about what turns on mothering-like
behaviors in males, and I won’t have time to
talk about that today, but I think it’s an important point. So the first indication that experience might be an important regulator came from work that was done studying the onset of maternal behavior in rats. And this work was conducted
by Alison Fleming, and at the time, people
were really interested in hormonal changes that happened around the time of birth that
function to synchronize birth with the onset of maternal motivation, and the onset of care. And those hormonal changes
are undoubtedly important, but Alison really wanted to ask, what happens in a situation where mom isn’t allowed to interact
with her infants anymore? Will those hormonal events
produce a longterm change in how she perceives infant stimuli, or is it the experience of interacting with infants that’s really important? So to address this, she separated
mother and her offspring right at the time of
birth, and what she found is that this separation
actually completely blocked the onset of caregiving behavior, and produced this state
of infant avoidance. So rats are not particularly keen on interacting with infants if they haven’t given birth to their own, and so these animals
kind of reverted back, as though they had never given
birth to offspring at all. So this is a graph you
can see from her paper. On the left, you see
animals with no experience, so those that were completely
separated from their infants, literally took days to show
any caregiving behaviors at all when presented with foster infants. Animals with full experience that naturally interacted
with their infants at birth were immediately responsive to young. And so again, what’s important about this is that although hormonal changes that are associated with
pregnancy and birth are important, they certainly aren’t producing any lasting effect, in and of themselves. Instead, it’s interacting with infants in the context of those hormonal changes that’s so important. So she concluded, experience
is necessary for care. And when I started my own lab at UC Davis, I was actually interested
in the opposite question. So if we can remove experience, and completely obliterate the onset of maternal behavior at birth, can we deliver experience to animals that have never been pregnant, and can we get these animals to show a level of caregiving behavior that’s on par with what
a new mother would show? And I did this work using a mouse model, and I had to give them a challenging task, so rodents are very neophobic,
they hate new things, this is a novel environment, and I was asking whether
they would be willing to rescue infants in
this novel environment, rather than try to find an
escape route for themselves. And what I found is that if they had no experience at all with infants, they’d never seen an infant before, they were more likely to spend
all their time on the maze trying to find a way out. However, if they had as little
as eight hours of experience, as you can see, they retrieve
pups back to the nest. And so this graph actually represents a meta-analysis from my lab. I’ve shown this now several
times, replicated it on a number of publications, and these are all of the
data lumped together. And you can see that around 80% of females with no experience
at all avoid infants, look for an escape route on the maze, whereas as little as
eight hours of experience produces a completely different effect. And what I found to be most exciting when I ran these first
experiments is I thought, new mothers respond to infants with high levels of motivation, and that tends to be consistent for a long period of time. And so I said, “What
happens a month later?” And what I found is that, a month later, even though these animals had not had any additional interactions with infants, really seems like some
plasticity took place, because they responded
in exactly the same way. So I concluded, then, that
experience with infants in the absence of pregnancy and birth can promote maternal care,
it can block avoidance, and therefore, experience
is sufficient for care. So I was excited when I
conducted these studies, and it kind of led me to think, well, if experience is so critical for caregiving behavior, what if neglect is actually related to some disruption or dysfunction in experience-dependent plasticity? And I had to ask myself
the obvious question. Is neglect a failure to learn? But is this relevant at all to humans? Is there any evidence at all that experience is involved
in human parenting? So I scoured the literature,
and lo and behold, I found that there is a lot of evidence that increased contact
between mother and infant just after birth can promote attachment, can promote maternal care for years beyond that period of time. But I found one paper that I thought was particularly compelling, and this work was done in the ’80s, and at this time, it wasn’t very common for mothers to actually be able to interact with their
infants after birth. The infants were typically
taken to a nursery, unless the mothers were
financially well off enough to afford their own maternity suite. So in this paper, the
authors looked at mothers that were considered to be high risk. So these were very young women, low socioeconomic status,
considered to be high risk for potential abuse and neglect. And they conducted a
really simple manipulation. Half these women were
upgraded to a maternity suite, in which they could spend
just a few extra hours with their infants on the day of birth, and then the authors followed
these women for years. And what they found is that, women who had experienced
this rooming-in manipulation were significantly less likely to show any signs, or show any
pathology in their parenting. On the other hand, control women that were subject to the
standard procedures of the time had substantially more instances of child abuse and neglect, and I thought this was
really compelling evidence. So in my laboratory, what
we’ve been focusing on is trying to understand the
neurobiological mechanisms that regulate caregiving behavior, and importantly, prevent neglect. And in thinking about this, I’ve turned to what we
know about the neurobiology of the onset of care, again, work that comes from rats. And this work suggests that not only do maternal neural systems need to be turned on for motivation to occur, but also, infant access to
