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OCR for page 154
C H A P T E R 9
Poc
h
MY favorite thing about the concept of allostasis is that it helps
move us away from a siege mentality when we confront life's challenges.
Medical science tends to equate health with the mere absence of ill-
ness; even someone who acknowledges the adaptive, energizing sys-
tems at the brain's command may still be thinking in defensive terms.
But allostasis in its truest sense does much more than stave off disease-
pro(lucing onslaughts; by changing your life in ways that help keep
allostasis on track by exercising, following a healthy (lies, and cher-
ishing your friends an(1 family you (lo more than just keep yourself
out of trouble. You actively enhance the body and brain's own proper-
ties that strengthen, nourish, build up, calm, and protect. Scientists are
on the threshhol(1 of un(lerstan(ling these processes, which are techni-
cally (and unromantically) known as anabolic factors. The term I pre-
fer is positive health.
Positive health refers to the repetoire of systems and substances
that confer the body's innate ability to keep allostasis from descending
154
OCR for page 155
Positive Health / 155
into allostatic load and to bounce back after the system has become
temporarily overwhelmed. Some of the players in positive health fall
within the domain of allostasis proper, such as restorative effects of the
parasympathetic nervous system and the checks-and-balances system
of cortisol. Other built-in positive health factors provide for resilience
and recovery even after a brief descent into ahostatic load; these are
just beginning to reveal their possibilities, and many are best studied in
the brain.
For starters the brain manufactures the body's own painkillers, the
endorphins. "Bonding" hormones, which may explain the benefits of
strong social support, are pro(luce(1 in the brain, as are substances that
nourish and protect brain cells. New brain cells are produced through-
out life, particularly in that all-important region, the hippocampus.
And the multifaceted hormone estrogen is revealing itself as a power-
fu] protector of the brain and the memory.
Overriding the Pain Signal
Endorphins, or enkephalins, were discovered in the 1970s; they are the
human body's version of opium. Their best-understood job is to sup-
port the fight-or-flight response by bringing about a phenomenon
known as stress-induced pain relief This usually happens in a state of
extreme emergency, however. In general, having one's pain sensitivity
shut off is a dangerous thing, so I don't consider the endorphins per se
to be positive health players. But their discovery was the prelude to
further research that slid heighten un(lerstan(ling of positive health.
When an animal is in the throes of allostasis it doesn't fee] pain
very keenly, for the simple reason that it can't adorn to. To ensure sur-
vival, the most important thing is to either win the battle or make the
escape. Sitting (lawn and howling with pain isn't part of the scenario;
that can come later. So the brain steps in with a temporary overri(le to
the pain signal. Studies have shown that animals under stress really are
less sensitive to pain; they aren't just valiantly ignoring it. Among hu-
mans there are legen(ls about Viking warriors called berserkers who in
the heat of battle were oblivious to pain and injury. In modern times
we hear anecdotes about people walking away from car wrecks on two
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156 / The End of Stress as We Know It
broken legs and professional athletes notoriously"playing through the
pain." This altered state of perception is made possible by the activity
of endorphins in the brain. Endorphins also explain, in a roundabout
way, how the best painkillers of all the derivatives of the product of
the poppy plant, opium have such (lramatic effects on the human
brain and body.
The ancient Greeks and Romans were familiar with opium's abil-
ity to ease pain, promote sleep, and produce a calm and quiet sense of
euphoria. In 1805 a German chemist named Friedrich Serturner iso-
late(1 opium's active ingredient, pure morphine, from the poppy a
breakthrough discovery. Medicines obtained directly from plants can
only be taken orally because they are impure. Many of their compo-
nents are foreign to the human body and could be irritants when in-
jected. And because drugs taken by mouth must make their way
through the digestive system, they are slower to act and less effective.
But the effects of pure injectable morphine are consistent and quick,
making it the first of the opiate drugs to be widely used for pain relief,
particularly in the Civil War (from which many soldiers returned as
addicts). Even quicker are the effects of another purified version of
opium: heroin, which has become a devastating drug of abuse.
