J Comp Physiol A (2007) 193:1013–1019
DOI 10.1007/s00359-007-0256-4
R EV IE W
Evolutionary origin of autonomic regulation of physiological
activities in vertebrate phyla
Hiroshi Shimizu · Masataka Okabe
Received: 5 February 2007 / Revised: 17 July 2007 / Accepted: 17 July 2007 / Published online: 15 September 2007
© Springer-Verlag 2007
Abstract Proper regulation of physiological activities is
crucial for homeostasis in animals. Autonomic regulation
of these activities is most developed in mammals, in which
a part of peripheral nervous system, termed the autonomic
nervous system plays the dominant role. Circulatory activity
and digestive activity in vertebrates change in opposite
phases to each other. The stage where circulatory activity is
high and digestive activity is low is termed the “Wght or
Xight stage” while the stage where circulatory activity is
low and digestive activity is high is termed the “rest and
digest stage”. It has been thought that the autonomic
nervous system originated in early vertebrate phyla and
developed to its greatest extent in mammals. In this study,
we compared the pattern of change of circulatory and
digestive activities in several invertebrates and found that
the two stages seen in mammals are also present in a wide
variety of animals, including evolutionarily early-diverging
invertebrate taxa. From this and other arguments we
propose a novel possibility that the basic properties of the
autonomic nervous system were established very early in
metazoan evolution.
Keywords Autonomic nervous system · Heart rate ·
Fight or Xight response · Sympathetic nervous system ·
Parasympathetic nervous system
H. Shimizu
Department of Developmental Genetics,
National Institute of Genetics, Mishima, Japan
M. Okabe (&)
Department of Anatomy,
The Jikei University School of Medicine,
3-25-8, Nishi-Shinbashi, Minato-ku,
Tokyo 105-8461, Japan
e-mail: [email protected]
Abbreviations
ANS
Autonomic nervous system
SNS
Sympathetic nervous system
PSNS
Parasympathetic nervous system
CNS
Central nervous system
ENS
Enteric nervous system
NE
Norepinephrine
ACh
Acetylcholine
5-HT
5-Hydroxytryptamine
GABA 4-Aminobutanoic acid
HU
Hydroxyurea
Introduction
Regulation of physiological activities in animals is critical
for the maintenance of homeostasis (Cannon 1932). Such
activities include pumping of the heart and peristalsis in the
digestive tract. Physiological regulation is concentrated in a
part of peripheral nervous system termed the autonomic
nervous system (ANS) that resides in the spinal cord and
extends to the various organs (Robertson et al. 1996). The
ANS is made up of two subsystems, the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS). These two systems have opposite eVects on
the activity of organs. Typically, excitation of the SNS elevates the heart rate by means of epinephrine and norepinephrine (NE). Excitation of the PSNS lowers the heart rate
by means of acetylcholine (ACh). Similarly, excitation of
the SNS decreases digestive movements such as peristalsis
while excitation of the PSNS increases such movements.
Therefore, activities of organs are adjusted to proper levels
by push–pull dynamics through the two subsets of the nervous system. As a result of this arrangement, circulatory
activity and digestive activity change in opposite phases to
123
1014
each other. The SNS dominant situation, with high heart
rate and low digestive movements, is termed the “Wght or
Xight” stage. This stage depicts the behavior of animals that
Wght against enemy or Xee from enemy or from danger. The
PSNS dominant situation, with a high level of digestive
movements and a low heart rate is termed the “rest and
digest” stage (Cannon 1929, 1932).
The ANS is found in Wshes (lower vertebrates) with an
architecture (Nieuwenhuys et al. 1998) similar to that seen
in mammals, suggesting that the ANS originated with vertebrates (Sarnat and Netsky 2002). Then an emerging problem is how the physiological activities are regulated in
invertebrates. Obviously, there is no midline (vertebra) in
invertebrates implying that there is no structural counterpart to the ANS. Then could there be a “functional counterpart” in invertebrates? Or is there a totally diVerent type of
mechanism involved?
In the present study, we use experimental approaches
and archival sources to determine the patterns of change of
circulatory and digestive activities of various invertebrates.
From our results we conclude that the functional basis of
the ANS was already in place in the ancestor of cnidarians
and bilaterians.
Pattern of change of digestive and circulatory activities
in invertebrate phyla
We investigated the pattern of change of circulatory and
digestive activities that occur upon feeding using experimental approaches for hydra and from archival sources for
nematodes and mollusks. From evolutionary point of view,
experimental data from invertebrate taxa that are phylogenetically close to vertebrates, e.g. Amphioxus, was of particular interest but was not available.
