[MUSIC]
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.
[MUSIC]
I'm really excited to share some of our work looking into
the evolutionary links between
physical activity and brain health.
We all know that physical activity has benefits to
our physiology literally from our bones to our brains.
I become very interested in understanding more
about why physical activity affects our brain health.
Why is it that when we move our bodies,
it can have benefits to our brains?
Some of these benefits were first really
detailed by Fred Gage in his lab.
Fred Gage is one of the founders of Carta.
In the late 90s, he showed with
Henri Van Praag that if you
give mice access to running wheels,
you can actually lead to the generation of
new neurons in the hippocampus,
as you can see here.
The hippocampus is a really important structure
because it's associated with memory and
it's associated with navigation and
atrophy in this structure occurs during aging,
and is exacerbated by diseases like Alzheimer's disease.
Finding that physical activity
can lead to the generation of
new neurons was a very amazing finding.
It's since been shown that physical activity
has similar effects on the hippocampus in humans.
These are data from Kirk Erickson's work showing that
a one-year physical activity intervention
in older adults,
led to increases in the volume of
both the left and the right hippocampus.
Now, it's not really clear whether this
is due to neurogenesis or other mechanisms,
but clearly physical activity has
some effects on the human hippocampus.
In humans,
physical activity effects are
not solely found in the hippocampus,
but there are associations
between being physically active and having
larger volumes of areas of
the prefrontal cortex which are associated
with executive cognitive functions.
Obviously, these beneficial effects of
physical activity are really important for public health.
But as evolutionary biologists were
often really interested in why?
Why is it the case that if you move your body,
that can have an impact on the brain?
If we want to think about this
from an evolutionary perspective,
and some of what you've already heard about today
is that during human evolution,
our physical activity levels shifted
likely when we became a hunter gatherers.
This is just one way of looking at those shifts comparing
daily travel distances in great apes compared
with what we see today in humans hunter gatherers,
that they're just big changes
that must have occurred going from
an ape-like lifestyle to
a hunting and gathering lifestyle.
It seems likely that our physiology evolved
to respond to these high levels of activity.
If we want to understand why
physical activity affects the brain,
we really want to put it into
this evolutionary perspective.
We might ask why physical activity impacts any organ.
We can answer that question
by thinking about the adaptive capacity model,
which suggests that physical activity
is really a stressor,
and our organ systems evolved to adapt
to these stressors to improve their capacity.
For example, if we think of
our cardiovascular system during exercise,
our muscles demand more oxygen.
That leads to adaptations in
our cardiovascular system like
increased vasculature or improved cardiac efficiency.
If we think about our musculoskeletal system,
when you're physically active,
your bones experience higher forces that leads to
adaptations in your skeletal system
like laying down more bone.
These physical activity stressors have important effects.
As I just showed you,
physical activity seems to lead to brain adaptations,
but it's not entirely
clear what it is about activity that's
stressing the brain and that's really what I want to
focus on for the rest of the talk today.
I've split this question up into two separate sections,
thinking about what it is that
the links physical activity of the brain?
I want to start by discussing how
selection might actually act on this system
and think about some of
the molecular mechanisms that might
act as targets of selection.
Then talk about why selection would act on this system?
What is the advantage of linking
physical activity with the brain?
But I'll start with thinking about molecular mechanisms.
While there are many mechanisms
we can think about and choose from,
I'm going to focus on endocannabinoids.
Endocannabinoids are endogenous compounds that act as
agonists for cannabinoid receptors
in the brain and in the periphery.
One of them, anandamide,
functions similar to our body's own form
of the active ingredient in marijuana THC.
When it's produced, it activates
cannabinoid receptor 1 or the CB_1 receptor,
which plays a role in pain reduction,
in generating feelings of reward.
What we've recently learned is that
this activation of CB_1 receptors seem to
play a role in both neurogenesis
and an enhanced cerebral blood flow.
They may be a target of
selection for this exercise induced effects.
In fact, we know that
exercise increases Anandamide signaling.
These are data showing an increase in
Anandamide from before to after a running balance.
Endocannabinoids make an attractive target for selection,
and there's some evidence that selection actually does
link endocannabinoid signaling with physical activity.
Data from Ted Garland's Lab shows
this nicely here over the last few decades,
has led a selection experiment
where he's generated highly
physically active mice by taking mice that
run voluntarily long distances on a running wheel,
and breeding them together over successive generations.