Despite their dangers, the opiate drugs are unsurpassed even today
as far as their ability to relieve pain is concerned. The powerful effects
of these ([rugs, goo(1 an(1 ba(l, le(1 scientists seeking effective painkillers
to wonder just how the opiates worked. In the early 1970s, Solomon
Snyder and Candace Pert of Johns Hopkins University found strong
evidence of opiate receptors in cultured brain tissue using an opiate
blocker, naloxone, that was radioactively labeled to make it visible when
it boun(1 to the receptor. A few years later these scientists teamed up
with Michael Kuhar, then at Johns Hopkins and now at Emory Univer-
sity, to pinpoint the location of these receptors using a technique that
Kuhar had developed for viewing microscopically thin layers of brain
tissue. The researchers injected radioactive opiates into rats; examina-
tion of tissue from the animals' nervous systems showed that receptors
were located in the spinal cord, where opiates work by raising the pain
threshold; in the thalamus, which is involved in perception; the
amyg(lala, the cornerstone of the fear response; and several other
OCR for page 157
Positive Health / 157
sites thus serving to explain the many levels at which opiate drugs
help people fee] better. Opiate receptors are also found in the brain
stem, where breathing is regulated, which explains why large doses can
kill by bringing breathing to a halt.
Having established the presence of opiate receptors in the human
brain, the next logical question was: What were they doing there? Why
should the human brain have evolved receptors for a chemical that
(loesn't exist in the bo(ly a chemical that's pro(luce(1 by only one type
of plant? It turns out that the efficacy of opiate drugs is an accident.
The receptors foun(1 by Snyder and Kuhar are receptors for the en(lor-
phins, the brain's own kin(ls of opium, which the poppy's version re-
sembles closely enough to affect the brain by working at the same site.
The Brain's Own Pharmacopeia
The connection between endorphins, stress, and pain relief surfaced in
1977, when Roger Guillemin showed that stress triggers the pituitary
gland to produce one type of en(lorphin. (Guillemin was the scientist
whose 14-year feud with Andrew Schally culminated in both scientists
publishing, about three weeks apart in 1971, the structure of the first
neurohormone, thyrotropin-releasing factor. At the time of his endor-
phin discovery, he had won a Nobel Prize for his previous work.)
The role of endorphins in stress-induced pain relief represents a
turning point in the story of positive health, but let me explain why I
consider them only a prelude to the main story and not positive health
players in their own right. In general, it's (langerous to ignore pain,
intentionally or otherwise. Pain alerts us to injuries and illnesses that
nee(1 to be atten(le(1 to, encouraging us to stay quiet in the meantime
and leave the affected area alone. People with abnormal conditions that
leave them unable to fee] pain live in constant (langer of receiving un-
noticed injuries. So endorphin-induced pain insensitivity should be
considered an attempt by the brain to deal with emergency and not a
· r A
sign of resilience.
Even the famed runner's high, thought to result from endorphins,
may be the brain's last-ditch attempt to keep the body going in what it
perceives to be a life-threatening situation. Exercise is a stressor when
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taken to the extreme. Fanatical runners super from cardiovascular dis-
ease, and though they tend to be trim, the little body fat they do have is
concentrated in the abdomen a sign of allostatic load. When a per-
son runs for prolonged periods, the body assumes that some grave dan-
aer exists and cranks un the endornhins to facilitate escape, causing a
an-- ----- -- ~--~ -- A----- Or ---- -----or -
euphoria that's actually the advent of ahostatic load.
It may be that endorphins exert their painkilling, calming effects
in nonemergencies, but the hard evidence is lacking. Some studies show
that acupuncture triggers their production. What can be said about
the endorphins, though, is that their discovery paved the way to identi-
fying other chemicals that do seem to be involved in positive health.
These include oxytocin, a hormone produced during social interaction
and bonding, and prolactin, a hormone released during breastieeding
that appears to have calming effects on the brain. To identify these
neurohormones, scientists had to look beyond the traditional neuro-
transmitters as they were understood in the 1950s and 1960s, and en-
dorphins were like a stepping stone.
Beyond Endorphins
Earlier I talked about acety~choline, the first of the brain's chemical
messengers to be identified. Acety~choline was discovered in the 1930s
as the chemical that the vagus nerve uses to slow (lawn the beating of
the heart. Later it proved to be one of the key neurotransmitters in the
brain as well. By the late 1960s, many of the best-known neurotrans-
mitters had been i(lentifie(l, inclu(ling nora(lrenaline; serotonin;
(lopamine; glutamate, which tells brain cells to speed up their rate of
activity; and gamma-aminobutyric aci(l, which sen(ls the signal to slow
([own. Some scientists thought the brain's cast of characters was now
complete.
Around the same time, suspicion was (1awning that there might be
more players in the signal-sen(ling game. Sir Geoffrey Harris pre(licte(1
that the brain influences the endocrine system through specialized hor-
mones, the first of which was (liscovere(1 by the rancorous Guillemin
and Schally. The neurohormone that sets off the fight-or-flight re-
sponse, corticotropin-releasing factor, was identified as recently as 1983
by Wylie Vale of the Salk Institute, one of Guillemin's former students.
