[Paleopsych] why is the amygdala so sneaky?

Thu Jul 1 03:30:43 UTC 2004

The following tidbit from an article in The Scientific American on stress and 
memory gives a  neurobiological explanation for something  Sigmund Freud 
described way back in the early days of psycho-speculation…repression and 
suppression.  

When something ghastly happens to us, says this piece, which derives its 
wisdom from Joseph LeDoux, a strange thing happens in our brain.  The hippocampus, 
the traffic center that sends material to the conscious mind, goes through 
shut down.  It’s paralyzed by glucocorticooids, stress hormones.  But something 
very different happens to our fear and body-knowledge traffic center, the 
amygdala.  The amygedala thrives, grows new threads of connection to the 
sympathetic nervous system, and implants memories of the frightful experience in us.  
Not only ss that memory of a nightmare event woven into our permanent store of 
lessons about life, it gets woven way down at a level that can kick our heart 
into a high-speed trot, get our sweat glands oozing, and tie knots in our 
stomach.  But it also gets woven in at a level that’s impossible for us to “see” 
and think out.

Here’s the question.  What could the evolutionary value be of keeping key 
experiences locked in a vault that the conscious mind can’t crack into?  Is this 
one of the shortcuts the mind uses to speed up our reactions by cutting the 
dither of thinking out of the process?  Is it one of those things that helps Val 
Geist sprint away from a murderous grizly bear before he has a chance to 
think out a response, thus letting Val win the race with the grizzly and live 
another 30 years or so?

Many of  the responses encoded into us by this trauma-reaction process are 
nowhere near as helpful as Val’s instant dash to the nearest sturdy tree, his 
climb up its trunk, and his victory swing  high in the branches above the grizzly
’s head.  Many, in fact, are paralyzing.  They’re the high-anxiety 
mind-and-body freezes of extreme anxiety.  They’re the torture-terrors of 
post-traumatic stress disorders.

The Bloom Grand Unified Theory of Everything In the Universe Including the 
Human Soul says that when they’re failing, individual components of a learning 
system, components like cells in the body or like bacteria in a colony, disable 
themselves or worse, kill themselves off.  Why? So their influence will be 
minimized.  Sp their mistaken strategies won’t sway the decisions of the group. 
And so their mistakes will stand as a warning to the others in the 
consultative assemblies of collective intelligence.

Are humans disabled by their traumas and slowed to a painful crawl by the 
mark of experiences they can’t remember as a lesson to the rest of us?   If those 
who suffer this sort of amygdalic sabotage can’t remember why they are 
breaking out in a cold sweat and hiding in a corner, how in the world can their 
agonies add to our understanding?

Or is the bypass of consciousness an accidental result of a system that was 
wired long before there was a thinking center in the brain, long before there 
was a theater of awareness beneath the dome of the skull?  Has that old system 
been retained so it can take care of things too difficult for the conscious 
mind to handle—tasks like digestion and orchestrating muscles to walk or ride a 
bicycle?

One thing this amygdala-centered understanding hints at is this.  Freud 
implied that repression was a conscious act, a mistaken act of will or cowardice.  
We were conscious of the trauma when it happened, couldn’t face its 
consequences, so tucked it out of sight.  That’s not the way the LeDoux scenario 
explains it.  LeDoux’s work seems to imply that our experiences of horror trigger a 
system that never bothers to show the conscious mind its perceptions and its 
decisions about how to handle what it sees.  I suspect there’s a little bit of 
truth to both points of view.  What do you think?  Howard

glucocorticoid exposure can impair LTP in the hippocampus and can even cause 
atrophy of neurons there. This phenomenon constitutes the opposite of the 
stress response in the amygdala. Severe stress can harm the hippocampus, 
preventing the consolidation of a conscious, explicit memory of the event; at the same 
time, new neuronal branches and enhanced LTP facilitate the amygdala's 
implicit memory machinery. In subsequent situations, the amygdala might respond to 
preconscious information--but conscious awareness or memory may never follow. 
Retrieved June 30, 2004, from the World Wide Web  EBSCOhost
Taming stress ,  By: Salzano, Robert, Scientific American, 00368733, Sep2003, 
Vol. 289, Issue 3

Retrieved June 30, 2004, from the World Wide Web 
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0+%2D+cli%5B1+%2DSO+cli%5B0+%2DDT1+st%5B0+%2Damygdala+1438&cf=1&fn=1&rn=1
EBSCOhost
: Taming stress ,  By: Salzano, Robert, Scientific American, 00368733, 
Sep2003, Vol. 289, Issue 3

An emerging understanding of the brain's stress pathways points toward 
treatments for anxiety and depression beyond Valium and Prozac

OVER THE CENTURIES, SOCIETY'S APPROACHES TO TREATING the mentally ill have 
shifted dramatically. At present, drugs that manipulate neurochemistry count as 
cutting-edge therapeutics. A few decades ago the heights of efficacy and 
compassion were lobotomies and insulin-induced comas. Before that, restraints and 
ice baths sufficed. Even earlier, and we've entered the realm of exorcisms.