Mollusks (Protostomia)
The phylum Mollusca includes some of the most complex
protostomes (Sugden et al. 2003; Pennisi 2003). They have
been used extensively for physiological analyses because of
large body size, large nerve cells, and resultant ease of
manipulation (Dieringer et al. 1978; Koch et al. 1984;
Koester and Koch 1984). We Wnd in herbivores mollusk
Aplysia that circulatory and digestive activities change in a
manner similar to “Wght or Xight” and “rest and digest”
stages in mammals. Aplysia rover on the sea Xoor searching
for seaweeds which Aplysia feed on. The heart rate of Aplysia is conspicuously elevated when they capture and ingest
seaweeds because of the following reason. Although mollusks have no skeletal system, rigidity is absolutely needed
in the foraging process for mechanically grinding the tough
seaweeds. In order to compensate for the lack of rigidity,
Aplysia uses a unique strategy. Mollusks have open circula-
123
J Comp Physiol A (2007) 193:1013–1019
tory systems and blood circulates not only through vessels
but also through the coelomic space (painted red in Fig. 1a,
b), which is surrounded by a muscular system in the mouth
termed the buccal mass. When the prey is captured, the elevated heart rate provokes the inXation and the hardening of
the buccal mass (Fig. 1b) by the hydraulic pressure of the
blood (Ellis 1944; Parry and Brown 1959) creating what is
known as a “hydrostatic skeleton”. This inXation and hardening further provides mechanical support for grazing prey
with the teeth on the buccal mass termed the radula1
(Drushel et al. 1997). Thus heart pumping in mollusks
plays a role not only as a means of supplying oxygen and
nutrients to the tissue but also as a means of supplying
rigidity to the tissue. After the food enters the pharynx, the
heart rate is lowered and the hydraulic pressure is reduced.
An increase in digestive movements then occurs. Since
digestive movement is autonomous, requiring no involvement of hydraulic force, the heart rate remains at a low
level during this phase. Overall, the stage before the ingestion of prey is characterized by high heart rate and low
digestive movements as in the “Wght or Xight” stage of
mammals and the stage after the ingestion is characterized
by low heart rate and high digestive movements as in the
“rest and digest” stage.
Regulation of circulatory and digestive activities in
Aplysia is in part similar to that in mammals. 5-Hydroxytryptamine (5-HT) elevates heart rate whereas it lowers the
digestive movements, just as NE does in mammals. This
suggests that 5-HT plays a similar role to NE in mammals
(Kier and Smith 1985). ACh has similar eVects in both
Aplysia and mammals, reducing the heart rate while
increasing digestive movements (Kier 1988). Therefore, 5HT and ACh in Aplysia are able to regulate the circulatory
and digestive activities in a push–pull manner as NE and
ACh do in mammals (Goldstein et al. 1984; Kupfermann
1991; Ram et al. 1981). ACh and 5-HT containing neurons
are distributed in the central nervous system (CNS), however, not in a highly concentrated form as in ANS (e.g. Ono
and McCaman 1984).
Switching between the “Wght or Xight stage” and the
“rest and digest stage” also seems to occur in invertebrates
that have no heart pumping system, as described in the following section for nematodes.
Nematodes (Protostomia)
Nematodes do not have a heart, blood, or vascular system.
Therefore, it might seem irrelevant to discuss regulation of
circulatory activity in nematodes. Nevertheless, it is possible
1
Various types of feeding habit are employed in Mollusks including
herbivores (Aplysia), carnivores (Octopus) and scavengers (Babylonia). One thing common to all types is that they use radula for feeding.
J Comp Physiol A (2007) 193:1013–1019
1015
Fig. 1 Schematic representation of the buccal mass of mollusks before (a) and after (b) extension. The space in red color denotes the coelomic space. Rugged structure on the buccal mass denotes radula by
which mollusks graze food. Note that this Wgure is aimed to describe
the systematic feature of the animals, hence may not represent the precise morphology and structure of the animals and their organs
to estimate circulatory activity in nematodes. The space that
resides between the digestive tract and the outer epithelium
of nematodes is known as pseudocoel (Fig. 2). The pseudocoel is Wlled with pseudocoelomic Xuid. Since this Xuid
abounds in nutrients released from the basal surface of the
intestine (Ruppert and Barnes 1996; Riddle et al. 1997), it
is reasonable to assume that the pseudocoelomic Xuid distributes nutrients throughout the body. Thus, we are able to
estimate the “circulatory activity” of nematodes by estimating circulatory activity of the pseudocoelomic Xuid. Circulatory activity and digestive activity in nematodes change
in opposite phases to each other as they do in mammals and
mollusks.