OCR for page 159
Positive Health / 159
In the meantime the hunt for these and other releasing factors pro-
vided evidence that other types of neurotransmitters besides the basic
ones did in fact exist. It also provided the technology to identify sub-
stances that the brain produces in minuscule amounts. In the mid-
1970s two teams John Hughes and Hans Kosterlitz of the University
of Aberdeen, Scotland, and Solomon Snyder and colleagues at
Hopkins used this technology to work out the chemical structure of
the endorphins (which the Scottish team called enkephalins, from the
Greek for "in the heady. Both the endorphins and the releasing factors
fit into a class of neurotransmitters known as neuropeptides very
short chains of amino acids, which are the building blocks of proteins.
Now it's becoming clear that some neuropeptides are clues to positive
health.
One likely candidate is oxytocin, a neuropeptide that may explain
the phenomenon that social support improves the outlook for people
with cancer, AIDS, and heart disease. Oxytocin may be a bonding hor-
mone. Larry Young and Thomas Inset at Emory University have shown
that a typical female rat avoids baby rats until she has some of her
own. Then surges in oxytocin help to rank her among the best of
mothers. Oxytocin "knockout" mice, which are bre(1 missing the gene
that encodes for the hormone, fad] to recognize cage mates with whom
they've been raised. In humans, oxytocin is triggered by pleasant
stimuli such as touch and warm temperatures and in the brain of
mother and child during breastfeeding. Oxytocin's effects aren't lim-
ited to the psychological. In both male and female rats, injected oxyto-
cin lowers blood pressure, heart rate, and cortiso] levels for up to
several weeks. So it's possible that, when social interactions ward off
some of the physical as well as the psychological ill effects of stress,
oxytocin is what makes this happen.
Another potential bestower of positive health is prolactin. In
women this hormone is release(1 by the pituitary glan(1 to trigger lacta-
tion, but in both sexes it may be an inherent remedy against anxiety
and stress. In 2001, Luz Torner and colleagues at the Max Planck Insti-
tute in Munich infuse(1 prolactin (1irectly into the brains of rats. The
rats were then put in mildly stressful situations, such as being placed
on an elevate(l, expose(1 platform, which rats fin(1 (disconcerting (1ue to
their preference for cover. Observations of the rats' behavior indicated
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that the prolactin dramatically reduced anxiety in a dose-dependent
way, meaning the more prolactin the animals got, the less anxious they
appeared to be. Prolactin also reduced levels of stress hormones and
hypothalamic-pituitary-adrenal axis activity. Because levels of prolac-
tin in the blood increase during times of stress, and studies show evi-
dence of both prolactin and its receptors in the hypothalamus and
amyg(lala, it's possible that Torner and colleagues mimicke(1 a process
that goes on all the time that prolactin is one of the natural com-
pounds that help keep allostasis functional.
Exercise is known to increase circulating levels of prolactin, al-
though it isn't yet clear how this elevation affects the nervous system.
However, there is increasing evidence that prolactin in the blood gains
access to some parts of the brain that contain prolactin receptors and
that the peptide may protect against specific forms of allostatic load. It
is known to prevent stress-induced stomach ulcers in animals! In the
future, both oxytocin and prolactin may be boosted by medications
that could work more specifically against allostatic load than could
antidepressants or sedatives. A drug that increases levels of oxytocin in
the brain an oxytocin agonist, as pharamacologists call it is un(ler
levelopment. A similar approach could be used for prolactin.
If the endorphins and neuropeptides help us to withstand stress
and avoi(1 going into allostatic loa(l, other aspects of positive health
help us pull out of it. These include growth factors or "neurotrophins,"
neurogenesis, and the hormone estrogen.
Helping Nerve Cells Grow
The growth factors or neurotrophins nourish and protect growing neu-
rons, encouraging them to repair themselves and proliferate. Much at-
tention is being paid to growth factors as possible treatments for spinal
cord injury and neuro(legenerative (lisor(lers, but researchers are also
beginning to explore the role of these compounds un(ler ordinary cir-
cumstances. Growth factors may be important players in the brain's
(lefenses against many kin(ls of stress, providing benefits that scientists
may one (lay be able to augment.