Society has also shifted its view of the causes of mental illness. Once we 
got past invoking demonic possession, we put enormous energy into the debate 
over whether these diseases are more about nature or nurture. Such arguments are 
quite pointless given the vast intertwining of the two in psychiatric disease. 
Environment, in the form of trauma, can most certainly break the minds of its 
victims. Yet there is an undeniable biology that makes some individuals more 
vulnerable than others. Conversely, genes are most certainly important factors 
in understanding major disorders. Yet being the identical twin of someone who 
suffers one of those illnesses means a roughly 50 percent chance of not 
succumbing.

Obviously, biological vulnerabilities and environmental precipitants 
interact, and in this article I explore one arena of that interaction: the relation 
between external factors that cause stress and the biology of the mind's 
response. Scientists have recently come to understand a great deal about the role 
that stress plays in the two most common classes of psychiatric disorders: 
anxiety and major depression, each Of which affects close to 20 million Americans 
annually, according to the National Institute of Mental Health. And much 
investigation focuses on developing the next generation of relevant pharmaceuticals, 
on finding improved versions of Prozac, Wellbutrin, Valium and Librium that 
would work faster, longer or with fewer side effects.

At the same time, insights about stress are opening the way for novel drug 
development. These different tacks are needed for the simple fact that despite 
laudable progress in treating anxiety and depression, currently available 
medications do not work for vast numbers of people, or they entail side effects 
that are too severe.

Research in this area has applications well beyond treating and understanding 
these two illnesses. The diagnostic boundary that separates someone who is 
formally ill with an anxiety disorder or major depression from everyone else is 
somewhat arbitrary. Investigations into stress are also teaching us about the 
everyday anxiety and depression that all of us experience at times.
Out of Balance,

WHEN A BODY is in homeostatic balance, various measures--such as temperature, 
glucose level and so on--are as close to "ideal" as possible. A stressor is 
anything in the environment that knocks the body out of homeostasis, and the 
stress response is the array of physiological adaptations that ultimately 
reestablishes balance. The response principally includes the secretion of two types 
of hormones from the adrenal glands: epinephrine, also known as adrenaline, 
and glucocorticoids. In humans, the relevant glucocorticoid is called cortisol, 
also known as hydrocortisone.

This suite of hormonal changes is what stress is about for the typical 
mammal. Iris often triggered by an acute physical challenge, such as fleeing from a 
predator. Epinephrine and glucocorticoids mobilize energy for muscles, 
increase cardiovascular tone so oxygen can travel more quickly, and turn off 
nonessential activities like growth. (The hormones work at different speeds. In a 
fight-or-flight scenario, epinephrine is the one handing out guns; glucocorticoids 
are the ones drawing up blueprints for new aircraft carriers needed for the 
war effort.)

Primates have it tough, however. More so than in other species, the primate 
stress response can be set in motion not only by a concrete event but by mere 
anticipation. When this assessment is accurate ("This is a dark, abandoned 
street, so I should prepare to run" ), an anticipatory stress response can be 
highly adaptive. But when primates, human or otherwise, chronically and 
erroneously believe that a homeostatic challenge is about to come, they have entered the 
realm of neurosis, anxiety and paranoia.

In the 1950s and 1960s pioneers such as John Mason, Seymour Levine and Jay 
Weiss--then at the Walter Reed Army Medical Center, Stanford University and the 
Rockefeller University, respectively-began to identify key facets of 
psychological stress. They found that such stress is exacerbated if there is no outlet 
for frustration, no sense of control, no social support and no impression that 
something better will follow. Thus, a rat will be less likely to develop an 
ulcer in response to a series of electric shocks if it can gnaw on a bar of 
wood throughout, because it has an outlet for frustration. A baboon will secrete 
fewer stress hormones in response to frequent fighting if the aggression 
results in a rise, rather than a fall, in the dominance hierarchy; he has a 
perception that life is improving. A person will become less hypertensive when 
exposed to painfully loud noise if she believes she can press a button at any time 
to lower the volume; she has a sense of control.

