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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New">The
vagal nerve's role in enteric processes, cardiac operation, speech, and hearing
have grabbed my attention.<SPAN style="mso-spacerun: yes"> </SPAN>A single
nerve connecting the gut, the heart, and the speaker and listener we call the
self?<SPAN style="mso-spacerun: yes"> </SPAN>It's potentially an amazing
social integrator.<SPAN style="mso-spacerun: yes"> </SPAN>I've been
searching for the social centers of the brain for years and these seem to be a
part of that complex. Howard</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New">---</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New">vagus
nerve</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New">n.</FONT></P>
<P class=bullets--quadrafoil style="MARGIN: 0in 0in auto"><FONT face=Verdana size=1>Either of the tenth and longest of the cranial nerves, passing through
the neck and thorax into the abdomen and supplying sensation to part of the ear,
the tongue, the larynx, and the pharynx, motor impulses to the vocal cords, and
motor and secretory impulses to the abdominal and thoracic viscera. Also called
pneumogastric nerve.<SPAN style="mso-spacerun: yes"> </SPAN><U>The
American Heritage® Dictionary of the English Language, Fourth Edition</U>
Copyright © 2004, 2000 by </FONT><A href="http://www.eref-trade.hmco.com/" target=GuruWnd><FONT face=Verdana size=1>Houghton Mifflin
Company</FONT></A><FONT face=Verdana size=1>. Published by Houghton Mifflin
Company. All rights reserved. </FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New">----------</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New">Retrieved May 26, 2005, from the World Wide Web </FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New">http://www.stressrelease.info/polyvagal_eng.html <SPAN style="mso-tab-count: 1"> </SPAN><SPAN style="mso-spacerun: yes"> </SPAN>The polyvagal theory: phylogenetic
substrates of a social nervous system<SPAN style="mso-spacerun: yes">
</SPAN>Stephen W. Porges, Ph.D.<SPAN style="mso-spacerun: yes">
</SPAN>Abstract<SPAN style="mso-spacerun: yes"> </SPAN>The evolution of
the autonomic nervous system provides an organizing principle to interpret the
adaptive<SPAN style="mso-spacerun: yes"> </SPAN>significance of
physiological responses in promoting social behavior. According to <B>the
polyvagal theory</B>, the<SPAN style="mso-spacerun: yes">
</SPAN>well-documented phylogenetic shift in neural regulation of <B>the
autonomic nervous system passes through three</B><SPAN style="mso-spacerun: yes"> </SPAN>global <B>stages</B>, each with an
associated behavioral strategy. <B>The first stage is characterized by a
primitive unmyelinated<SPAN style="mso-spacerun: yes"> </SPAN>visceral
vagus that fosters digestion and responds to threat by depressing metabolic
activity.</B> Behaviorally, the first<SPAN style="mso-spacerun: yes">
</SPAN>stage is associated with immobilization behaviors. <B>The second stage is
characterized by the sympathetic nervous<SPAN style="mso-spacerun: yes">
</SPAN>system</B> that is capable of <B>increasing metabolic output and
inhibiting the visceral vagus to foster mobilization</B><SPAN style="mso-spacerun: yes"> </SPAN>behaviors necessary for ‘fight or
flight’. <B>The third stage, unique to mammals, is characterized by a myelinated
vagus<SPAN style="mso-spacerun: yes"> </SPAN>that can rapidly regulate
cardiac output to foster engagement and disengagement with the environment.</B>
<B>The<SPAN style="mso-spacerun: yes"> </SPAN>mammalian vagus is
neuroanatomically linked to the cranial nerves that regulate social engagement
via facial<SPAN style="mso-spacerun: yes"> </SPAN>expression and
vocalization.</B> As the autonomic nervous system changed through the process of
evolution, so did the<SPAN style="mso-spacerun: yes"> </SPAN>interplay
between the autonomic nervous system and the other physiological systems that
respond to stress, <B>including<SPAN style="mso-spacerun: yes"> </SPAN>the
cortex, the hypothalamic-pituitary-adrenal axis, the neuropeptides of oxytocin
and vasopressin, and the immune<SPAN style="mso-spacerun: yes">
</SPAN>system.</B> From this phylogenetic orientation, the polyvagal theory
proposes a biological basis for social behavior and<SPAN style="mso-spacerun: yes"> </SPAN>an intervention strategy to enhance
positive social behavior. Copyright 2001 Elsevier Science B.V. All rights
reserved.<SPAN style="mso-spacerun: yes"> </SPAN>Keywords: Vagus;
Respiratory sinus arrhythmia; Evolution; Autonomic nervous system; Cortisol;
Oxytocin; Vasopressin; Polyvagal theory; Social behavior<SPAN style="mso-spacerun: yes"> </SPAN>Read the entire paper: PDF file (470 Kb)