When nematodes forage for food (e.g. bacteria), they are
highly motile and this motility stirs and agitates the pseudocoelomic Xuid (T. Ishihara, personal communication;
Ruppert and Barnes 1996). It is therefore reasonable to
assume that the high motility of the animal is closely
related to high circulatory activity in the pseudocoel. On
capturing and ingesting prey, nematodes decrease their
movement, which is known as “slowing down” (Sawin
et al. 2000). This implies that circulation in the pseudocoel
is also reduced. Instead, digestive movement is activated
owing to the pumping movement of pharynx, with its radially oriented muscle Wbers (Albertson and Thomson 1976).
Contraction of the pharyngeal muscle which transfers the
bolus of food forward in the digestive tract is autonomous,
requiring no innervation from the neurons (Avery and Horvitz 1989). However, neurons are involved in regulating the
pumping frequency (Avery 1993). Overall, the stage before
the ingestion of food is characterized by high animal motility,
high circulatory activity, and low digestive movement as
in the “Wght or Xight” stage despite the fact that nematodes
do not “Wght” with other animals. Meanwhile the stage after
the ingestion of prey is characterized by low animal motility, low circulatory activity, and high digestive movement
as in the “rest and digest” stage. Thus, although they have
no heart and do not Wght with other animals on feeding,
nematodes show stages similar to the “Wght or Xight” and
the “rest and digest” stages that occur in mammals and also
show switching between the two stages triggered by feeding stimulus. The pharyngeal tissue of the nematode, the
tissue that shows pumping movement and activates digestive movement, expresses ceh-22 (Okkema et al. 1997), an
Nk-2 class homeobox gene that speciWes mesodermal tissue
of the heart and pharynx formation in Xies and mammals.
Information is meager concerning factors involved in regulating feeding activities in nematodes. Although dopamine,
ACh, 5-HT, and 4-aminobutanoic acid (GABA) have been
found to aVect locomotory activity of nematodes (Walker
et al. 2000; Weinshenker et al. 1995), their speciWc functions in the physiology of the animal remain undetermined.
Hydra (Cnidaria)
The phylum Cnidaria, that includes hydra, diverged from
the metazoan lineage before the appearance of deuterostomes and protostomes. The body of hydra is a closed sac
containing a gastrovascular cavity that is used for both
circulation and digestion. The gastrovascular Xuid of
hydra is rich in nutrients such as amino acids (LenhoV
1961) suggesting that nutrients of middle to low molecular weight substances are able to circulate throughout the
cavity by diVusion. The cavity is small, being less than
Fig. 2 Schematic representation of the body structure of nematodes (C. elegans). Yellow space represents the digestive tract and pink space represents pseudocoelom where circulation of pseudocoelomic Xuid occurs
123
1016
J Comp Physiol A (2007) 193:1013–1019
Fig. 3 Digestive and circulatory movements in hydra. a esophageal
reXex-like movement. A polyp which ingested Wve Artemia is shown.
The uppermost part shows the polyp 3 min after feeding and subsequent images show their change recorded 30, 60, and 90 s later. b Peristalsis-like movement. Images recorded every 10 s are shown.
Arrowheads show the position of primary food contents. c Defecation
reXex-like movement. Images captured 60 s before the onset of defe-
cation (¡60), immediately before (0) and 10 and 20 s (10, 20) after the
onset of defecation are shown. A dark shadow in the upper gastric region shows the feces. d Contraction and subsequent elongation of the
polyp whose gastrovascular Xuid is labeled with India ink. Bars represent 1 mm. (Copied and modiWed from Shimizu et al. (2004) and Shimizu and Fujisawa (2003). copyright Elsevier (a–c) and Wiley (d)
1 cm in length and about 0.1 cm in width. Thus diVusion
would be an eYcient means for moving materials
throughout the cavity. Furthermore, diVusion is a physical
phenomenon hence requires no energy for its occurrence
and is uncontrollable by nervous system. Therefore, hydra
has long been thought to be a representative diVusion
dominant organism (Crick 1970; Wolpert 1971; Meinhardt
1997). The nerve net of hydra has long been considered
to resemble the ancient form of animal nervous system
which was functionally meager, structurally simple and
served primarily to transmit external stimuli throughout
the animal (Matthews 1997). In sharp contrast to this
expectation, recent Wndings by Shimizu et al. (2004) and
Shimizu and Fujisawa (2003) provided convincing
evidence that hydra controls digestion and circulation by
using dynamic movements similar to those used in
mammals.