But suppose such buffers are not available and the stress is chronic. 
Repeated challenges may demand repeated bursts of vigilance. At some point, this 
vigilance may become overgeneralized, leading an individual to conclude that he 
must always be on guard--even in the absence of the stress. And thus the realm 
of anxiety is entered. Alternatively, the chronic stress may be insurmountable, 
giving rise to feelings of helplessness. Again this response may become 
overgeneralized: a person may begin to feel she is always at a loss, even in 
circumstances that she can actually master. Depression is upon her.
Stress and Anxiety

FOR ITS PART, anxiety seems to wreak havoc in the limbic system, the brain 
region concerned with emotion. One structure is primarily affected: the 
amygdala, whi.ch is involved in the perception of and response to fear-evoking 
stimuli. (Interestingly, the amygdala is also central to aggression, underlining the 
fact that aggression can be rooted in fear--an observation that can explain 
much sociopolitical behavior.)

To carry out its role in sensing threat, the amygdala receives input from 
neurons in the outermost layer of the brain, the cortex, where much high-level 
processing takes place. Some of this input comes from parts of the cortex that 
process sensory information, including specialized areas that recognize 
individual faces, as well as from the frontal cortex, which is involved in abstract 
associations. In the realm of anxiety, an example of such an association might 
be grouping a gun, a hijacked plane and an anthrax-tainted envelope in the 
same category. The sight of a fire or a menacing face can activate the 
amygdala--as can a purely abstract thought.

The amygdala also takes in sensory information that bypasses the cortex. As a 
result, a subliminal preconsci0us menace can activate the amygdala, even 
before there is conscious awareness of the trigger.

Imagine a victim of a traumatic experience who, in a crowd of happy, talking 
people, suddenly finds herself anxious, her heart racing. It takes her moments 
to realize that a man conversing behind her has a voice similar to that of 
the man who once assaulted her.

The amygdala, in turn, contacts an array of brain regions, making heavy use 
of a neurotransmitter called corticotropin-releasing hormone (CRH). One set of 
nerve cells projecting from the amygdala reaches evolutionarily ancient parts 
of the midbrain and brain stem. These structures control the autonomic nervous 
system, the network of nerve cells projecting to parts of the body over which 
you normally have no conscious control (your heart, for example). One half of 
the autonomic nervous system is the symigathetic nervous system, which 
mediates "fight or flight." Activate your amygdala with a threat, and soon the 
sympathetic nervous system has directed your adrenal glands to secrete epinephrine. 
Your heart is racing, your breathing is shallow, your senses are sharpened.

The amygdala also sends information back to the frontal cortex. In addition 
to processing abstract associations, as noted above, the frontal cortex helps 
to make judgments about incoming information and initiating behaviors based on 
those assessments. So it is no surprise that the decisions we make can be so 
readily influenced by our emotions. Moreover, the amygdala sends projections to 
the sensory cortices as well, which may explain, in part, [hb: could this 
explain why everything goes into slow motion in an accident?] why sensations seem 
so vivid when we are in certain emotional states--or perhaps why sensory 
memories (flashbacks) occur in victims of trauma.

Whether it orchestrates such powerful reimmersions or not, the amygdala is 
clearly implicated in certain kinds of memory. There are two general forms of 
memory. Declarative, or explicit, memory governs the recollection of facts, 
events or associations. Implicit memory has several roles as well. It includes 
procedural memory: recalling how to ride a bike or play a passage on the piano. 
And it is involved in fear. Remember the woman reacting to the similarity 
between two voices without being aware of it. In that case, the activation of the 
amygdala and the sympathetic nervous system reflects a form of implicit memory 
that does not require conscious awareness.

Researchers have begun to understand how these fearful memories are formed 
and how they can be overgeneralized after repeated stress. The foundation for 
these insights came from work on declarative memory, which is most likely 
situated in a part of the brain called the hippocampus. Memory is established when 
certain sets of nerve cells communicate with one another repeatedly. Such 
communication entails the release of neurotransmitters--chemical messengers that 
travel across synapses, the spaces between neurons. Repeated stimulation of sets 
of neurons causes the communication across synapses to be strengthened, a 
condition called long-term potentiation (LTP).

Joseph LeDoux of New York University has shown that repeatedly placing rats 
in a fear-provoking situation can bring about LTP in the amygdala. Work by 
Sumantra Chattarji of the National Center for Biological Science in Bangalore 
extends this finding one remarkable step further: the amygdalic neurons of rats in 
stressful situations sprout new branches, allowing them to make more 
connections with other neurons. As a result, any part of the fear-inducing situation 
could end up triggering more firing between neurons in the amygdala. A victim 
if he had been robbed several times at night, for instance--might experience 
anxiety and phobia just by stepping outside his home, even under a blazing sun.

