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<DIV><FONT size=2>
<DIV><FONT face=Arial size=2>Howard</FONT></DIV>
<DIV><FONT face=Arial size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>Actually, Freud thought that repression is an
<EM>unconscious</EM> act. </FONT></DIV>
<DIV><FONT face=Arial size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>Freud thought that conscious states must have
sensory qualities in order to be conscious. Counscious is a fabric of
smells, tastes, sounds, sights etc. It follows that mental states
devoid of these 'qualia' (as they are nowadays called) must be
unconscious. Thought, then, has to be unconscious.</FONT></DIV>
<DIV><FONT face=Arial size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>How, then, do these nonsensory thoughts become
conscious? Freud thought that they have to become associated with
language. Language can serve as a go-between mediating the relationship
between thought and consciousness because it shares the same abstract structure
as thought but it is also a richly sensory symbol system. </FONT></DIV>
<DIV><FONT face=Arial size=2></FONT><FONT face=Arial size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>Freud thought that repression is a motiviated
failure to translate unconscious thought into language, a failure to articulate
our own thoughts to ourselves. According to this thesis repression can't
be conscious because it <EM>undercuts</EM> consciousness.</FONT></DIV>
<DIV><FONT face=Arial size=2></FONT> </DIV>
<DIV><FONT face=Arial size=2>Cheers</FONT></DIV>
<DIV><FONT face=Arial size=2>David</FONT></DIV></FONT></DIV>
<BLOCKQUOTE
style="PADDING-RIGHT: 0px; PADDING-LEFT: 5px; MARGIN-LEFT: 5px; BORDER-LEFT: #000000 2px solid; MARGIN-RIGHT: 0px">
<DIV style="FONT: 10pt arial">----- Original Message ----- </DIV>
<DIV
style="BACKGROUND: #e4e4e4; FONT: 10pt arial; font-color: black"><B>From:</B>
<A title=HowlBloom@aol.com
href="mailto:HowlBloom@aol.com">HowlBloom@aol.com</A> </DIV>
<DIV style="FONT: 10pt arial"><B>To:</B> <A title=paleopsych@paleopsych.org
href="mailto:paleopsych@paleopsych.org">paleopsych@paleopsych.org</A> </DIV>
<DIV style="FONT: 10pt arial"><B>Sent:</B> Wednesday, June 30, 2004 11:30
PM</DIV>
<DIV style="FONT: 10pt arial"><B>Subject:</B> [Paleopsych] why is the amygdala
so sneaky?</DIV>
<DIV><BR></DIV>
<DIV>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman">The following tidbit from an article in The Scientific
American on stress and memory gives a<SPAN style="mso-spacerun: yes">
</SPAN>neurobiological explanation for something<SPAN
style="mso-spacerun: yes"> </SPAN>Sigmund Freud described way back in
the early days of psycho-speculation…repression and suppression.<SPAN
style="mso-spacerun: yes"> </SPAN></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><SPAN
style="mso-spacerun: yes"></SPAN></FONT></FONT> </P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><SPAN style="mso-spacerun: yes"></SPAN>When something
ghastly happens to us, says this piece, which derives its wisdom from Joseph
LeDoux, a strange thing happens in our brain.<SPAN
style="mso-spacerun: yes"> </SPAN>The hippocampus, the traffic center
that sends material to the conscious mind, goes through shut down.<SPAN
style="mso-spacerun: yes"> </SPAN>It’s paralyzed by glucocorticooids,
stress hormones.<SPAN style="mso-spacerun: yes"> </SPAN>But something
very different happens to our fear and body-knowledge traffic center, the
amygdala.<SPAN style="mso-spacerun: yes"> </SPAN>The amygedala thrives,
grows new threads of connection to the sympathetic nervous system, and
implants memories of the frightful experience in us.<SPAN
style="mso-spacerun: yes"> </SPAN>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. <SPAN
style="mso-spacerun: yes"> </SPAN>But it also gets woven in at a level
that’s impossible for us to “see” and think out.</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Here’s the question.<SPAN style="mso-spacerun: yes"> </SPAN>What
could the evolutionary value be of keeping key experiences locked in a vault
that the conscious mind can’t crack into?<SPAN
style="mso-spacerun: yes"> </SPAN>Is this one of the shortcuts the mind
uses to speed up our reactions by cutting the dither of thinking out of the
process?<SPAN style="mso-spacerun: yes"> </SPAN>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?</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Many of<SPAN style="mso-spacerun: yes"> </SPAN>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<SPAN style="mso-spacerun: yes"> </SPAN>high in the
branches above the grizzly’s head.<SPAN style="mso-spacerun: yes">