defense, fearful circuitry, needs to be limited,
needs to be turned off. And so there are kind of these
two distinct neural systems that need to be manipulated in order for the appropriate response
to infants to be selected. So to get a little bit more
specific about what I mean, when I refer to infant stimuli and behavioral responses, I’m talking about sensory cues from the infants, vocalizations, odors, etc., and I’m wondering how these cues lead to these two distinct
behavioral responses, neglect versus care. We know from rat literature that there’s a defensive neural system that can be activated before
a female becomes maternal, before the onset of care, and my work recently in mice has shown that when females are ignoring pups on that novel maze, we see an activation of
this same defense system. On the other hand, caregiving responses are associated with activation of reward pathways within the brain. And the idea really is that
the medial preoptic area, which is the central
site for maternal care, it’s an important region
in the hypothalamus that we know regulates caregiving behavior in many studied species likely plays a role in
coordinating appropriate responses by simultaneously
inhibiting the activation of this defense system, and activating the activation
of this approach system in response to infant cues. And so the idea is that
sensory cues from infants might reach this defensive
system to induce neglect, but once plasticity has
occurred in the MPOA, the MPOA inhibits that activation. So even if sensory cues are still capable of reaching this defense system, they don’t result in
any neglectful behavior. And then simultaneously,
this approach system is activated to induce care. So in my laboratory, what I’ve been particularly focused on over the last few years
is trying to understand how this plasticity occurs within the medial preoptic area. And specifically, if we think
about hypothetical neurons which project to these
two different systems, I’m interested in how pup
cues alter gene expression. So the idea is that, infant cues, which are processed by
receptors at the cell surface, can induce cascades which function to alter the activity
of regulatory molecules that then affect which
genes are expressed, when these genes are expressed, to mediate plasticity, or change the way these neurons respond to
infant cues in the future. And through this plasticity, we’ve hypothesized that there’s a permanent reduction in neglect, and a permanent upregulation in care. So in summary, caregiving behavior is critically regulated by
experience, we’ve seen that. Understanding how experience sustains care and prevents neglect, I think, has really critical
implications for child neglect. Work from rodent models indicates that infant neglect occurs
when infant cues fail to activate a neural reward system, and instead activate a
neural defense system. And I think the key to understanding the neural basis of neglect is to uncover the critical events that happen within these neurons of the medial preoptic area, which then program the
appropriate neural system, and hence, appropriate
response to infant cues. So I just would like to
acknowledge members of my lab who have contributed to the
ideas and work I’ve show here, and of course, also,
my funding from NICHD. Thank you. (audience applauds) – It’s a pleasure to be here, and the first thing I should say is that I’m not actually a nutritionist, but I’ve had a very long standing interest in what contributes to the
developmental variation in people at a population level. Now of course, if I wanted
to follow up that interest, one needs a population. (chuckles) And, being a geneticist, I also not only wanted the children, but also both parents. So Jean Golding and I set up the Avon Longitudinal
Study of Parents and Children in the late ’80s. And that has a wealth of information about nutrition and so on, and so that’s partly, I think,
why I was asked to talk. The first thing I would
say, right at the start, is that the development variation we see in the population is not just down to the DNA code that you inherited from your parents and the prevailing environment. There is a lot more to that, and I hope to bring that out in this talk. Now, nutrition and human cognitive
development and evolution is an absolutely massive topic, so I had to focus on something,
and iodine was the one. This is one of the many
minerals and vitamins that are absolutely essential for normal cognitive development, and of course, it operates through the thyroid. I’m then going to look to the payoff between a large enough birth canal and maintaining body size in the face of variable food supply. And along the way, I will
point to the evidence that information about the early
life nutritional experience of parents and grandparents
is biologically transmitted to the next generations, along with genes. Now the story of iodine deficiency, this is an admirable
statement here, from UNICEF. “Iodine deficiency is so easy to prevent “that it is a crime to let a single child “be born mentally
handicapped for that reason.” Well, I’m going to demonstrate that it’s not as simple as all that. The message which will keep coming back is what happened in
the previous generation that sets the scene for the current? But there was a bit of
luck in the early days. Iodized oil was developed as
a contrast to use in X-rays, so when you were looking for TB, and so you could see the cysts, and so on. And it had already been proven to be safe to be injected in humans. And so this gentleman in New Guinea, he had this nodular goiter
of his thyroid, and we can see that that was reduced within just three months. But what about the less
severe end of the spectrum? Now this is the ALSPAC cohort data, and you will see that on the top, we’ve got the verbal IQ, to the left, and then the total IQ, and then the reading accuracy and the reading comprehension, below. And this is in relation to the maternal urinary
iodide concentration in the first stages of
pregnancy, the first trimester. In fact, during the first trimester, the fetus itself is not
generating very much iodine. I think the point I want to show here is that it isn’t an all or none situation. Even the suboptimal situation here, of iodine, has a significant