The first to be discovered was called, simply, nerve growth factor,
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Positive Health / 161
or NGF. NGF had been known to exist in the peripheral nervous sys-
tem the nerves outside the brain and spinal cord that run through-
out the body where it encourages growth and proliferation. In the
1970s Hans Thoenen of the Max Planck Institute found that NGF also
exists in the brain. As to its exact job, scientists were not certain, but
the discovery dovetailed another line of research: the fact that in
Alzheimer's disease, cells that produce the neurotransmitter acety~cho-
line die ok in an area called the basal forebrain. Loss of this neurotrans-
mitter, widely used in parts of the brain associated with memory, is a
major cause of Alzheimer's symptoms. In the 1980s several groups
working with animals found that NGF injected directly into the dam-
aged brain could improve the survival rate of these acety~choline-pro-
ducing or"cholinergic" cells. Some researchers, including Fred Gage at
the Salk Institute, have found that when skin cells genetically modified
to produce large amounts of NGF are transplanted into the brains of
experimental animals, the transplants prevent cholinergic cells from
dying and form a sort of bridge across which damaged neurons can
regrow. Other teams have found that, when transplanted into the
brains of rats, NGF-secreting cells can prevent and even reverse age-
related memory loss.
Scientists are using a similar treatment approach to help axons
regrow through the site of a spinal cord injury in rats, with skin cells
engineered to produce both NGF and a neurotrophin called NT-3. An-
other neurotrophin, caped glial cell-derived neurotrophic factor, shows
promise in helping (lopamine-pro(lucing cells survive when trans-
planted into the brains of patients with Parkinson's disease, another
neurological disorder that involves the death of brain cells. Much re-
search is un(ler way to stu(ly the culinary, everyday effects of growth
factors.
A relative newcomer is insulin-like growth factor, or IGF, which
the brain actively takes up from the blood during exercise. IGF lowers
elevated blood glucose levels and has been shown to help experimental
animals recover their ability to function after lesion-induced damage
to the spinal cor(l. IGF may explain how walkers in a (liabetes stu(ly by
the National Institutes of Health were able to reduce their risk of the
disease so drastically. But by far the best-understood neurotrophin as
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far as allostatic load is concerned is brain-derived neurotrophic factor,
or BDNF.
BDNF and Positive Health
BDNF's beneficial effects on the brain are legion. In particular, it may
be the biological go-between that brings about the spectacular results
of exercise on the brain. BDNF also protects the brain against ischemia
(damage that results from lack of oxygen, such as might occur during a
stroke) and against other types of neurodegenerative damage. It is also
involved in memory.
Several labs have shown that, at the level of the synapse, BDNF and
other neurotrophins play a role in the learning process known as long-
term potentiation. BDNF is involved with higher levels of memory as
well. Yasushi Miyashita of the University of Tokyo School of Medicine
investigated whether BDNF was increased or "up-regulated" when
monkeys were trained to form associations between pairs of visual
stimuli. Intriguingly, the tests were performed on"split-brain" mon-
keys in which the corpus callosum, which connects the two hemi-
spheres of the brain, had been severed. This procedure is sometimes
performed on humans to treat otherwise incurable epilepsy, but the
result is that the right side of the brain literally doesn't know what the
left side is doing. The researchers trained the monkeys to form memo-
ries of paired shapes that were shown to one side of each monkey's
brain, while the other side of the brain merely had to distinguish the
shapes, not remember them. On the memory task side of the brain,
BDNF was increased in a part of the cortex known to be involved in
long-term memory of objects. But on the object recognition side, no
increase in BDNF was seen, indicating that the memory, not visual
processing, requires BDNF.
Many clues suggest that BDNF protects against allostatic load and
possibly even the stress on the brain associated with aging. In particu-
lar, it may explain why exercise is helpful in so many situations. Re-
search with rats conducted by Car] Cotman of the University of
California at Irvine has shown that exercise significantly increases lev-
els of both BDNF and NGF in the brains of rats that are allowed free
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Positive Health / 163
access to running wheels for two nights (when rats, being nocturnal
animals, are most likely to use them). The increase is most dramatic in
the hippocampus. Cotman has also shown that the benefits of exercise
make themselves apparent shortly after the exercise period begins-
perhaps implying that one (loesn't have to jog miles a (lay for years to
protect the brain.
Studies presented at the 2001 annual meeting of the Society for
Neuroscience extend Cotman's work. For example, Fernando Gomez-
PinilIa and colleagues confirmed that voluntary exercises increased
BDNF levels in the brains of rats and that the rats scored higher on
maze tests than their sedentary cage mates. In a follow-up the research-
ers showed that exercise and BDNF can work together to counteract a
known trigger of allostatic load poor diet. Rats fed a typical Ameri-
can diet, high in fat and refined carbohydrates, showed a decrease in
BDNF. But when the rats were allowed onto their running wheels, lev-
els of BDNF began to climb again.