<SPAN style="mso-tab-count: 1"> </SPAN><SPAN style="mso-spacerun: yes"> </SPAN>Stanley Rosenberg Institut · Nygade
22 B II, 8600 Silkeborg · Tel: +45 86 82 04 00 · Fax: +45 86 82 03 44 · E-mail:
institut@stanleyrosenberg.com</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New">________</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New"> <o:p></o:p></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New"> </FONT><FONT face="Courier New">Retrieved April 11,
2005, from the World Wide Web </FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New">http://www.hosppract.com/issues/1999/07/gershon.htm</FONT></P>
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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><SPAN class=title1><B><FONT face="Courier New" size=2>The Enteric Nervous
System:</FONT></B></SPAN><B><BR><SPAN class=title1><FONT face="Courier New" size=2>A Second Brain</FONT></SPAN></B><BR><BR><FONT face="Courier New" size=2>MICHAEL D. GERSHON<BR>Columbia University
</FONT></P>
<P><FONT face="Times New Roman"><SPAN class=title2><B>Once dismissed as a
simple collection of relay ganglia, the enteric nervous system is now
recognized as a complex, integrative brain in its own right. Although we
still are unable to relate complex behaviors such as gut motility and
secretion to the activity of individual neurons, work in that area is
proceeding briskly--and will lead to rapid advances in the management of
functional bowel disease.</B></SPAN> </FONT></P>
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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><BR><FONT face="Courier New" size=2>Dr. Gershon is Professor and Chair, Department
of Anatomy and Cell Biology, Columbia University College of Physicians and
Surgeons, New York. In addition to numerous scientific publications, he is
the author of <I>The Second Brain</I> (Harper Collins, New York, 1998).
</FONT></P>
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<P><FONT face="Times New Roman">Structurally and neurochemically, the
enteric nervous system (ENS) is a brain unto itself. Within those yards of
tubing lies a complex web of microcircuitry driven by more
neurotransmitters and neuromodulators than can be found anywhere else in
the peripheral nervous system. These allow the ENS to perform many of its
tasks in the absence of central nervous system (CNS) control--a unique
endowment that has permitted enteric neurobiologists to investigate nerve
cell ontogeny and chemical mediation of reflex behavior in a laboratory
setting. Recognition of the importance of this work as a basis for
developing effective therapies for functional bowel disease, coupled with
the recent, unexpected discovery of major enteric defects following the
knockout of murine genes not previously known to affect the gut, has
produced a groundswell of interest that has attracted some of the best
investigators to the field. Add to this that the ENS provides the closest
thing we have to a window on the brain, and one begins to understand why
the bowel--the second brain--is finally receiving the attention it
deserves. </FONT></P>
<H3 style="MARGIN: auto 0in"><FONT face="Arial Unicode MS">Discovery of
the ENS</FONT></H3>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">The field of
neurogastroenterology dates back to the nineteenth-century English
investigators William M. Bayliss and Ernest H. Starling, who demonstrated
that application of pressure to the intestinal lumen of anesthetized dogs
resulted in oral contraction and anal relaxation, followed by a propulsive
wave (which they referred to as the "law of the intestine" and we now call
the peristaltic reflex) of sufficient strength to propel food through the
digestive tract. Because the reflex persisted even after all of the
extrinsic nerves to the gut had been severed, Bayliss and Starling
deduced--correctly--that the ENS was a self-contained hub of neuronal
activity that operated largely independent of CNS input. </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Eighteen years
later, the German scientist Paul Trendelenburg confirmed these findings by
demonstrating that the peristaltic reflex could be elicited in vitro in
the isolated gut of a guinea pig, without participation of the brain,
spinal cord, dorsal root, or cranial ganglia. Trendelenburg knew this
finding was unique; no other peripheral organ had such a highly developed
intrinsic neural apparatus. Cut the connection linking the bladder or the
skeletal muscles to the CNS, and all motor activity ceases. Cut the
connection to the gut, however, and function persists. </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Trendelenburg's results were published in 1917.
