[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 
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 
Retrieved April 11,  2005, from the World Wide Web  
 (http://www.hosppract.com/index.htm)  (http://www.hosppract.com/toc.htm)  
(http://www.hosppract.com/past.htm)  (http://www.hosppract.com/past.htm)  
(http://www.hosppract.com/genetics.htm)  (http://www.hosppract.com/cc.htm)  
(http://www.hosppract.com/cme.htm)  (http://www.hosppract.com/adver.htm)  

The Enteric Nervous  System:
A Second Brain

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 
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  
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 
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 
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 


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  

_HOME_ (http://www.hosppract.com/index.htm)  | _CURRENT  ISSUE_ 
(http://www.hosppract.com/toc.htm)  | _PAST  ARTICLES_ (http://www.hosppract.com/past.htm)  
| _SEARCH_ (http://www.hosppract.com/past.htm)  | _GENETICS  SERIES_ 
_CAPSULE & COMMENT_ (http://www.hosppract.com/cc.htm)  | _CME_ 
(http://www.hosppract.com/cme.htm)  | _ADVERTISER SERVICES_ 
(http://www.hosppract.com/adver.htm)  | _ABOUT  US_ (http://www.hosppract.com/about.htm)   


Copyright (C) 2001. The McGraw-Hill Companies. All Rights  Reserved
_Privacy  Policy._ (http://www.mcgraw-hill.com/privacy.html)    _Privacy  
Notice._ (http://www.physsportsmed.com/eprivacy.htm)  

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
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: 
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
-------------- next part --------------
An HTML attachment was scrubbed...
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment.html>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 2712 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 644 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0001.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 658 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0002.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 646 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0003.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 522 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0004.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 735 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0005.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 846 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0006.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 438 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0007.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 821 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0008.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 826 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0009.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/jpeg
Size: 34017 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment.jpe>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/jpeg
Size: 62178 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0001.jpe>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/jpeg
Size: 64757 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0002.jpe>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/jpeg
Size: 63536 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0003.jpe>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/jpeg
Size: 48264 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0004.jpe>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/jpeg
Size: 21852 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0005.jpe>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/jpeg
Size: 27242 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0006.jpe>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 41361 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0010.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/gif
Size: 1141 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0011.gif>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: not available
Type: image/jpeg
Size: 795 bytes
Desc: not available
URL: <http://lists.extropy.org/pipermail/paleopsych/attachments/20050526/89f8c74e/attachment-0007.jpe>

More information about the paleopsych mailing list