David Albeck and colleagues at the University of Colorado have
shown that rats forced to exercise for 20 minutes showed even more of
an increase in BDNF levels than rats that exercised voluntarily. Since
rats consider forced exercise to be a stressor, the message for humans
seems to be that, by undertaking moderate exercise in times of stress,
we can make positive health factors like BDNF work overtime.
Doctors an(1 advocacy groups emphasize the importance of exer-
cise in keeping one's memory sharp as the years go by. Exercise is also
one of the best things that people suffering from depression can do for
themselves. Because exercise increases BDNF, which is known to pro-
tect neurons, it's likely that the growth factor is the intermediary
through which exercise benefits the aging brain.
Upping the "Anti" in Anticlepressants
According to Eric Nestler of Yale University, antidepressants may work
by increasing the levels of BDNF in the brain. All of the antidepres-
sants now on the market act at the level of the neurotransmitter and
receptor. They work by interfering with neuronal "housekeeping"-
metho(ls that brain cells use to clear excess amounts of neurotransmit-
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ter out of the synapse, so that the space will be clear for the next mes-
sage, which might come from a different messenger chemical. Prozac
and its progeny are the latest antidepressants. Known as selective sero-
tonin reuptake inhibitors, they attach to sites called transporters on
the "sending" neuron, thereby preventing that neuron from sucking
back the excess serotonin. In both cases, the result is that the neu-
rotransmitter remains in the synapse for longer periods, so that more
of it can reach the next cell in line and exert its positive effects.
What those effects are is anybody's guess, according to Nestler. The
fact is that scientists don't know what antidepressants do that helps
depressed people fee] better. It's true that Prozac, for example, inhibits
serotonin reuptake, but what does that accomplish? Many researchers
believe that it's only the first step in a much more complex process.
They argue that Prozac and related drugs begin inhibiting reuptake
within 24 hours, yet people who take the drug for depression don't
start feeling better for three to four weeks. It's logical to assume that
something else is going on during those weeks, and if scientists were to
identify and unravel the process, they might be able to design more
effective antidepressants. Prozac and its progeny aren't any better than
the older drugs at relieving the symptoms of depression; they just work
more cleanly, with fewer undesirable side effects. A true breakthrough
in treatment awaits a better un(lerstan(ling of how the ([rugs actually
work. Nestler believes that by prolonging the presence of neurotrans-
mitters, such as serotonin and noradrenaline, in the synapse, antide-
pressants let loose a cascade of events that ultimately raise the levels of
BDNF in the hippocampus.
Although today's drugs have fewer side effects than earlier ones,
there has yet to be a qualitative improvement in the treatment of (le-
pression. Antidepressants fad] to relieve symptoms in about a third of
patients. There may be explanations other than the BDNF story; some
researchers believe, for example, that serotonin itself holds the key to
why antidepressants work. But it will be interesting to see what hap-
pens once we go beyond the level of neurotransmitters and their re-
ceptors. The notion that BDNF or other neurotrophins may be
involved takes us in that (1irection an(l, perhaps, a step closer to un-
(lerstan(ling the pathways of positive health.
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Positive Health / 165
Neurogenesis and Positive Health
A continually replenished supply of nerve cells, especially in key areas
like the hippocampus, may be the brain's built-in buffer against wear
and tear. It also looks as if neurogenesis may play a role in memory
formation in times of stress.
Researchers sometimes set themselves up in opposition to prevail-
ing medical wisdom. Hans Selye shocked his professors by studying
the supposedly miscellaneous symptoms of illness; John Mason wanted
to investigate psychosomatic illness. Even the concept of allostasis-
that stress can be healthy and protective up to a point has met with
some resistance in the scientific community. But no medical dogma
has been so firmly entrenched as the assumption that new cells don't
grow in the adult brain.
As early as the mid-1960s, Joseph Altman, a researcher at the Mas-
sachusetts Institute of Technology found evidence of neurogenesis in
various parts of the mouse brain. But his work went largely unnoticed
by the scientific community. A big reason was that the fin(lings flew in
the face of clinical observation. It's undeniable that, while people grow
taller and their bodies grow larger, their brains stay the same size. And
neurons lost due to injury or neurodegenerative disease aren't replaced
the way old skin cells are. Miraculous tales are told of children as old as
9 who have entire hemispheres remove(1 to treat epilepsy and grow up
absolutely fine. But this is due to the remarkable plasticity of the sur-
viving hemisphere, not to the brain's having sprouted a new one.