Campbell 1978). Analysis of the nerve free hydra fed by
ingesting Artemia into the digestive tract by hand showed no
digestive movements except that a weak peristalsis occurs.
This demonstrates that the digestive movements are basically
neurogenic events. Paralleling the behavioral similarities,
structural similarities are also found between the hydra
body,3 existing as a diVuse nerve net in hydra (Sakaguchi
et al. 1996) and as a myenteric plexus (Auerbach’s plexus),
which is a part of enteric nervous system (ENS) in mammals
(Gabella 1979; Gershon and Erde 1981).
Digestion by means of digestive movements in hydra
Shimizu et al. (2004) showed that three types of movements
occur during the digestive process in hydra (Fig. 3), an
“esophageal reXex-like movement” for the transfer of prey
forward in the gastrovascular cavity (Fig. 3a), a “peristalsislike movement” causing a back and forth movement of the
food bolus (Fig. 3b) and a “defecation reXex-like movement”
ejecting feces from the mouth (Fig. 3c). The three movements are similar to the esophageal reXex (Ganong 1999), the
peristaltic reXex in the intestine (Hukuhara et al. 1958,
1961a, b ) and the defecation reXex in the rectum (Takaki
et al. 1987), which occur in the digestive process of mammals. This demonstrates that digestion in hydra is based upon
dynamic mechanisms similar to those in mammals. In hydra,
it is technically possible to construct animals devoid of neurons and maintain them in healthy situation2 (Marcum and
123
Circulation by pumping movements in hydra
Shimizu and Fujisawa (2003) showed that the peduncle
region of hydra, which is located right next to the basal disc
of the anima, shows pumping movements when not occu2
In hydra, it is possible to construct animals that have no neurons by
treating animals with drugs, e.g. hydroxyurea (HU). HU blocks the
transition of cells from G1 to S phase. Virtually, however, a large fraction of cells in S phase are also severely damaged and preferentially
eliminated. Since multipotent stem cells in hydra have shorter cell
cycle time than epithelial cells, the stem cells that spend larger fraction
of time in S phase are more easily damaged and eliminated than epithelial cell lineage. The polyps thus constructed have no neurons leaving
secretory gland cells other than epithelial cells. By feeding them by
transferring Artemia into the digestive tract by hand, it is possible for
the nerve free hydra to survive and moreover even to proliferate by
asexual budding.
3
The myenteric plexus in mammals is made up of multiple ganglia and
bundles of neural Wbers that connect the ganglia. In contrast, the diVuse
nerve net in hydra is made up of single neural cell bodies and single
neural Wbers that connect the cell bodies. Therefore, the two systems
have netlike structure. In the nerve net of hydra, two neuropeptides
GLWamide and Hym-355 (FPQSFLPRGamide) are found in the neurons whereas cholinergic neurons and serotonergic neurons are not.
Since those two neuropeptides had no eVect on digestive movements
(T. Fujisawa, personal communication), the hormonal factor that activates digestive movements remains to be discovered.
J Comp Physiol A (2007) 193:1013–1019
1017
pied by a food bolus. A small volume of India ink injected
into the gastrovascular cavity to outline the cavity (to next
page) demonstrated that the gastrovascular Xuid is pumped
in and out of the peduncle region of the cavity by the overall contraction of the animal (Fig. 3d). This movement was
found to be neurogenic because nerve free hydra did not
show the movement. Moreover, the movement was activated by treatment with a neuropeptide, Hydra RFamide III
(KPHLRGRFamide) (Moosler et al. 1996; Mitgutsch et al.
1999). RFamides were Wrst identiWed in clams as cardioexcitatory peptides by Price and Greenberg (1977). The endodermal epithelium of the hydra peduncle expresses a
homologue of the cardiac mesoderm marker gene Nkx-2.5
(Lints et al. 1993), termed CnNk-2 (Grens et al. 1996,
1999). The C. elegans Nkx-2.5 homologue, ceh-22 (Okkema et al. 1997), is expressed in the pharynx, and the Drosophila Nkx-2.5 homologue, tin, is expressed in the heart
and pharynx (Bodmer 1993; Chen and Fishman 2000).