That they were accepted by at least some of his contemporaries is evident
from the description of the ENS contained in John N. Langley's classic
textbook, <I>The Autonomic Nervous System, </I>published in 1921. Like
Trendelenburg, Langley knew that intestinal function must involve not only
excitatory and inhibitory motor neurons to innervate the smooth muscle,
glands, and blood vessels but also primary afferent neurons to detect
increases in pressure, as well as interneurons to coordinate the wave of
activity down the length of the bowel. The brain could not perform these
complex functions alone, he reasoned, because the gut is innervated by
only a few thousand motor fibers. Logic dictated that the nerve cells in
the bowel--which Langley suspected, and we now know, number in the
millions--had to have their own separate innervation. Thus, when he
described the autonomic nervous system, it was as three distinct parts:
the sympathetic, the parasympathetic, and the enteric. </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Unfortunately,
Langley, who was owner and editor of the <I>Journal of Physiology,
</I>alienated many of his colleagues. After his death, editorship of the
<I>Journal </I>passed to the Physiological Society, whose members
<B>reclassified the enteric neurons as parasympathetic relay ganglia, part
of the vagal supply that directs gut motility.</B> To an extent, of
course, they were right. <B>The vagus nerve <I>is </I>normally responsible
for commanding the vast microcircuits of the ENS to carry out their
appointed tasks. What it cannot do, as Langley and his predecessors
intuitively grasped, is tell them <I>how</I> to carry them out. That is
strictly an inside job</B>, and one that the gut is marvelously capable of
performing. <B>In addition to propulsion, the ENS bears primary
responsibility for self-cleaning, regulating the luminal environment,
working with the immune system to defend the bowel, and modifying the rate
of proliferation and growth of mucosal cells. Neurons emanating from the
gut also innervate ganglia in neighboring organs, such as the gallbladder
and pancreas (Figure 1). </B></FONT></P></TD></TR></TBODY></TABLE></DIV>
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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New" size=2>After Langley's death, however, the concept of an independent ENS
fell by the wayside, as investigators turned their attention to new
developments in chemical neurotransmission.<B> Epinephrine and
acetylcholine had been identified as the sympathetic and parasympathetic
transmitters, respectively (although the true sympathetic transmitter was
later revealed to be norepinephrine), and neuroscientists were taken with
the idea of a neatly matched set of chemical modulators, one for each
pathway. The "two neurotransmitters, two pathways" theory remained
essentially unchallenged until 1965-1967, when I proposed in a series of
papers in <I>Science </I>and the <I>Journal of Physiology </I>that there
existed a third neurotransmitter, namely <SPAN style="BACKGROUND: yellow; mso-highlight: yellow">serotonin
(5-hydroxytryptamine, 5-HT), that was both produced in and targeted to the
ENS.</SPAN></B> </FONT></P>
<H3 style="MARGIN: auto 0in"><FONT face="Arial Unicode MS">A Third
Neurotransmitter</FONT></H3>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Since
serotonin was already known to possess neurotransmitterlike qualities, the
storm of protest that greeted this suggestion came as quite a shock to me.