</SPAN>Many, in fact, are paralyzing.<SPAN style="mso-spacerun: yes">
</SPAN>They’re the high-anxiety mind-and-body freezes of extreme anxiety.<SPAN
style="mso-spacerun: yes"> </SPAN>They’re the torture-terrors of
post-traumatic stress disorders.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.<SPAN
style="mso-spacerun: yes"> </SPAN>Why? So their influence will be
minimized.<SPAN style="mso-spacerun: yes"> </SPAN>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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?<SPAN style="mso-spacerun: yes"> </SPAN>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?</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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? <SPAN
style="mso-spacerun: yes"> </SPAN>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?</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>One thing this amygdala-centered understanding hints at is this.<SPAN
style="mso-spacerun: yes"> </SPAN>Freud implied that repression was a
conscious act, a mistaken act of will or cowardice.<SPAN
style="mso-spacerun: yes"> </SPAN>We were conscious of the trauma when
it happened, couldn’t face its consequences, so tucked it out of sight.<SPAN
style="mso-spacerun: yes"> </SPAN>That’s not the way the LeDoux scenario
explains it.<SPAN style="mso-spacerun: yes"> </SPAN>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.<SPAN style="mso-spacerun: yes"> </SPAN>I suspect there’s a
little bit of truth to both points of view.<SPAN
style="mso-spacerun: yes"> </SPAN>What do you think?<SPAN
style="mso-spacerun: yes"> </SPAN>Howard</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><SPAN
style="mso-spacerun: yes"><FONT face="Times New Roman"
size=2></FONT></SPAN> </P>
<P class=MsoNormal style="MARGIN: 0in 0.5in 0pt"><FONT size=2><FONT
face="Times New Roman"><B>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.</B> Retrieved
June 30, 2004, from the World Wide Web<SPAN style="mso-spacerun: yes">
</SPAN>EBSCOhost</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0.5in 0pt"><FONT face="Times New Roman"
size=2>Taming stress ,<SPAN style="mso-spacerun: yes"> </SPAN>By:
Salzano, Robert, Scientific American, 00368733, Sep2003, Vol. 289, Issue
3</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Retrieved June 30, 2004, from the World Wide Web </FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>http://web9.epnet.com/citation.asp?tb=1&_ug=sid+BB4951D1%2DC74E%2D42C7%2DAB5A%2D27F66A8435DD%40sessionmgr6+dbs+aph+cp+1+D09B&_us=hs+True+cst+0%3B2+or+Date+ss+SO+sm+KS+sl+0+dstb+KS+ri+KAAACB4A00000109+37EF&_uso=tg%5B0+%2D+db%5B0+%2Daph+hd+False+clv%5B1+%2Dscientific++american+clv%5B0+%2D20030900%2D20030900+op%5B0+%2D+cli%5B1+%2DSO+cli%5B0+%2DDT1+st%5B0+%2Damygdala+1438&cf=1&fn=1&rn=1</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>EBSCOhost</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>: Taming stress ,<SPAN style="mso-spacerun: yes"> </SPAN>By:
Salzano, Robert, Scientific American, 00368733, Sep2003, Vol. 289, Issue
3</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>An emerging understanding of the brain's stress pathways points toward
treatments for anxiety and depression beyond Valium and Prozac</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Out of Balance,</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress and Anxiety</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>To carry out its role in sensing threat, <B><SPAN
style="BACKGROUND: yellow; mso-highlight: yellow">the amygdala receives input
from </SPAN>neurons in the outermost layer of the brain, the cortex</B>, where
much high-level processing takes place.<B> Some of this input comes from parts
of the cortex that process sensory information, including<SPAN
style="BACKGROUND: yellow; mso-highlight: yellow"> specialized areas that
recognize individual faces</SPAN>, as well as from the frontal cortex, which
is involved in abstract associations.</B> 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoBodyText style="MARGIN: 0in 0in 0pt"><STRONG><FONT
face="Times New Roman" size=2>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.</FONT></STRONG></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><B>The amygdala, in turn, contacts an array of brain
regions, making heavy use of a neurotransmitter called corticotropin-releasing
hormone (CRH).</B> 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.</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><B>The amygdala also sends information back to the
frontal cortex.</B> 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.