Another stumbling block to the acceptance of neurogenesis is that
only recently has equipment sophisticated enough to label and count
neurons become available. Altman, for example, used radioactive "tags"
to identify dividing cells, but these could only be seen in the top few
microns of brain tissue. Since the available slices were usually thicker
than that, there was no way to tell for sure how many new neurons
were present. It wasn't until the 1980s that the stain called bromo-
dioxiuridine came into widespread use. A side-by-side development,
confocal microscopy, has ma(le it possible to see these markers in their
three dimensions and to visualize the totality of a nerve cell that could
never be seen with the conventional two-dimensional microscope.
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These are the techniques that Elizabeth Gould, now at Princeton Uni-
versity, used to prove neurogenesis in the brains of primates. Fred Gage
and co-workers at the Salk Institute used the same methods to study
neurogenesis in the brains of adult human volunteers who had died of
cancer (although not cancer of the brain).
Neurogenesis most likely contributes to positive health by acting
as a built-in buffer against aHostatic load. It's no coincidence that stud-
ies confirming the existence of neurogenesis found it in the hippocam-
pus, the region most vulnerable to stress-induced wear and tear.
Neurogenesis in the hippocampus is an exemplar of the protection ver-
sus damage theory. Gould, for example, showed that the production of
new neurons in adult life is suppressed by excitatory neurotransmit-
ters and by stress, while Gage and colleagues showed that an enriched
environment and exercise cause an increase in neurogenesis.
In addition to compensating for wear and tear, neurogenesis in the
hippocampus may help form stress-in(luce(1 memories. A 1999 stu(ly
by Elizabeth Gould and Tracy Shors, now at Rutgers University, sug-
geste(1 that a stressful event may earmark new hippocampal cells born
around the same time, dedicating them to the memory of that event.
The team used a procedure caped trace conditioning in which rats hear
a tone that is followed a second or so later by a pub of air that causes
the eye to blink (an unpleasant stimulus for the rat). Gradually the rat
begins to blink its eye when it hears the tone; the time lag between the
tone and the pub brings the hippocampus into play for this type of
learning. During trace conditioning, the newborn hippocampal
neurons survived for much longer than in the so-called classical condi-
tioning experiment, when the tone and the puff come simulta-
neously a form of learning that does not involve the hippocampus.
So when the hippocampus participates in learning, newly formed (len-
tate gyros nerve cells seem to live longer. The life span of these kinds of
nerve cells may be connected in some way to the durability of certain
types of memory.
Evidence of neurogenesis is exciting for another reason: it suggests
another way of looking at brain (lamage an(1 neuro(legenerative (lis-
ease. Both are currently viewe(1 in terms of the cells that (lie, an(1 cer-
tainly, the fact that cells (lie in Alzheimer's (lisease or spinal cor(1 injury
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Positive Health / 167
is beyond dispute. But what if such conditions are also due to a failure
of neurogenesis? This might extend future treatment options beyond
protecting and replacing the (lying cells; therapies (still to be invented
that restore neurogenesis might come into the picture as wed. Other
parts of the brain besides the hippocampus show signs of neurogenesis.
Working with primates, Gould has found new cells in the prefrontal
cortex, a nexus of another type of memory working memory, the
ability to hold information transiently in mind while completing a task
or solving a problem. Jeffrey Macklis and colleagues at Harvard Medi-
cal School and Children's Hospital have shown neurogenesis to occur
in the mouse cortex. An intriguing aspect of this study is that the team
stimulated neurogenesis in a roundabout way by inducing apoptosis,
or encouraging the neurons to self-destruct. In other words, cell death
stimulated cell birth. An obvious question is: Why aren't similar repair
mechanisms triggered in other instances of cell death, in neurodegen-
erative disease, for example, or brain or spinal cord injury or chronic
stress? Perhaps these situations generate an environment full of ob-
stacles to regrowth. Once scientists figure out what these obstacles are
and how to overcome them, we might usher in a whole new school of
thought not only for treating brain (lisease but also regarding posi-
tive health and the brain and neurogenesis may play a role.