LeDoux has proposed a fascinating model to relate these changes to a feature 
of some forms of anxiety. As discussed, the hippocampus plays a key role in 
declarative memory. As will become quite pertinent when we turn to depression, 
glucocorticoid exposure can impair LTP in the hippocampus and can even cause 
atrophy of neurons there. This phenomenon constitutes the opposite of the stress 
response in the amygdala. Severe stress can harm the hippocampus, preventing 
the consolidation of a conscious, explicit memory of the event; at the same 
time, new neuronal branches and enhanced LTP facilitate the amygdala's implicit 
memory machinery. In subsequent situations, the amygdala might respond to 
preconscious information--but conscious awareness or memory may never follow. 
According to LeDoux, such a mechanism could underlie forms of free-floating 
anxiety.

It is interesting that these structural changes come about, in part, because 
of hormones secreted by the adrenal glands, a source well outside the brain. 
As mentioned, the amygdala's perception of stress ultimately leads to the 
secretion of epinephrine and glucocorticoids. The glucocorticoids then activate a 
brain region called the locus coeruleus. This structure in turn, sends a 
powerfully activating projection back to the amygdala, making use of a 
neurotransmitter called norepinephrine (a close relative of epinephrine). The amygdala then 
sends out more CRH, which leads to the secretion of more glucocorticoids. A 
vicious circle of mind-body feedback can result.
Assuaging Anxiety

AN UNDERSTANDING of the interactions between stress and anxiety has opened 
the way for new therapies, some of which hold great promise. These drugs are not 
presumed better or safer than those available today. Rather, if successful, 
they will give clinicians more to work with.

The medicines that already exist do target aspects of the stress system. The 
minor tranquilizers, such as Valium and Librium, are in a class of compounds 
called benzodiazepines. They work in part by relaxing muscles; they also 
inhibit the excitatory projection from the locus coeruleus into the amygdala, 
thereby decreasing the likelihood that the amygdala will mobilize the sympathetic 
nervous system. The net result is a calm body--and a less anxious body means a 
less anxious brain. While effective, however, benzodiazepines are also sedating 
and addictive, and considerable research now focuses on finding less 
troublesome versions.

In their Search for alternatives, researchers have sought to target the 
stress response upstream of the locus coeruleus and amygdala. Epinephrine activates 
a nerve called the vagus, which projects into a brain region that 
subsequently stimulates the amygdala. A new therapy curtails epinephrine's stimulation of 
the vagus nerve.

Chemical messengers such as epinephrine exert theft effects by interacting 
with specialized receptors on the surface of target cells. A receptor is shaped 
in such a way that it can receive only a certain messenger-just as a mold will 
fit only the statue cast in it. But by synthesizing imposter messengers, 
scientists have been able to block the activity of some of the body's natural 
couriers.

Drugs called beta blockers fit into some kinds of epinephrine receptors, 
preventing real epinephrine from transmitting any information. Beta blockers have 
long been used to reduce high blood pressure driven by an overactive 
sympathetic nervous system, as well as to reduce stage fright. But Larry Cahill and 
James McGaugh of the University of California at Irvine have shown that the drugs 
also blunt the formation of memories of emotionally disturbing events or 
stories. Based on their findings and others, clinicians such as Roger Pitman of 
Harvard University have started studies in which beta blockers are given to 
people who have experienced severe trauma in the hope of heading off the 
development of post-traumatic stress disorder.

Other therapies are being designed to act in the amygdala itself. As 
described, the amygdala's shift from merely responding to an arousing event to 
becoming chronically overaroused probably involves memory formation as well as the 
growth of new synapses. Work in my laboratory is exploring the molecular biology 
underlying those changes. Because prolonged stress has opposite effects on 
synapse formation in the hippocampus and the amygdala, we would like to know how 
the profiles of genes turned on and off by stress differ in those two 
structures. Our goal is to then try to block the changes by introducing genes into 
the amygdala that might give rise to proteins that could inhibit synapse 
formation during stress. In this work, viruses that have been rendered safe are used 
to ferry genes to the amygdala [see Gene Therapy in the Nervous System, by 
Dora Y. Ho and Robert M. Sapolsky; SCIENTIFIC AMERICAN, July 1997].