Thus widely divergent metazoans share the feature of
expressing an Nkx-2.5 homologue in pumping tissue.
search for ACh or 5-HT containing neurons by immunohistochemical methods have been unsuccessful (Fujisawa, personal communication). Several neuropeptides that activate
body muscle contraction have been found in recent years
e.g. KPHLRGRFa (Shimizu and Fujisawa 2003), Hym-176
(Yum et al. 1998), Hym-248 (Takahashi et al. 2003). However, there have been found no factors that regulate circulatory and digestive movements in an explicit manner. An
extensive search for factors is being undertaken.
Changes of circulatory and digestive activities
in opposite phases to each other
Discussion
Circulation and digestion in hydra occur in the same cavity,
the gastrovascular cavity. To examine the pattern of use of
this space for the two purposes, the contractile frequency of
hydra polyps before and after feeding stimulus was measured4. As a typical example, during 18 min before feeding,
which was one day after the last feeding, contraction
occurred ten times (Fig. 4). This contraction ceased completely after feeding. Subsequently, an esophageal reXexlike movement was observed (Fig. 3a). This demonstrates
that circulatory and digestive processes do not occur simultaneously in the cavity. Rather, the animal undergoes a
transition from a circulation dominant stage to a digestion
dominant stage and that this transition is triggered by food
intake and is regulated by the nervous system.
Possible substances that regulate the circulatory
and digestive activities
It remains unknown what kind of neurotransmitters are
involved in regulating the two physiological activities.
ACh, and 5-HT have been tested to Wnd no eVect. Also,
4
The measurement was carried out using a wild type strain of Hydra
magnipapillata (strain 105) cultured under standard mass culture conditions (Sugiyama and Fujisawa 1977). They were fed three times a
week and for each feeding animals were transferred to fresh culture
medium 3–5 h after the feeding. An animal that had been starved for
24 h was placed in culture solution in a plastic dish of 50 mm in diameter. Behavior of the animal before and after feeding was recorded with
a CCD camera on a dissecting microscope connected to a VCR.
Fig. 4 Pattern of contraction of a hydra polyp (strain 105) during
30 min (15 min before and 15 min after feeding stimulus). Each bar
represents one contraction. The abscissa represents the minutes before
the feeding stimulus (<0) or after the stimulus (>0)
To summarize, we have found that mammals (deuterostomes), mollusks, nematodes (protostomia), and hydra (diploblast) all have the “Wght or Xight” (circulation dominant)
and the “rest and digest” (digestion dominant) stages and
that the transition from the former stage to the latter stage
occurs at least by feeding stimulus, although the majority of
invertebrates do not “Wght or Xight” in the way vertebrates
do. The two stages until now have been thought to be a
characteristic feature of physiology of vertebrates. We
interpret the observations described in the present study to
demonstrate that the two stages which originate from the
properties of nervous systems of organisms are evolutionarily as diverse as cnidarians and mammals. Although the
reason for the universality of the two stages in metazoan
phyla and involvement of nervous system in regulating
switching between the two stages is unknown, we propose
a novel scenario for how the nervous system that regulates
physiological activities of animals appeared and evolved.
Even in primitive metazoan phyla, circulatory and digestive movements were clearly important activities and
occurred in a distinct manner showing pumping and peristaltic movements. Although the detailed body plans of
early metazoans are unknown, it is likely that there was no
coelomic space (Fig. 5a). This implies that both digestion
and circulation took place in the space that corresponds to
the gastrovascular cavity found in extant organisms such as
cnidarians and Xatworms. To pursue digestion and circulation using this space in an eYcient manner, a strategy was
developed to use the space alternatively for circulation and
123
1018
J Comp Physiol A (2007) 193:1013–1019
Fig. 5 Schematic representation of circulatory space (pink) and digestive space (yellow) in hydra (a), nematodes (b), mollusks (c) and Wshes
(d). Blood vessels in c and d are painted in red. Since mollusks have
open circulatory system and the blood Xows through the coelomic
space, the whole coelomic space is painted pink. The gastrovascular
cavity of hydra (a) painted in a patchwork pattern reXects the fact that
the cavity plays dual roles as circulatory space and digestive space. The
heart and gills in mollusks and Wshes are indicated by H and G, respectively. As the animals evolved, the more the circulatory space was separated from digestive space, and the more sophisticated the circulatory
mechanism became. Note that this Wgure is aimed to describe the systematic feature of the animals
digestion. Even after the circulatory space was separated
from the digestive space in nematodes and mollusks
(Fig. 5b, c), the switching between a circulation dominant
stage and a digestion dominant stage occurred. The high
level of circulation generally coincided with high animal
motility and capture of the prey reduced the motility and
elevated digestive movements. When vertebrates appeared
(Fig. 5d), the nervous system that was responsible for controlling digestion and circulation in opposite phases to each
other came to be concentrated along the midline (spinal
chord) (Meinhardt 2002) and the nervous system responsible for physiological regulation was also concentrated there
to form the primitive version of the ANS. Therefore,
despite the fact that the ANS originated in early vertebrate
phyla, the nervous system that regulates the physiological
activities using the “Wght or Xight” and the “rest and digest”
modes was present even in primitive organisms before
structural concentration at the midline had occurred. Thus
the roots of mammalian physiology could lie much deeper
in the animal evolutionary tree than has been appreciated
previously.