Neurogenesis and Depression
As our work with the tree shrews (lemonstrate(l, a breakdown of
neurogenesis as usual may at least partly explain the hippocampal at-
rophy detected long after depression and trauma. The news is encour-
aging because it shows that hippocampal shrinkage isn't just a matter
of cortisol corroding the neurons like battery acid; the reduction is a
long time in the making, and scientists hope it can be prevented. Since
both stress and cortiso] are shown to block neurogenesis, it stands to
reason that recruiting the agents of positive health, such as exercise-
in(luce(1 BDNF, can get it going again. Interventions that are successful
in treating depression, such as antidepressants and physical exercise,
have also been found to trigger neurogenesis. Ronald Duman of Yale
University has foun(1 that rats given antidepressants have significantly
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more dividing cells in the hippocampus. Eberhard Fuchs of the Ger-
man Primate Center in Gottingen has shown that an antidepressant
reverses the effects of a form of animal-to-animal stress in tree shrews
that causes symptoms of depression and suppresses the formation of
new nerve cells in the hippocampus.
Scientists would love to know if, in addition to being vulnerable
to trauma and long-term (repression, the hippocampus plays a role in
everyday mood. It is linked to two structures that do play such a role-
the amygdala and the prefrontal cortex. It's possible that the loss of
cells at this site, plus the dysregulation of neurotransmitters and hor-
mones in a larger network, contributes to depression. And it's conceiv-
able that medications designed to boost neurogenesis or other
measures, such as exercise might add to our arsenal of weapons
against both depression and allostatic load.
The Estrogen Story
For many of us at Rockefeller University, the discovery that there are
estrogen receptors in the brain was the beginning of our research into
allostasis. At the time, we thought the fin(ling was just a signpost point-
ing us toward the (discoveries regarding cortisol. We still viewed estro-
gen in terms of its effect on sexual behavior; we didn't think that this
sex hormone would itself turn out to be a key player in allostasis. Yet
that's just what estrogen proved to be. In addition to its role in repro-
duction, estrogen has a plethora of effects on the brain. Many are in-
terrelated, and many seem to be pathways through which the brain
achieves positive health. Estrogen stimulates neurons to form new syn-
apses and synapses to form new branches; it encourages the growth of
new neurons and protects against the destructive effects of free radi-
cals. Of all the potential benefits to the brain, the most striking is
estrogen's ability to protect memory.
This possibility first surfaced in the late 1970s, when en(locrinolo-
gist Victoria Luine and I gave estrogen to rats whose ovaries had been
removed. We foun(1 that the treatment raised levels of an enzyme that
increased levels of acety~choline in the basal forebrain. The signifi-
cance and the memory connection didn't dawn on us until a few
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Positive Health / 169
years later when researchers began to find that Alzheimer's patients
showed a massive die-off of acety~choline-producing neurons in the
same part of the brain. Around the same time another link emerged on
the opposite end of the research spectrum. Barbara Sherwin at
Concordia University in Canada found that women whose ovaries had
been removed (and who thus could not produce estrogen) complained
of changes in their memory. Apparently, estrogen, acety~choline, and
memory are connected.
Until then most of the estrogen research had zeroed in on the hy-
pothalamus and pituitary gland the areas most likely to be involved
in reproduction. But when the memory connection surfaced, research-
ers began to fin(1 estrogen receptors in many parts of the brain associ-
ated with memory, such as the hippocampus and cerebral cortex. We
now know that estrogen and related hormones have several actions
related to memory in these brain structures.
Estrogen working together with progesterone, another ovarian
hormone, may play a role in the adaptive plasticity calle(1 synaptic re-
modeling. In a checks-and-balances relationship, these hormones regu-
late the formation of new connections between nerve cells in the
hippocampus. In particular, the formation of new"excitatory" syn-
apses ones that receive "speeding up" messages is influence(1 by the
estrogen-like hormone estradiol. Glutamate is involved in this process,
working through specialized receptors called NMDA receptors, after
N-methyI-D-asparate, a chemical used to identify them. (Estrogens ac-
tually induce the formation of NMDA receptors on certain key neu-
rons in the hippocampus. Progesterone, on the other han(l,
down-regulates or inhibits these synapses. This push-and-pull effect
of the two hormones may be the intermediary through which synaptic
remodeling protects, in the short term, against the effects of stress.)
As an irresistible digression, the sex hormones also underlie the
basic differences in hippocampal structure between males and females,
possibly explaining the (lifferences in spatial navigation strategies use
by the two sexes (in rats at least). Male rats are more efficient than
females at fin(ling their way around mazes. When it comes to homo-
sapiens, men are more likely to use global spatial cues and know ap-
proximately in which (Erection something is relative to where they are,
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whereas women tend to use "local" cues or landmarks, remembering
to turn right at the church and left at the gas station, for example. In
rats these distinctions take shape in utero. During a key period of em-
bryonic development, when the sex hormone testosterone is el-
evated in the male, a group of enzymes actually convert testosterone to
estradiol; more estrogen receptors are expressed at the same time.