At the time, of course, there was no scientific proof that enteric neurons
contain endogenous serotonin or can synthesize it from its amino acid
precursor, L-tryptophan. By the early 1980s, however, enough evidence had
accumulated--not only about serotonin but also about dozens of other
previously unknown neurotransmitters--that <B>most investigators agreed
that the old "two and two" hypothesis no longer seemed credible. It is now
generally recognized that at least 30 chemicals of different classes
transmit instructions in the brain, and that all of these classes are also
represented in the ENS.</B> </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Recent
attempts to determine which peptides and small-molecule neurotransmitters
are stored (often collectively) in various enteric neurons have begun to
shed light on this remarkable confluence and have provided a more detailed
picture of the functional anatomy of the bowel. By assigning a chemical
code to each combination of neurotransmitters and then matching the code
with the placement of lesions in animal models, investigators have been
able to determine the location of specific, chemically defined subsets of
enteric neurons. This work provides ample evidence that the ENS is no
simple collection of relay ganglia but rather a complex integrative brain
in its own right. However, a number of serious questions must be addressed
before we can state with assurance that we understand how the neurons of
the gut mediate behavior. Species differences have been found in the
chemical coding of enteric nerve cells, so observations made in guinea
pigs cannot be directly applied to rodents and certainly not to humans.
This is somewhat baffling, because if there are patterns of enteric
behavior that are common to all mammalian species, then the neurons
responsible for those behavior patterns ought to be fairly uniform.
</FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Another issue
concerns the degree to which the various neurotransmitters identified in
the bowel are physiologically relevant. The criteria are stringent: in
addition to being present in the appropriate cells and synapses, the
substance being tested should 1) have demonstrable biosynthesis, 2) be
released on nerve stimulation, 3) mimic the activities of the endogenously
secreted transmitter, 4) have an adequate means of endogenous
inactivation, and 5) be antagonized by the same drugs in the laboratory
and in vivo. Acetylcholine, norepinephrine, nitric oxide, serotonin, and
vasoactive intestinal peptide meet the criteria, but less is known about
other candidate molecules. </FONT></P>
<H3 style="MARGIN: auto 0in"><FONT face="Arial Unicode MS">Anatomy of the
ENS</FONT></H3>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">The ENS is
remarkably brainlike, both structurally and functionally. Its neuronal
elements are not supported by collagen and Schwann cells, like those in
the rest of the peripheral nervous system, but by glia that resemble the
astrocytes of the CNS (Figure 2). These qlia do not wrap individual axons
in single membranous invaginations; rather, entire bundles of axons are
fitted into the invaginations of enteric glia. The axons thus abut one
another in much the same manner as those of the olfactory nerve. The ENS
is also vulnerable to what are generally thought of as brain lesions: Both
the Lewy bodies associated with Parkinson's disease and the amyloid
plaques and neurofibrillary tangles identified with Alzheimer's disease
have been found in the bowels of patients with these conditions. It is
conceivable that Alzheimer's disease, so difficult to diagnose in the
absence of autopsy data, may some day be routinely identified by rectal
biopsy. </FONT></P></TD></TR></TBODY></TABLE></DIV>
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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New" size=2>In addition to the neurons and glia of the ENS, the gut contains
interstitial cells of Cajal (ICC), which do not display neural and glial
markers such as neurofilaments or glial fibrillary acidic proteins and are
therefore believed to be a distinct cell type. Because ICC tend to be
located between nerve terminals and smooth muscle cells, Ramón y Cajal
believed that they were intermediaries that transmitted signals from nerve
fibers to smooth muscle. For a while, this concept was abandoned, because
it was thought that no intermediaries were required. Now, however, Cajal's
concept is being reconsidered. </FONT></P>
<P><FONT face="Times New Roman">ICC are also thought to act as pacemakers,
establishing the rhythm of bowel contractions through their influence on
electrical slow-wave activity. This assumption is supported by 1) the
location of ICC in regions of smooth muscle where electrical slow waves
are generated, 2) the spontaneous pacemakerlike activity displayed by ICC
when they are isolated from the colon, and 3) the disappearance or
disruption of electrical slow-wave activity when ICC are removed or
uncoupled from gut smooth muscle. </FONT></P>
<P><FONT face="Times New Roman">The entire structure of the ENS is
arranged into two ganglionated plexuses (Figure 3). The larger, myenteric
(Auerbach's) plexus, situated between the muscle layers of the muscularis
externa, contains the neurons responsible for motility and for mediating
the enzyme output of adjacent organs. The smaller, submucosal (Meissner's)
plexus contains sensory cells that "talk" to the neurons of the myenteric
plexus, as well as motor fibers that stimulate secretion from epithelial
crypt cells into the gut lumen. The submucosal plexus contains fewer
neurons and thinner interganglionic connectives than does the myenteric
plexus, and has fewer neurons per ganglion. Electrical coupling between
smooth muscle cells enables signals to rapidly alter the membrane
potential of even those cells that have no direct contact with neurons and
ensures that large regions of bowel--rather than small groups of muscle
cells--will respond to nerve stimulation.