Another strategy--for both anxiety and depression--targets CRH, the 
neurotransmitter used by the amygdala when it sends information elsewhere. Based on 
insights into the structure of CRH and its receptors, scientists have developed 
chemical imposters to bind with the receptors and block it. In research by 
Michael Davis of Emory University, these compounds have proved effective in rat 
models of anxiety. They have reduced the extent to which a rat anxiously freezes 
when placed in a cage where it was previously shocked.
Stress and Depression

IN CONTRAST TO ANXIETY, which can feel like desperate hyperactivity, major 
depression is characterized by helplessness, despair,, an exhausted sense of 
being too overwhelmed to do anything (psychomotor retardation) and a loss of 
feelings of pleasure. Accordingly, depression has a different biology and requires 
some different strategies for treatment. But it, too, can be related to 
stress, and there is ample evidence of this association. First of all, 
psychological stress entails feeling a loss of control and predictability--an accurate 
description of depression. Second, major stressful events seem to precede 
depressive episodes early in the course of the disease. Finally, treating people with 
glucocorticoid hormones to control conditions such as rheumatoid arthritis 
can lead to depression.

One way in which stress brings about depression is by acting on the brain's 
mood and pleasure pathways. To begin, prolonged exposure to glucocorticoid 
hormones depletes norepinephrine levels in the locus coeruleus neurons. Most 
plausibly, this means that the animal--or person--becomes less attentive, less 
vigilant, less active: psychomotor retardation sets in.

Continued stress also decreases levels of serotonin--which may be important 
in the regulation of mood and sleep cycles, among other things--as well as the 
number of serotonin receptors in the frontal cortex. Serotonin normally 
arrives in the frontal cortex by way of the raphe nucleus, a structure that also 
communicates with the locus coeruleus. You can probably see where this is going. 
Normally, serotonin stimulates the release of norepinephrine from the locus 
coeruleus. When serotonin becomes scarce, less norepinephrine is 
released--exacerbating the shortage caused by earlier unremitting glucocorticoid bombardment.

Stress affects dopamine, the main currency of the pleasure pathway, in a way 
that seems counterintuitive at first. Moderate and transient amounts of 
stress--and the ensuing presence of glucocorticoids--increase dopamine release in 
the pleasure pathway, which runs between a region called the ventral 
tegmentum/nucleus accumbens and the frontal cortex. More dopamine can lead to a feeling 
of well-being in situations of moderate or transient stress during which a 
subject is challenged briefly and not too severely. For a human, or a rat, this 
situation would entail a task that is not trivial, but one in which there is, 
nonetheless, a reasonably high likelihood of success--in other words, what we 
generally call "stimulation." But with chronic glucocorticoid exposure, dopamine 
production is curbed and the feelings of pleasure fade.

Not surprisingly, the amygdala also appears relevant to depression. Wayne 
Drevets of the National Institute of Mental Health reports that the images of the 
amygdala of a depressed person light up more in response to sad faces than 
angry ones. Moreover, the enhanced autonomic arousal seen in anxiety-- thought 
to be driven by the amygdala--is often observed in depression as well. This 
fact might seem puzzling at first: anxiety is characterized by a skittish: 
torrent of fight-or-flight signals, whereas depression seems to be about torpor. Yet 
the helplessness of depression is not a quiet, passive state. The dread is 
active, twitching, energy-consuming, distracting, exhausting--but internalized. 
A classic conceptualization of depression is that it represents aggression 
turned inward--an enormous emotional battle fought entirely internally--and the 
disease's physiology supports this analysis.
Memory and New Cells

STRESS ALSO ACTS ON the hippocampus, and this activity may bring about some 
of the hallmarks of depression: difficulty learning and remembering. As I 
explained before, stress and glucocorticoids can disrupt memory formation in the 
hippocampus and can cause hippocampal neurons to atrophy and lose some of their 
many branches. In the 1980s several laboratories, including my own, showed 
that glucocorticoids can kill hippocampal neurons or impair their ability to 
survive neurological insults such as a seizure or cardiac arrest.

Stress can even prevent the growth of new nerve cells. Contrary to long-held 
belief, adult brains do make some new nerve cells. This revolution in our 
understanding has come in the past decade. And although some findings remain 
controversial, it is clear that new neurons form in the olfactory bulb and the 
hippocampus of many adult animals, including humans [see "Brain, Repair Yourself," 
by Fred H. Gage]. Many things, including learning, exercise and environmental 
enrichment, stimulate neurogenesis in the hippocampus. But stress and 
glucocorticoids inhibit it.

As would be expected, depression is associated with impaired declarative 
memory. This impairment extends beyond remembering the details of an acute trauma. 
Instead depression can interfere with declarative memory formation in 
general--in people going about their everyday routine or working or learning. Recent 
and startling medical literature shows that in those who have been seriously 
depressed for years, the volume of the hippocampus is 10 to 20 percent smaller 
than in well-matched control subjects. There is little evidence that a small 
hippocampus predisposes someone toward depression; rather the decreased volume 
appears to be a loss in response to depression.

