[Paleopsych] the gut, the heart, and the self--a quick note on the wandering vagus nerve
HowlBloom at aol.com
HowlBloom at aol.com
Thu May 26 05:10:28 UTC 2005
The vagal nerve's role in enteric processes, cardiac operation, speech, and
hearing have grabbed my attention. A single nerve connecting the gut, the
heart, and the speaker and listener we call the self? It's potentially an
amazing social integrator. I've been searching for the social centers of the
brain for years and these seem to be a part of that complex. Howard
---
vagus nerve
n.
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. The American Heritage® Dictionary of the English
Language, Fourth Edition Copyright © 2004, 2000 by _Houghton Mifflin Company_
(http://www.eref-trade.hmco.com/) . Published by Houghton Mifflin Company.
All rights reserved.
----------
Retrieved May 26, 2005, from the World Wide Web
http://www.stressrelease.info/polyvagal_eng.html The polyvagal theory:
phylogenetic substrates of a social nervous system Stephen W. Porges, Ph.D.
Abstract The evolution of the autonomic nervous system provides an
organizing principle to interpret the adaptive significance of physiological
responses in promoting social behavior. According to the polyvagal theory, the
well-documented phylogenetic shift in neural regulation of the autonomic nervous
system passes through three global stages, each with an associated
behavioral strategy. The first stage is characterized by a primitive unmyelinated
visceral vagus that fosters digestion and responds to threat by depressing
metabolic activity. Behaviorally, the first stage is associated with
immobilization behaviors. The second stage is characterized by the sympathetic nervous
system that is capable of increasing metabolic output and inhibiting the
visceral vagus to foster mobilization behaviors necessary for ‘fight or flight’
. The third stage, unique to mammals, is characterized by a myelinated vagus
that can rapidly regulate cardiac output to foster engagement and
disengagement with the environment. The mammalian vagus is neuroanatomically linked
to the cranial nerves that regulate social engagement via facial expression
and vocalization. As the autonomic nervous system changed through the process
of evolution, so did the interplay between the autonomic nervous system and
the other physiological systems that respond to stress, including the
cortex, the hypothalamic-pituitary-adrenal axis, the neuropeptides of oxytocin
and vasopressin, and the immune system. From this phylogenetic orientation, the
polyvagal theory proposes a biological basis for social behavior and an
intervention strategy to enhance positive social behavior. Copyright 2001
Elsevier Science B.V. All rights reserved. Keywords: Vagus; Respiratory sinus
arrhythmia; Evolution; Autonomic nervous system; Cortisol; Oxytocin;
Vasopressin; Polyvagal theory; Social behavior Read the entire paper: PDF file (470 Kb)
Stanley Rosenberg Institut · Nygade 22 B II, 8600 Silkeborg · Tel: +45 86 82
04 00 · Fax: +45 86 82 03 44 · E-mail: institut at stanleyrosenberg.com
________
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The Enteric Nervous System:
A Second Brain
MICHAEL D. GERSHON
Columbia University
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.
____________________________________
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 The Second Brain
(Harper Collins, New York, 1998).
____________________________________
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 b
rain, and one begins to understand why the bowel--the second brain--is finally
receiving the attention it deserves.
Discovery of the ENS
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.
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.
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, The Autonomic Nervous
System, 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.
Unfortunately, Langley, who was owner and editor of the Journal of
Physiology, alienated many of his colleagues. After his death, editorship of the
Journal passed to the Physiological Society, whose members reclassified the
enteric neurons as parasympathetic relay ganglia, part of the vagal supply that
directs gut motility. To an extent, of course, they were right. The vagus nerve
is 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 how to carry them out. That is
strictly an inside job, and one that the gut is marvelously capable of
performing. 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).
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. 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 Science and the Journal of Physiology that there existed
a third neurotransmitter, namely serotonin (5-hydroxytryptamine, 5-HT), that
was both produced in and targeted to the ENS.
A Third Neurotransmitter
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 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.
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.
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.
Anatomy of the ENS
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.
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.
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.
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.
The Serotonin Model
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.)
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-HT3, 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-HT3 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.
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
(Figure 5).
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.
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.
Clinical Implications. 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.
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.
More About the Brain-Gut Connection
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.
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.
Correlation or Causation? 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 Helicobacter pylori 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.
Embryonic Development: New Insights
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?
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.
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.
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.
A second lineage depends on Mash-1, 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 Mash-1, develops later, and gives
rise to peptidergic neurons such as those that contain calcitonin gene-related
peptide.
Sublineages of enteric neurons include those dependent on neurotrophin 3
(NT-3) and endothelin 3 (ET-3). The peptide-receptor combination ET-3-ETB 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 ETB. 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 ETB
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.)
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.
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).
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.
Future Directions
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.
Selected Reading
Costa M et al: Neurochemical classification of myenteric neurons in the
guinea-pig ileum. Neuroscience 75:949, 1996
Furness JB et al: Intrinsic primary afferent neurons of the intestine. Prog
Neurobiol 54:1, 1998
Gershon MD: Genes, lineages, and tissue interactions in the development of
the enteric nervous system. Am J Physiol 275:G869, 1998
Gershon MD: The Second Brain. Harper Collins, New York, 1998
Gershon MD, Chalazonitis A, Rothman TP: From neural crest to bowel:
Development of the enteric nervous system. J Neurobiol 24:199, 1993
Gershon MD, Erde SM: The nervous system of the gut. Gastroenterology
80:1571, 1981
Gershon MD, Kirchgessner AL, Wade PR: Functional anatomy of the enteric
nervous system. In Physiology of the Gastrointestinal Tract, 3rd ed, vol 1,
Johnson LR et al (Eds). Raven Press, New York, 1994, pp 381-422
Kirchgessner AL, Gershon MD: Identification of vagal efferent fibers and
putative target neurons in the enteric nervous system of the rat. J Comp Neurol
285:38, 1989
Kirchgessner AL, Gershon MD: Innervation of the pancreas by neurons in the
gut. J Neurosci 10:1626, 1990
Pomeranz HD et al: Expression of a neurally related laminin binding protein
by neural crest-derived cells that colonize the gut: Relationship to the
formation of enteric ganglia. J Comp Neurol 313:625, 1991
Rosenthal A: The GDNF protein family: Gene ablation studies reveal what they
really do and how. Neuron 22:201, 1999
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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; Core
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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