</FONT></P></TD></TR></TBODY></TABLE></DIV>
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<H3 style="MARGIN: auto 0in"><FONT face="Arial Unicode MS">The Serotonin
Model</FONT></H3>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Some sensory
neurons are directly activated by the stimuli to which they respond,
making them both sensory receptors and primary afferent neurons. Other
sensory neurons, such as the auditory and vestibular ganglia, do not
respond to sensory stimuli but are driven by other, nonneuronal cells that
act as sensory receptors. It has not yet been conclusively shown to which
of these categories the primary afferent neurons of the submucosal plexus
belong. They could be mechanoreceptors that become excited when their
processes in the intestinal mucosa are deformed. Or they could be
stimulated secondarily to the activation of a mechanosensitive mucosal
cell. Such cells do exist in the gut--they are the enterochromaffin cells
of the gastrointestinal epithelium, and they contain over 95% of the
serotonin found in the body. (A small amount of serotonin is also secreted
by ENS interneurons.) </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">The serotonin
in enterochromaffin cells is stored in subcellular granules that
spontaneously release the amine into the adjacent lamina propria, which is
endowed with at least 15 distinct serotonin receptor subtypes (Figure 4).
Additional serotonin is released when the cells are stimulated either by
increased intraluminal pressure, vagal stimulation, anaphylaxis,
acidification of the duodenal lumen, or exposure to norepinephrine,
acetylcholine, cholera toxin, or a variety of other chemical substances.
In a patient receiving radiation therapy for cancer, for example, excess
serotonin leaking out of enterochromaffin cells activates receptor subtype
5-HT<SUB>3</SUB>, located on the extrinsic nerves, rapidly leading to
nausea and vomiting. The symptoms can be blocked by giving an antagonist
like ondansetron that is specific for 5-HT<SUB>3</SUB> receptors. The
antagonist does not interfere with other serotonin-mediated functions,
such as peristalsis or self-cleaning activities, because they involve
other 5-HT receptor subtypes. </FONT></P></TD></TR></TBODY></TABLE></DIV>
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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT face="Courier New">We now have extensive data (from studies of the
serotonin antagonist 5-HTP-DP and anti-idiotypic antibodies that recognize
5-HT receptors) confirming that 1) serotonin stimulates the peristaltic
reflex when it is applied to the mucosal surface of the bowel, 2)
serotonin is released whenever the peristaltic reflex is initiated, and 3)
the reflex is diminished when the mucosal source of serotonin is removed.
Consequently, there is wide support for the hypothesis, first proposed by
Edith Bülbring in 1958, that enterochromaffin cells act as pressure
transducers and that the serotonin they secrete acts as a mediator to
excite the mucosal afferent nerves, initiating the peristaltic reflex
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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Courier New" size=2>The serotonergic neurons of the ENS probably inactivate the amine
by a rapid reuptake process similar to that described for the CNS. A
specific 5-HT plasma membrane transporter protein has recently been
cloned; it is expressed in epithelial cells scattered throughout the gut
as well as in the brain. Serotonin blockade can also be achieved by other
means, such as removal of acetylcholine or calcitonin gene-related
peptide. </FONT></P>
<P><FONT face="Times New Roman">Uptake of serotonin can be blocked in both
the ENS and CNS by antidepressant drugs such as chlorimipramine,
fluoxetine, and zimelidine that have an affinity for the transporter. In
the absence of rapid uptake, serotonin continues to flow outward in the
direction of neighboring nerve cells, which become excited in turn.