reduction in verbal IQ. And at the bottom, as I say, we have the maternal concentration. So clearly, and one thing I should say before leaving this is
that it’s the verbal IQ that has been replicated when you bring all the different studies together from different populations. And you can see, it’s the
more significant one here. So that’s a thing to hang onto, there. So, iodine is central
to the thyroid system, and it’s essential for the cognition. You’ll note that the thyroid hormones, here, which are produced by the thyroid gland, and stimulated the thyroid
gland to produce them from the anterior pituitary
and the hypothalamus, T3 has three iodines,
and T4, four iodines, so you can see the connection. And thyroid hormones are crucial for increasing metabolism, growth, and development of all sorts, and also maintaining the
flight and fight response. But the thing that we need to emphasize is this negative feedback system. The negative feedback system is sensitized to developmental experiences, and adjusts for the long term. Also, that it’s not just the
long term of the individual, but even can across the generations. And it’s maintaining brain plasticity. Thyroid hormones tends to make cells reach their full differentiation,
and if you want plasticity, that’s got to be delayed. But what about this situation
across the generations? Well this just takes
us to the lovely island of Sao Miguel in the Azores, and there was a natural experiment which assessed the
non-genetic transmission of altered thyroid function,
down the generations. There was an ancestor, five
or six generations back, who had a very rare standard
genetic monogenic mutation, involving one of the
thyroid hormone receptors, which meant that 50% of her children would inherit that mutation. Now, the ones who did
not inherit the mutation, they were, of course, exposed to the very large dose of thyroid. It’s as if the mother, during pregnancy, was the environment, a very high dose of thyroid. And they followed the
genetically unaffected males down for three generations, from that exposure. And this induced… And what happened was that the exposure led to a low sensitivity
to thyroid hormone. But remarkably, it was
then transmitted on, long after that situation. Now we move to the bonobos. They live in communities, and there’s a two year bonobo
project that I’m referring to, and here’s a picture of them fishing for, in this case, the white water lily. The Congo Basin, where they live, is known to be iodine-deficient. And so it was particularly interesting to look at the mineral
content of the various things that were found in these fishing trips. They go to the swamp, during
this two years of observation, they would go every two weeks, and when they were there, they’d spend about 96 hours feeding. They would go with their… All the adult bonobos would go and feed. So would the juveniles, and
the older infant bonobos. So they analyzed what they were eating, and they found that they
were particularly going for the stem of this lotus. They would discard all the rest, but just choose the stem. And that had this iodine content of milligrams per kilogram of dry matter. And then they went for
the pith of the Juncus, which is a form of reed,
which I’ve shown here. And again, it’s the root just
under the water they go for, and that has 7.4 iodine level, and that is comparable to
the algae along the coast, and it ties in with the notion that early hominids
tended to be on the coast, because there was a
ready supply of iodine. Now interestingly, you might say, “Well what about the
humans in the Congo Basin?” Most of them, and this is why it got a iodine-deficient classification
by the WHO, is that they show symptoms of iodine deficiency. The only exception that
didn’t show marked symptoms of iodine deficiency in a large proportion were the Efe tribe, but they’re a tribe of pygmies. And the speculation is that the relative lack of iodine there, there were genetic mutations,
variants, that selected for, so that they basically became pygmies. They wouldn’t grow so much, so, much less demand. Now these next people are certainly not pygmies. The neanderthal. Now we’re all, in a way, related to the neanderthal. All of us, most of us, in this audience would have neanderthal DNA in us. And a group this size, you could construct a very large part of the
neanderthal genome sequence. Now as you can see here,
the neanderthals are big, they have big heads, and
they have wide pelvises. And that fits with the pattern that if you have a large
brain, and a large cranium, you need a wide pelvis and a birth canal. So you have to have a big size. And then the problem comes,
what if there is lack of food? What of the variation in the food supply? Unless of course there’s
a different strategy, that the baby is born
relatively early in development, and can be successfully
nurtured by the group, as the brain develops,
the development continues. And one can wonder, was
this the virtuous circle for the emergence of modern humans? That just because of the food supply and everything else, the variation in it, they needed to have smaller
babies born earlier. But that strategy would
only survive and work if there was that cooperative
nurturing, and so on. So now, let’s look at the situation with regard to the previous generations. Now, what we have here is, the situation, we’re all inside our
mothers for nine months, and it’s a sort of Russian doll effect. And Chris Kuzawa refers to this integrated
nutritional signal. So you have these intergenerational
phenotypic inertia. What he’s really saying is that, when there’s a swing in the food supply, you don’t suddenly get babies
being born bigger or smaller, there’s something that
integrates the past experience. But what about the fathers? Now these are human males. (chuckles) Human males, sorry. (audience laughs) The human sperm, from… The question is, do they carry information about the ancestral environment? Well, we looked at this
in Northern Sweden. Some of you may have seen the film, “The Ghost in Your Genes.” And it was a relatively small study, it was obviously started
by Professor Bygren, and, we had 303 probands, they were essentially the grandchildren that we would
know what they had died of, and what their mortality rate was. And then the food supply