There's evidence that this pathway is behind the "masculinization" of
both the structure and the function of the hippocampus, though it
(loesn't explain why men will (lo seemingly anything rather than ask
directions.
Protective Effects of Estrogen
Many of the actions of estrogen seem to have a protective effect on the
brain. Patima Tanapat and Elizabeth Gould of Princeton have shown
that estrogen stimulates neurogenesis in the dentate gyros of the fe-
male hippocampus in rats. Female rats also seem to be resistant to the
stress-induced atrophy of hippocampal dendrites seen in males. In
Alzheimer's (lisease, estrogen appears to protect against the rapi(l-fire
cell death known as excitotoxicity. Another feature of Alzheimer's dis-
ease, in addition to the death of cholinergic cells in the basal forebrain,
is the buildup in the brain of a toxic protein known as beta-amyloid.
Estrogen appears to protect against the (lestructive effects of this pro-
tein as well.
One of the most impressive studies in humans was conducted by
Victor Henderson, a neurologist at the University of Southern Califor-
nia School of Medicine, and his colleague Annlia Paganini Hill. These
scientists analyzed a group of over 8,000 ol(ler women and foun(1 that
the risk of (leveloping Alzheimer's was sharply re(luce(1 in women who
took estrogen replacement therapy. Their study also showed that the
higher the dose and the longer the duration of the therapy, the lower
the risk of the disease. Richard Mayeux and colleagues at Columbia
University also found that elderly women who took estrogen after
menopause had a significantly re(luce(1 risk of (1eveloping Alzheimer's
disease and that those who developed the disease did so much later.
Another striking finding is from the Baltimore Longitu(linal Stu(ly of
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Positive Health / 171
Aging, in which Claudia Kawas and colleagues at Johns Hopkins Uni-
versity studied over 450 older women who had been followed for up to
16 years. This team also found a similar reduction in risk of Alzheimer's
disease in women taking estrogen replacement therapy.
Operating on the Edge of the Neuron
By stimulating neurogenesis and protecting against hippocampal atro-
phy, estrogen takes its place as a contributor to positive health. To learn
more about these processes and the neuroprotective effects of estrogen
in Alzheimer's (lisease, many scientists are studying estrogen's effects
in and about the neuron. Part of this research involves understanding
in more detail how brain cells are affected by their environment.
An intriguing fin(ling is another type of estrogen receptor that
differs from the ones discovered in the 1960s and 1970s. The estrogen
receptors discovered first actually reside in the cell nucleus, close to
the DNA, where they regulate the way the genetic code is turned into
reality. This is how sex differences emerge in the hippocampus, for
example.
Many of estrogen's actions, however, take place so quickly that the
hormone probably doesn't have time to affect gene expression. Den-
(lritic remodeling may be (lue to these quick actions. A better-stu(lie(1
example is the way estrogens protect the smooth muscle cells of car-
diac tissue an effect that may explain the dramatic increase in heart
attacks in postmenopausal women. Estrogen's "nongenomic" actions
operate through receptors located not inside the cell nucleus but on
the cell surface, which takes researchers into uncharted waters.
Tames Eberwine of the University of Pennsylvania School of Medi-
cine believes that messenger RNA, which turns the genetic code of
DNA into usable proteins, might be found not only in the nucleus of
neurons but also in the axons and dendrites, where it may be activated
by purely local signals that don't have to travel all the way to the cell's
nucleus. Eberwine has also found that the transcription factor CREB is
present in the cell's extremities, where it may be activated by new events
in the cell's environment. Axons and dendrites are both sites of the
plasticity that occurs in response to stress. The presence of genetic play-
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ers in these structures might mean that neurons can respond to stress
by making changes only in the parts of the cell involved in the particu-
lar connection related to the event without having to invoke the com-
mand center in the nucleus and make changes that affect the entire
cell. Since estrogen receptors are also found on the cellular outposts,
our group at Rockefeller University is investigating a possible connec-
tion. This type of autonomy in the axons and dendrites may be one
way through which estrogen exerts its protective effects.
Endorphins, growth factors, neurogenesis, and estrogens are the
vanguard of positive health factors. This research will give rise to a
newer understanding of how our brains take care of us, and the impli-
cations will be discussed in the next and final chapter.
Representative terms from entire chapter:
allostatic load