Eventually, however, desensitization takes place, and the process grinds
to a halt. In the guinea pig model, insertion of an artificial fecal
pellet into the distal colon was followed by rapid proximal-to-distal
propulsion. The same effect was achieved even when the experiment was
repeated for eight hours. Addition of a low dose of fluoxetine accelerated
propulsion, while at higher doses the 5-HT receptors became desensitized
and intestinal motility slowed and eventually stopped. </FONT></P>
<P><FONT face="Times New Roman"><B>Clinical Implications.</B> Obviously,
these data have important implications for physicians who regularly
prescribe mood-altering drugs. Because the neurotransmitters and
neuromodulators present in the brain are nearly always present in the
bowel as well, drugs designed to act at central synapses are likely to
have enteric effects. Early in the course of antidepressant therapy, about
25% of patients report some nausea or diarrhea. With higher dosages or
longer duration of therapy, serotonin receptors become desensitized, and
constipation may occur. (Presumably, the 75% of patients who do not
complain of gastrointestinal disturbance either are not taking enough of
the antidepressant or have compensatory mechanisms that reduce the impact
of prolonged serotonin availability.) If these effects--which are not side
effects per se but predictable consequences of transporter protein
blockade--are not anticipated and carefully explained to the patient, they
are likely to reduce adherence and limit the value of treatment.
</FONT></P>
<P><FONT face="Times New Roman">On the other hand, the same drugs that
tend to cause difficulty for patients who take them for emotional illness
may be a godsend to those with functional bowel disease. Moreover, because
the ENS reacts promptly to changes in serotonin availability, patients
with chronic bowel problems often find their symptoms relieved at
pharmacologic concentrations far below those used in conventional
antidepressant therapy. </FONT></P>
<H3 style="MARGIN: auto 0in"><FONT face="Arial Unicode MS">More About the
Brain-Gut Connection</FONT></H3>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Provided that
the vagus nerve is intact, a steady stream of messages flows back and
forth between the brain and the gut. We all experience situations in which
our brains cause our bowels to go into overdrive. But in fact, messages
departing the gut outnumber the opposing traffic on the order of about
nine to one. Satiety, nausea, the urge to vomit, abdominal pain--all are
the gut's way of warning the brain of danger from ingested food or
infectious pathogens. And while the brain normally responds with
appropriate signals, the ENS can take over when necessary, as for example
when vagal input has been surgically severed. </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Naturally, the
balance of power between the two nervous systems is a topic of
considerable scientific interest. It has been proposed that vagal motor
axons innervate specialized command neurons in the myenteric plexus, which
are responsible for regulating the intrinsic microcircuits of the ENS. In
favor of this concept is the observation that vagal motor fibers appear to
synapse preferentially on certain types of enteric neuron (Figure 6). For
example, vagal efferent axons preferentially innervate neurons in the
myenteric plexus of the stomach that express serotonin or vasoactive
intestinal peptide. Other recent studies have suggested that vagal input
may be more widely dispersed than the command-neuron hypothesis would
imply, especially in the stomach. The interplay between the two systems is
thus still a bit unclear. </FONT></P></TD></TR></TBODY></TABLE></DIV>
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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2><FONT face="Courier New"><B>Correlation or Causation?</B> Whatever the exact
connection, the relationship between the cerebral and enteric brains is so
close that it is easy to become confused about which is doing the talking.