<B>Moreover, the amygdala sends projections to the sensory cortices as
well</B>, which may explain, in part, <B>[hb: could this explain why
everything goes into slow motion in an accident?]</B> why sensations seem so
vivid when we are in certain emotional states--or perhaps why sensory memories
(flashbacks) occur in victims of trauma.</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman">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, <B>the activation of the amygdala and the sympathetic nervous
system reflects a form of implicit memory that does not require conscious
awareness.<o:p></o:p></B></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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).</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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:<B><SPAN
style="BACKGROUND: yellow; mso-highlight: yellow"> the amygdalic neurons of
rats in stressful situations sprout new branches, allowing them to make more
connections with other neurons.</SPAN></B> 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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, <B>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.</B> According to LeDoux, such a mechanism could
underlie forms of free-floating anxiety.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Assuaging Anxiety</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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<B> 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.</B> 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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].</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress and Depression</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman">One way in which stress brings about depression is by
acting on the brain's mood and pleasure pathways. To begin, <B>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.</B></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"><B>Continued stress also decreases levels of
serotonin</B>--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.</FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Memory and New Cells</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>New Drugs for Depression</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>The Stress Continuum</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress and Genes</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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."</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>SOME NOVEL THERAPEUTIC STRATEGIES</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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).</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>MORE TO EXPLORE</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Why Zebras Don't Get Ulcers. Robert M. Sapolski. W. H. Freeman and
Company, 1998.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>The End of Stress as We Know It. Bruce McEwen, with Elizabeth Norton
Lasley. Joseph Henry Press, Washington D.C., 2002.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Better Than Prozac. Samuel H. Barondes. Oxford University Press,
2003.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>OVERVIEW / Battling Stress</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>• 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>• 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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>• Finding these alternatives is crucially important because many people
are not helped by currently available medications.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>VICIOUS CYCLE OF STRESS</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>DEPRESSION'S EFFECTS</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>DOPAMINE DEPLETION</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>NOREPINEPHRINE DEPLETION</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Because stimulation from the raphe nucleus falls off after chronic
stress, the locus coeruleus secretes less norepinephrine, and attentiveness is
accordingly diminished.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>SEROTONIN DEPLETION</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Stress brings about reduced secretion of the neurotransmitter serotonin
from the raphe nucleus, which communicates with the locus coerlueus and the
cortex.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>HIPPOCAMPAL SHRINKAGE</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>DIAGRAM</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>DIAGRAM</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>GRAPH</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>GRAPH</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>GRAPH</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>PHOTO (COLOR)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>PHOTO (COLOR)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>PHOTO (COLOR)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>~~~~~~~~</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>By Robert Salzano</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT
face="Times New Roman"> <o:p></o:p></FONT></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>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.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Copyright of Scientific American is the property of Scientific American
Inc. and its content may not be copied or e-mailed to multiple sites or posted
to a listserv without the copyright holder`s express written permission.
However, users may print, download, or e-mail articles for individual
use.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Source: Scientific American, Sep2003, Vol. 289 Issue 3, p88,
10p</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"
size=2>Item: 10544899</FONT></P>
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<DIV> </DIV>
<DIV><FONT lang=0 face=Arial size=2 PTSIZE="10"
FAMILY="SANSSERIF">----------<BR>Howard Bloom<BR>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<BR>Visiting Scholar-Graduate Psychology Department, New York
University; Faculty Member, The Graduate
Institute<BR>www.howardbloom.net<BR>www.bigbangtango.net<BR>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.<BR>For
information on The International Paleopsychology Project, see:
www.paleopsych.org<BR>for two chapters from <BR>The Lucifer Principle: A
Scientific Expedition Into the Forces of History, see
www.howardbloom.net/lucifer<BR>For information on Global Brain: The Evolution
of Mass Mind from the Big Bang to the 21st Century, see
www.howardbloom.net<BR></FONT></DIV>
<P>
<HR>
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