At present, it is not clear whether this shrinkage is caused by the atrophy 
or death of neurons or by the failure of neurogenesis. Disturbingly, both the 
volume loss and at least some features of the cognitive impairments persist 
even when the depression resolves. (It is highly controversial whether new 
neurons are required for learning and memory; thus, it is not clear whether an 
inhibition of neurogenesis would give rise to cognitive deficits.)

Glucocorticoids may act on the hippocampus by inhibiting levels of a compound 
called brain-derived neurotrophic factor (BDNF)--which may aid neurogenesis. 
Several known antidepressants increase amounts of BDNF and stimulate 
hippocampal neurogenesis in laboratory animals. These findings have led some scientists 
to speculate that the stress-induced inhibition of neurogenesis and of BDNF 
are central to the emotional symptoms of depression. I find it to be somewhat 
of a stretch to connect altered hippocampal function with the many facets of 
this disease. Nevertheless, these hippocampal changes may play a large part in 
the substantial memory dysfunction typical of major depression.
New Drugs for Depression

THE CURRENT GENERATION of antidepressants boost levels of serotonin, dopamine 
and norepinephrine, and there is tremendous ongoing research to develop more 
effective versions of these drugs. But some novel therapies target steps more 
intimately related to the interactions between stress and depression.

Not surprisingly, some of that work focuses on the effects of 
glucocorticoids. For example, a number of pharmaceuticals that are safe and clinically 
approved for other reasons can transiently block the synthesis of glucocorticoids in 
the adrenal glands or block access of glucocorticoids to one of their 
important receptors in the brain. Fascinatingly, the key compound that blocks 
glucocorticoid receptors is RU486, famous and controversial for its capacity to also 
block progesterone receptors in the uterus and for its use as the "abortion 
drug." Beverly Murphy of McGill University, Owen Wolkowitz of the University of 
California at San Francisco and Alan Schatzberg of Stanford have shown that 
such antiglucocorticoids can act as antidepressants for a subset of severely 
depressed people with highly elevated glucocorticoid levels. These findings are 
made even more promising by the fact that this group of depressed individuals 
tend to be most resistant to the effects of more traditional antidepressants.

Another strategy targets CRH. Because depression, like anxiety, often 
involves an overly responsive amygdala and sympathetic nervous system, CRH is a key 
neurotransmitter in the communication from the former to the latter. Moreover, 
infusion of CRH into the brain of a monkey can cause some depressionlike 
symptoms. These findings have prompted studies as to whether CRH-receptor blockers 
can have an antidepressant action. It appears they can, and such drugs are 
probably not far off.

Using the same receptor-blocking strategy, researchers have curbed the action 
of a neurotransmitter called Substance P, which binds to the neurokinin-1 
(NK-1) receptor. In the early 1990s workers discovered that drugs binding with 
NK-1 prevent some aspects of the stress response. In one trial and several 
animal studies, Substance P has worked as an antidepressant.

Other approaches center on the hippocampus. Investigators are injecting BDNF 
into the brains of rats to counteract the inhibitory effects of 
glucocorticoids on neurogenesis. My own laboratory is using gene therapy to protect the 
hippocampus of rats from the effects of stress--much as we are doing in the 
amygdala to prevent anxiety. These genes are triggered by glucocorticoids; once 
activated, they express an enzyme that degrades glucocorticoids. The net result 
blocks the deleterious effects of these hormones. We are now exploring whether 
this treatment can work in animals.

As is now clear, I hope, anxiety and depression are connected. Yet a state of 
constant vigilance and one of constant helplessness seem quite different. 
When does stress give rise to one as opposed to the other? The answer seems to 
lie in how chronic the stress is.
The Stress Continuum

IMAGINE A RAT trained to press a lever to avoid a mild, occasional shock--a 
task readily mastered. Thai rat is placed into a cage with the lever, and the 
anticipatory sense of mastery might well activate the pleasurable dopaminergic 
projections to the frontal cortex. When the increase in glucocorticoid 
secretion is moderate and transient--as would likely be the case here--the hormone 
enhances dopamine release.

Suppose that in this circumstance, however, the lever has been disconnected; 
pressing it no longer prevents shocks. Initially this alteration produces a 
wildly hypervigilant state in the rat as it seeks a new coping response to stop 
the shocks. The animal presses the lever repeatedly, frantically trying to 
regain control. This is the essence of anxiety and of the multiple, disorganized 
attempts at coping. Physiologically, this state is characterized by massive 
activation of the sympathetic nervous system by epinephrine and of the 
norepinephrine projection from the locus coeruleus, as well as moderately increased 
glucocorticoid secretion.