Until peptic ulcer was found to be an infectious disease, for example,
physicians regarded anxiety as the chief cause. Now that we recognize
<I>Helicobacter pylori </I>as the cause, it seems clear that the physical
sensation of burning epigastric pain is generally responsible for the
emotional symptoms, rather than the other way around. But because most
ulcer patients, if questioned, will admit to feeling anxious, the
misunderstanding persisted for decades. Another illustration is ulcerative
colitis, which was considered the prototypic psychosomatic disease when I
was in medical school. There were even lectures on the "ulcerative colitis
personality." The ulcerative colitis personality, if indeed there is one,
is a consequence of living with a disabling autoimmune disease that
prevents patients from feeling relaxed and comfortable in social
situations. It is altogether possible that with passage of time, many of
the ailments currently labeled as functional bowel diseases will prove to
have similarly identifiable physiologic causes. </FONT></FONT></P>
<H3 style="MARGIN: auto 0in"><FONT face="Arial Unicode MS">Embryonic
Development: New Insights</FONT></H3>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">In order to
better appreciate ENS functioning, it is helpful to know something about
its embryonic development. Which sites in the embryo give rise to the
precursors of enteric neurons and glia? What impels these precursors to
migrate to the bowel? And what features of the enteric microenvironment
ultimately cause these incipient nerve cells to arrest their journey and
undergo phenotypic differentiation? </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">The neural and
glial precursor cells of the ENS are the descendants of émigrés from the
vagal, rostral-truncal, and sacral levels of the neural crest. Of these
three, the vagal crest is the most influential, because its cells colonize
the entire gut. The rostral-truncal crest colonizes only the esophagus and
adjacent stomach, whereas the sacral crest colonizes the postumbilical
bowel. </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">It might be
assumed that premigratory cells in each of these regions are already
programmed to locate their appropriate portion of the gut and
differentiate as enteric neurons or glia. However, that idea has been
shown to be incorrect. The premigratory crest population is
multipotent--so much so that whole regions of the crest can be
interchanged in avian embryos without interfering with ENS formation.
Furthermore, even the group of crest-derived cells that are destined to
colonize the bowel contains pluripotent precursors with a number of
"career" options. Terminal differentiation does not take place until the
émigrés have reached the gut wall and interacted with the enteric
microenvironment via a number of specific chemical growth factor-receptor
combinations. If these molecules are unavailable, the migration of the
crest-derived cells will be cut short, and aganglionosis of the remaining
bowel will result. </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Nerve cell
lineages are defined by their common dependence on particular growth
factors or genes. For example, there is a very large lineage defined by
dependence on stimulation of the Ret receptor by glial cell-derived
neurotrophin factor (GDNF) and its binding molecule, GFR-alpha1. This
so-called first precursor gives rise to essentially all of the neurons of
the bowel, with the exception of those of the rostral foregut. Partial
loss of GDNF-Ret may result in a precursor pool that is too small to
colonize the entire gut, while complete loss of either GDNF or Ret
eliminates the possibility of nerve cells below the level of the
esophagus. </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">A second
lineage depends on <I>Mash-1</I>, a member of the basic helix-loop-helix
family of transcriptional regulators. These neurons, which include those
of the rostral foregut as well as a subset of cells in the remainder of
the bowel, are transiently catechola-minergic, develop early (enteric
neurons develop in successive waves), and generate the entire set of
enteric serotonergic neurons. A third lineage is independent of
<I>Mash-1,</I> develops later, and gives rise to peptidergic neurons such
as those that contain calcitonin gene-related peptide. </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Sublineages of
enteric neurons include those dependent on neurotrophin 3 (NT-3) and
endothelin 3 (ET-3). The peptide-receptor combination ET-3-ET<SUB>B</SUB>
is particularly interesting because it appears to act as a brake that
prevents migrating cells from differentiating prematurely--before
colonization of the gastrointestinal tract has been completed. Absence of
ET-3 results in loss of nerve cells in the terminal portion of the bowel.