of the father’s father, when he was very young, before puberty. So, a way we can look at it is that this is the grandfather’s age. This is the grandson’s
mortality risk ratio. So if it’s over one, they’re dying early. You can see that a good food
supply during this period leads to increased
mortality of the grandsons. And a poor food supply leads to increased longevity, of the grandsons. So this is what we’re seeing. The food supply between ages of 10 and 12, coming down through the
father to the grandson. No effect on the granddaughters, but quite a significant
increase in mortality. Now the good news is that
this has now been replicated by Denny Vagero and
his colleagues in 2018. So we have this original paper, and it was the sex-specific
male line response that we were particularly focused on. He looked at it and found
that exactly the same, he did exactly what they
did in the Overkalix study, in terms of the timings,
and everything else, all based on the harvest
records, and so on. And he found the paternal
grandfather’s access to food is critical, mid-childhood period, predicts all-cause, and also
cancer mortality in grandsons. And this is, the important take home message is it’s the poor food supply that leaves the grandsons living longer. And my conclusions are this. Mother’s nutrition affects her baby’s IQ. We’ve just seen the
example with the iodine. Mother’s nutritional
experience is a composite of hers and of her own parents’, in terms of the signals passed
on to her own offspring. And the father transmits information about his own father’s
access to food mid-childhood to his future offspring. This influence to the grandson’s longevity is on longevity at present, but cognitive studies are awaited. And these are the people
I’d like to thank. (audience applauds) – [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 life course, 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 an 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 disregulate our physiology. This slide highlights a
term called the exposome, which is really the sum
total of our experiences, which, an environment that
provides opportunities, but also limits 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 disregulated
in what 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 metabolic
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 having weights on the seesaw illustrates that. The system may maintain
its balance for a while, keep homeostasis, but
eventually, there is a breakdown, or wear and tear, a disorder. So we often talked 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 hippocampal region of the adult and developing. Hormones and other systemic mediators of the metabolic and 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 neuronal activity, gene expression, and alter
neuronal architecture. To do this, metabolic hormones like leptin, ghrelin, IGF-1, and insulin have largely pro-cognitive
and protective effects. Yet as we’ll see, when there
is resistance to these actions because of disease processes, then other things, not
so good things, happen. The brain also contains
cells called microglia, related to the immune system, and 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 nucleus 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 release of excitatory
amino acid neurotransmitters, and these have biphasic
effects on the hippocampus, that is, they promote, as we’ll see, structural remodeling,
which is not damaged but in the extreme, seizures
cause irreversible damage and neuronal loss to
these CA3 pyramidal cells, while, 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. One 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, and chronic jet lag, 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 PTSD,
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, immunoneutralizing it, actually prevents exercise
from stimulating neurogenesis. And there are other systemic factors that also appear to be involved, or 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 disregulation that also affects the overflow
of excitatory amino acids that can cause, ultimately,
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 the 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 seizure, 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 retains, 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 affected 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
our 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 brains
structures are involved both in the systemic
responses to stressors as well as in cognitive
and 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 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, affect 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 has 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 critical 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 the 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
approximately 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. 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 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 behavioral alterations, and 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 to experiences later in life. This has implications,
and 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, 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 these
various forms of adversity can alter the development
of the prefrontal cortex, 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, substance abuse, and antisocial behavior. So when the brain is
programmed for uncertainty, there is increased vigilance,
amygdala reactivity, and a reduced capacity for proactive, 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 adolescence, 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, epigenetic mediators, which can help us adapt. On the other hand, when
overused and disregulated, 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 life course, 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 life course
that allow interventions, specific for that stage
of the life course, in many case, 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 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 applauds) (cheerful electronic music)

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