And as the shocks continue and the rat finds each attempt at coping useless, 
a transition occurs. The stress response becomes more dominated by high 
glucocorticoid levels than by epinephrine and the sympathetic nervous system--which 
are largely in control of the immediate fight-or-flight reaction. The brain 
chemistry begins to resemble that of depression as key neurotransmitters become 
depleted and the animal ceases trying to cope. It has learned to be helpless, 
passive and involuted. If anxiety is a crackling, menacing brushfire, 
depression is a suffocating heavy blanket thrown on top of it.
Stress and Genes

I DO NOT WANT to conclude this article having given the impression that 
anxiety and depression are "all" or "only" about stress. Obviously, they are not:. 
Both illnesses have substantial genetic components as well. Genes code for the 
receptors for dopamine, serotonin and glucocorticoids. They also code for the 
enzymes that synthesize and degrade those chemical messengers, for the pumps 
that remove them from the synapses, for growth factors like BDNF, and so on.

But those genetic influences are not inevitable. Remember, if an individual 
has one of the major psychiatric disorders, her identical twin has only about a 
50 percent chance of having it. Instead the genetic influences seem to be 
most about vulnerability: how the brain and body react to certain environments, 
including how readily the brain and body reequilibrate after stress.

Experience, beginning remarkably early in life, also influences how one 
responds to stressful environments. The amount of stress a female rat is exposed to 
during pregnancy influences the amount of glucocorticoids that cross the 
placenta and reach the fetus; that exposure can then alter the structure and 
function of that fetus's hippocampus in adulthood. Separate a newborn rat from its 
mother for a sustained period and it will have increased levels of CRH as an 
adult. Seymour Levine, One of the giants of psychobiology, illustrates this 
point with a quotation from William Faulkner: "The past is not dead. It's not 
even the past."

An understanding of the role of stress in psychiatric disorders offers much. 
It teaches us that a genetic legacy of anxiety or depression does not confer a 
life sentence on sufferers of these tragic diseases. It is paving the way for 
some new therapies that may help millions. Given that there is a continuum 
between the biology of these disorders and that of the "normal" aspects of 
emotion, these findings are not only pertinent to "them and their diseases" but to 
all of us in our everyday lives. Perhaps most important, such insight carries 
with it a social imperative: namely, that we must find ways to heal a world in 
which so many people learn that they must always feel watchful and on guard 
or that they must always feel helpless.
SOME NOVEL THERAPEUTIC STRATEGIES

Substance P. This compound is released during painful sensations and stress 
and are found throughout the central nervous system but in greater amounts in 
the amygdala and locus coeruleus, among other stress related areas. Current 
work-including one clinical trial--suggests that blocking the action of Substance 
P may blunt anxiety and depression. But another clinical trial did not 
support this finding.

Corticotropin-Releasing Hormone. This hormone is released by the amygdala and 
initiates the stress cascade. Research efforts now include trying to block 
receptors for CRH in the brain stem. Without information from CRH, the brain 
stem will not set the sympathetic nervous system in motion,, thus preventing the 
release of epinephrine by the adrenal glands. This blockade could block 
anxiety and depression.

Brain-Derived Neurotrophic Factor. This substance is important to the 
creation of new nerve cells. By injecting BDNF into brains, researchers hope to 
counteract the deleterious effects of glucocorticoids on neurogenesis in the 
hippocampus, thereby maintaining healthy memory function and preventing the 
hippocampal atrophy often seen in depressed people.

Gene Therapy. This treatment can introduce novel genes to specific regions of 
the brain; these genes can then produce proteins that can undo or prevent the 
effects of stress. Current studies aim to figure out which genes are active 
in the amygdala during stress. Introducing genes that inhibit unwanted neural 
branching in the amygdala might then thwart the anxiety-inducing effects of 
stress. For depression, the goal is different: genes placed in the hippocampus 
could produce proteins that would break down glucocorticoids, preventing damage 
to nerve cells-and, accordingly, the memory impairment-that can accompany 
depression.

Anxiety becomes depression if stress is chronic and levels of dopamine [D}, 
glucocorticoids [ G} and epinephrine [E} change accordingly. If a rat knows how 
to press a lever to avoid a shock, it can feel pleasure in that mastery. If 
the lever no longer works, however, anxiety sets in and the animal desperately 
tries different strategies to avoid the shock (2}. As coping proves elusive, 
hypervigilance is replaced by passivity and depression (3).
MORE TO EXPLORE

Why Zebras Don't Get Ulcers. Robert M. Sapolski. W. H. Freeman and Company, 
1998.