In humans, this condition, known as Hirsch-sprung's disease (congenital
megacolon), occurs in roughly one in 5,000 live births. Without
innervation, intestinal traffic is blocked, and the colon becomes
enormously dilated above the blockage. Surgery is extremely difficult
because the aganglionic portion of the infant's intestine must be removed
without damaging functioning ganglionic tissue. One experimental model for
this disease, the lethal spotted mouse, lacks ET-3, while another
laboratory strain, the piebald mouse, lacks the endothelin receptor
ET<SUB>B</SUB>. In either case, the result is a mouse with the equivalent
of Hirschsprung's disease. (The link between ET-3 deficiency and
aganglionosis was discovered quite by accident, when Masashi Yanagisawa
knocked out genes coding for ET-3 and ET<SUB>B</SUB> to study their effect
on blood pressure regulation. The animals had such severe bowel
abnormalities that they did not live long enough to manifest
cardiovascular problems.) </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Our laboratory
is currently attempting to define exactly where the endothelins are
expressed, as well as to clarify the role of another putative factor in
the pathogenesis of Hirschsprung's disease, laminin-1. This is an
extracellular matrix protein excreted by smooth muscle precursors that
both encourages adhesion of migrating cells and promotes their
differentiation into neurons (Figure 7). We are trying to produce a
transgenic mouse that overexpresses laminin in the gut, and anticipate
that Hirschsprung's disease equivalent will result.
</FONT></P></TD></TR></TBODY></TABLE></DIV>
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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT size=2>We also are
studying an interesting group of molecules called netrins, which are
expressed in both gut epithelium and the CNS. Netrins are attraction
molecules that appear to guide migrating axons in the developing CNS and
neuronal precursors in the bowel and may be especially important in
forming the submucosal plexus. The attraction they create is so powerful
that if netrin-expressing cells are placed next to the gut, neuronal
precursors will migrate out of the bowel in search of the
netrin-expressing cells. Two potential receptors for the netrins have been
identified, neogenin and DCC (deleted in colorectal cancer). Antibodies to
DCC will counter the attraction of netrins and cause nerve cell precursors
to suspend their migration. Other teams are studying avoidance molecules
called sema-phorins that are the opposite of the attraction molecules
(i.e., they repel the enteric precursors). </FONT></P>
<P><FONT face="Times New Roman">Mention should also be made of the
important role that technology has played in accelerating scientific
progress in this area. In particular, the ability to isolate crest-derived
cell populations by magnetic immunoselection and then to culture them in
defined media has made it possible to test the direct effects of putative
growth factors on the precursors of neurons and glia, as well as to
analyze cell receptors, transcription factors, and other developmentally
relevant molecules (Figure 8). The alternative--carrying out experiments
with mixed populations of enteric precursor cells or cells cultured in
serum-containing media--would have produced unreliable results because of
the uncontrolled interaction of crest-derived and non-crest-derived cells
in media of unknown content. </FONT></P>
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<H3 style="MARGIN: auto 0in"><FONT face="Arial Unicode MS">Future
Directions</FONT></H3>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Clearly, much
has been accomplished since the days when the ENS was dismissed as an
inconsequential collection of relay ganglia. Although we still are unable
to relate such complex behaviors as gut motility and secretion to the
activity of individual neurons, work in that area is proceeding briskly.
Similarly, we are moving toward an overarching picture of how the CNS
interacts with the microcircuits of the bowel to produce coordinated
responses. Finally, it seems inevitable that advancement of basic
knowledge about the ENS will be followed by related clinical applications,
so that the next generation of medical practitioners and patients will
find fewer ailments listed under the catch-all heading of functional bowel
disease. </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><B>Selected
Reading</B> </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Costa M et al:
Neurochemical classification of myenteric neurons in the guinea-pig ileum.
Neuroscience 75:949, 1996 </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Furness JB et
al: Intrinsic primary afferent neurons of the intestine. Prog Neurobiol
54:1, 1998 </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Gershon MD:
Genes, lineages, and tissue interactions in the development of the enteric
nervous system. Am J Physiol 275:G869, 1998 </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Gershon MD:
The Second Brain. Harper Collins, New York, 1998 </FONT></P>
<P style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Gershon MD,
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<DIV><FONT lang=0 face=Arial size=2 FAMILY="SANSSERIF" PTSIZE="10">----------<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; Core 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></FONT></BODY></HTML>