Over many generations he is generated high running mice.
You can see this is one of
the selected mice over here on the left,
and on the right in this video
is one of the control lines.
Clearly there's a difference in activity.
The high running mice run up to 15 kilometers a day.
There's lots of their physiology that's been
associated with selection for high physical activity.
But it's group is also shown that
the endocannabinoid system has been selected in some way.
Both circulating endocannabinoids like
Anandamide as well as cannabinoid receptor 1 function.
Selection has acted in this case to
link endocannabinoids in physical activity.
We were interested in whether there's
any evidence that this has occurred in humans.
We started thinking about whether there might be
convergent evolution of
exercise-induced endocannabinoid signaling.
We looked at endocannabinoids signaling after
exercise in humans and dogs,
which are two physically active species,
and compare that with endocannabinoids
signaling after exercise in ferrets,
which are more lower physical activity species.
We found some evidence that's at least
consistent with convergent evolution that
anandamide signaling increases significantly
in humans and dogs after
a 30-minute exercise bout but doesn't
increase in ferrets after that same amount of exercise.
This is evidence that, like I said,
it's at least consistent with
convergent evolution and at the time we thought well,
perhaps this is due to the pain reduction benefits of
anandamide signaling or maybe
even the rewarding elements of anandamide signaling.
These are data that we collected showing that
this post-exercise change in an anandamide in
humans is highly correlated with
a post-exercise increase in mood.
Maybe pain reduction or
rewards were the real target of selection,
but the data showing
that endocannabinoids are associated with
brain structural effects caused us
to think about whether perhaps
exercise-induced endocannabinoid signaling may
be involved in brain structural effects in humans.
I want to talk a little bit about some of
the recent work we've done looking at whether
endocannabinoids play a role in
physical activity-related brain health in humans.
We used a little bit of a different
analysis technique for this study.
Here, we're using genetic variation
in endocannabinoid function in humans
as a natural experiment to look at
endocannabinoids' role and its effects.
We focused on the CNR1 gene,
which encodes cannabinoid receptor 1,
the receptor that's activated by anandamide.
It turns out that there's
a polymorphism in the CNR1 gene.
If you go along the genetic code of the CNR1 gene
at one point where most people have a G nucleotide,
some people have an A instead.
That switch to an A nucleotide is
associated with enhanced function of CB1 receptors.
We wanted to see whether this genetic variation
affects the way physical activity
might influence brain structure.
That is, do individuals that are
homozygous for that allele,
do they have a greater
physical activity-induced effect on the brain
than heterozygotes or than
individuals that are homozygous for the G allele?
To answer that question,
we used the UK Biobank where we have
access for about 16,000 individuals' neuroimaging,
so brain MRI scans, as well as, accelerometer data
from wearable accelerometers on their wrist,
which gives us an objective measure of physical activity.
What we looked at was how physical activity influences
different aspects of brain structure
broken up by genotype.
In this figure, moving further to the right,
that suggests that physical activity has
a greater effect on the volume of the brain structure,
in this case, total gray matter volume.
I've split this up by genotypes,
the effects of physical activity on
gray matter volume in individuals with the GG alleles,
with the GA alleles,
and who are homozygous for the A allele,
which is associated with enhanced CB1 receptor function.
You can see here
an enhance is a significantly
greater effect of physical activity
on gray matter volume in those individuals with
enhance CB1 receptor function.
That same effect occurs
in different aspects of brain structure.
If we look at the left hippocampus
and the right hippocampus,
you see those same patterns where that
AA individuals have a greater effect
of physical activity on brain structure.
It looks like endocannabinoids are playing a role
in these physical activity-induced effects on structure.
We're also interested in some of
the diseases that occur in the brain
and whether physical activity can
play a role in mitigating those.
This figure is showing the effects
of physical activity on
dementia risks as they vary
by this cannabinoid receptor genotype.
We know that physical activity
tends to reduce risk of dementia.
In this figure, going to the left is it
greater risk reduction for
dementia associated with increased physical activity.
This figure, this is from about
100,000 individuals in the UK Biobank,
and we're showing that individuals who are
carriers for that allele associated with
greater CB1 receptor function
have an even greater risk reduction for
dementia if they're physically active
compared to individuals with two of those G alleles.
