[Paleopsych] why is the amygdala so sneaky?
Lynn D. Johnson, Ph.D.
ljohnson at solution-consulting.com
Fri Jul 2 03:19:36 UTC 2004
I agree, Steve. Well put.
Lynn Johnson
ps - glad the list is running again.
Steve Hovland wrote:
> Repression of trauma may be an old survival response
> that preserves the body while killing the soul.
>
> People who have suffered a serious psychic trauma
> such as crime or incest may continue to function, but
> they are crippled by the things they don't care to think
> about. A frozen emotional response makes it hard
> for them to make life choices that would move them
> forward. The current problems of Michael Jackson, for
> example, undoubtedly result from early abuse that
> went untreated.
>
> In terms of Goleman's work on emotional intelligence
> these people have suffered a stroke. Sometimes the
> repression is so complete that people can't remember
> the cause even though they exhibit all of the symptoms.
>
> The challenge for unsuccessful components of a learning
> system is to figure out how to do better. While they are
> in their impaired state they emit poisons that hurt the
> performance of other components. It's in the interest
> of society to figure out how to prevent and repair this
> damage.
>
>
> ----- Original Message -----
> From: HowlBloom at aol.com <mailto:HowlBloom at aol.com>
> To: paleopsych at paleopsych.org <mailto:paleopsych at paleopsych.org>
> Sent: Wednesday, June 30, 2004 8:30 PM
> Subject: [Paleopsych] why is the amygdala so sneaky?
>
> 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
>
> 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
>
> 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.
>
> Copyright of Scientific American is the property of Scientific
> American Inc. and its content may not be copied or e-mailed to
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> holder`s express written permission. However, users may print,
> download, or e-mail articles for individual use.
>
> Source: Scientific American, Sep2003, Vol. 289 Issue 3, p88, 10p
>
> Item: 10544899
>
>
>
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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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