The End of Stress as We Know It. Bruce McEwen, with Elizabeth Norton Lasley. 
Joseph Henry Press, Washington D.C., 2002.

Better Than Prozac. Samuel H. Barondes. Oxford University Press, 2003.
OVERVIEW / Battling Stress

• Scientists understand a lot about the role stress plays in the development 
of anxiety disorders and major depression, which may affect as many as 40 
million people in the U.S. And they are coming to see the ways in which 
unremitting stress can transform anxiety into depression.

• Insights into the neurochemistry of stress are allowing researchers to 
develop new ways of thinking about drug development. In addition to refining drugs 
that are already on the market, these findings are leading to entirely novel 
strategies for treatments.

• Finding these alternatives is crucially important because many people are 
not helped by currently available medications.
VICIOUS CYCLE OF STRESS

STRESS PATHWAYS are diverse and involve many regions of the brain in feedback 
loops that sometimes greatly amplify a response. The process-simplified 
somewhat in this diagram-begins when an actual or perceived threat activates the 
sensory and higher reasoning centers in the cortex. The cortex then sends a 
message to the amygdala, the principal mediator of the stress response. 
Separately, a preconscious signal my precipitate activity in the amygdala. The amygdala 
releases corticotropin-releasing hormone, which stimulates the brain stem to 
activate the sympathetic nervous system via the spinal cord. In response, the 
adrenal glands produce the stress hormone epinephrine; a different pathway 
simultaneously triggers the adrenals to release glucocorticoids. The two types of 
hormones act on the muscle, heart and lungs to prepare the body for "fight or 
flight". If the stress becomes chronic, glucocorticoids induce the locus 
coeruleus to release norepinephrine that communicates with the amygdala, leading to 
the production of more CRH- and to ongoing reactivation of stress pathways.
DEPRESSION'S EFFECTS

DOPAMINE DEPLETION

Prolonged exposure to stress hormones can increase the risk of depression by 
depleting levels of dopamine. This neurotransmitter is integral to the 
pleasure pathway, which involves many brain structures, including the prefrontal 
cortex.

NOREPINEPHRINE DEPLETION

Because stimulation from the raphe nucleus falls off after chronic stress, 
the locus coeruleus secretes less norepinephrine, and attentiveness is 
accordingly diminished.

SEROTONIN DEPLETION

Stress brings about reduced secretion of the neurotransmitter serotonin from 
the raphe nucleus, which communicates with the locus coerlueus and the cortex.

HIPPOCAMPAL SHRINKAGE

Stress brings about cell death in the hippocampus- and studies have found 
that this brain region is 10 to 20 percent smaller in depressed individuals. Such 
impairment can lead to memory problems.

DIAGRAM

DIAGRAM

GRAPH

GRAPH

GRAPH

PHOTO (COLOR)

PHOTO (COLOR)

PHOTO (COLOR)

~~~~~~~~

By Robert Salzano

ROBERT SAPOLSKY is professor of biological science and neurology at Stanford 
University and a research associate at the National Museums of Kenya, where he 
has studied a population of wild baboons for more than two decades. He earned 
a Ph.D. in neuroendocrinology from the Rockefeller University in 1984. 
Sapolsky's research interests include neuronal death, gene therapy and the 
physiology of primates.
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Source: Scientific American, Sep2003, Vol. 289 Issue 3, p88, 10p
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----------
Howard Bloom
Author of The Lucifer Principle: A Scientific Expedition Into the Forces of 
History and Global Brain: The Evolution of Mass Mind From The Big Bang to the 
21st Century
Visiting Scholar-Graduate Psychology Department, New York University; Faculty 
Member, The Graduate Institute
www.howardbloom.net
www.bigbangtango.net
Founder: International Paleopsychology Project; founding board member: Epic 
of Evolution Society; founding board member, The Darwin Project; founder: The 
Big Bang Tango Media Lab; member: New York Academy of Sciences, American 
Association for the Advancement of Science, American Psychological Society, Academy 
of Political Science, Human Behavior and Evolution Society, International 
Society for Human Ethology; advisory board member: Youthactivism.org; executive 
editor -- New Paradigm book series.
For information on The International Paleopsychology Project, see: 
www.paleopsych.org
for two chapters from 
The Lucifer Principle: A Scientific Expedition Into the Forces of History, 
see www.howardbloom.net/lucifer
For information on Global Brain: The Evolution of Mass Mind from the Big Bang 
to the 21st Century, see www.howardbloom.net
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