These studies looking at the UK Biobank,
strongly suggest that endocannabinoid signaling plays
a role in the physical activity
induce effects on the brain.
If we think about our original question of how
selection might act on physical activity in the brain,
we know that endocannabinoids are up-regulated by
physical activity and there's some evidence
that selection can act on this system.
Why selection was acting on
this system is still an open question.
Certainly, rewards and pain reduction are
clear advantages of endocannabinoid
activity during physical activity,
but these brain structural events are intriguing and
suggests that may also be a target of selection.
But if that's the case, then why?
What is the advantage of linking
physical activity with brain structure or cognition?
That's what I want to spend the rest
of the talk on today.
I'm going to start by discussing
a model developed by Gerd Kempermann,
and this is a foraging base model.
He and his group suggested that the advantage of linking
physical activity with cognitive improvements
is that, for example, in mice
or other rodents forging actually requires
both being physically active and
using memory and spatial navigation,
so that might give you that advantage.
They tested this model by looking at
neurogenesis in mice that had access
to a running wheel and were then given
cognitive challenges through caging enrichment.
They showed that if you combine
physical activity and caging enrichment,
you actually get additive effects
on neurogenesis compared to
either physical activity alone or enrichment alone.
We were interested in whether this same linkage between
activity and cognition during foraging occurs in humans.
We know from work that we've done,
for example with Hadza hunter-gatherers in Tanzania,
that human foraging is an incredibly complex activity,
that while being physically active individuals have
to combine motor system and control,
spatial memory and navigation,
executive cognitive functions,
and include their sensory and attention systems.
We wanted to see whether we could tap into these demands,
these foraging-based demands, and actually,
enhance the effects of exercise on the brain in humans.
To do this, I worked with Gene Alexander at
the University of Arizona and we
develop the aerobic and cognitive training system,
which is a tablet-based game that you can
play while you're on a stationary exercise machine.
The game targets specific cognitive domains
and neural systems that we think should
be linked to forging-like activity,
so executive functions,
long-term memory, spatial navigation.
You're basically riding through
this maze and answering questions on these placards.
To see how this system functioned
and whether this system improves cognition,
we performed
a 12 week randomized controlled trial of older adults,
and we split them into four groups.
One group, we had doing this
combined exercising cognitive challenge.
We call them the EXCOG group.
Then we compare cognitive performance changes in them
with other groups and exercise
alone group who just exercised,
did not play the game.
A group that just played the game and didn't exercise
the COG group and then a control
group that watched neutral videos.
I'm just going to show you some of
the results from this study.
These are changes in
cognitive performance on a dual-task test.
This is a test where you walk and then do
serial subtractions from a large number at the same time.
This test is highly predictive of
fall risks as well as dementia risk.
Here we've got, in the control group,
cognitive performance on this test at baseline and blue,
at six weeks during the intervention in orange,
and at 12 weeks in red at the end of the intervention.
Our control group showed no change across
the 12 week period in performance on this test.
Both the exercise alone group and
the cognitive alone group showed changes in performance,
improvements in performance across the total 12 weeks.
We do get some improvements if
individual's exercise or played this cognitive game.
But if we combine them,
if we put the exercise and cognitive tasks together,
we get some differences.
We get, first of all,
improvements in performance in a shorter amount of
time after only six weeks.
Then the improvement that we get over
12 weeks is actually double what
we see in the exercise
alone or the cognitive alone groups.
There's some either synergistic or additive effect
of combining physical activity and cognition.
Building on our evolutionary model,
we can see how interventions can actually be
altered to enhance the effects of exercise on the brain.
Putting this all together, obviously,
there's a lot more work to do,
neither of these questions are fully resolved,
but I think there's some evidence that
molecular targets that are associated with
brain effects seem to respond to
selection for high levels of physical activity.
It's very possible that we can build on
evolutionary hypotheses for why this
occurs to actually enhance
physical activity-related brain benefits today.
Again, obviously much more work to do,
but to just overall conclude,
physical activity seems to have shaped
aspects of human neurobiology in really important ways,
and I think we can use these models
to improve health and well-being today.
Thanks again to CARTA and to the symposium organizers,
and I just want to thank all the colleagues that have
helped with these projects and our funding agencies.
Thank you.
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