The present scenario is currently purely hypothetical and
speculative. Extensive search for related factors is required.
We are currently undertaking an extensive analysis with the
help by hydra’s peptide project to test this scenario.
Avery L (1993) Motor neuron M3 controls pharyngeal muscle relaxation timing in Caenorhabditis elegans. J Exp Biol 175:283–
297
Avery L, Horvitz HR (1989) Pharyngeal pumping continues after laser
killing of the pharyngeal nervous system of Caenorhabditis elegans. Neuron 3:473–485
Bodmer R (1993) The gene tinman is required for speciWcation of the
heart and visceral muscles in Drosophila. Development
118:719–729
Cannon WB (1929) Bodily Changes in pain, hunger, fear and rage: an
account of recent research into the function of emotional excitement, 2nd edn. Appleton-Century-Crofts, New York
Cannon WB (1932) The wisdom of the body. Kegan Paul, London
Chen JN, Fishman MC (2000) Genetics of heart development. Trends
Genet 16:383–388
Crick F (1970) DiVusion in embryogenesis. Nature 231:420–422
Dieringer N, Koester J, Weiss KR (1978) Adaptive changes in heart
rate of Aplysia californica. J Comp Physiol 123:11–21
Drushel RF, Neustadter DM, Shallenberger LL, Crago PE, Chiel H.J
(1997) The kinematics of swallowing in the buccal mass of Aplysia californica. J Exp Biol 200:735–752
Ellis CH (1944) The mechanism of extension in the legs of spiders.
Biol Bull 86:41–50
Gabella G (1979) Innervation of the gastrointestinal tract. Int Rev Cytol 59:129–193
Ganong WF (1999) Review of medical physiology. 19th edn.
McGraw-Hill Medical Publishing, New York
Gershon MD, Erde SM (1981) The nervous system of the gut. Gastroenterology 80:1571–1594
Goldstein R, Kistler HB Jr, Steinbusch HWM, Schwartz JH (1984)
Distribution of serotonin-immunoreactivity in juvenile Aplysia.
Neurosci 11:535–547
Grens A, Gee L, Fisher DA, Bode HR (1996) CnNK-2, an NK-2
homeobox gene, has a role in patterning the basal end of the axis
in hydra. Dev Biol 180:473–488
Grens A, Shimizu H, HoVmeister SA, Bode HR, Fujisawa T (1999)
The novel signal peptides, pedibin and Hym-346, lower positional
value thereby enhancing foot formation in hydra. Development
126:517–524
Hukuhara T, Yamagami M, Nakayama S (1958) On the intestinal
intrinsic reXexes. Jpn J Physiol 8:9–20
Hukuhara T, Sumi T, Kotani S (1961a) The role of the ganglion cells
in the small intestine taken in the intestinal intrinsic reXex. Jpn J
Physiol 11:281–288
Hukuhara T, Kotani S, Sato G (1961b) EVects of destruction of intramural ganglion cells on colonic motility: possible genesis of congenital megacolon. Jpn J Physiol 11:635–640
Acknowledgments The authors wish to thank Dr. H. Morishita at
Hiroshima University for numerous advices and fruitful discussions
about mollusks. They also wish to thank Dr. W.M. Kier at University
of North Carolina and Dr. H.J. Chiel at Case Western Reserve University for providing reprints, information and encouragement. We would
also like to thank Prof. R. Steele at University of California at Irvine
for improving English. This research was supported by a grant from
Japanese Ministry of Education to H.S (No. 60170191).
References
Albertson DG, Thomson JU (1976) The pharynx of Caenohabditis elegans. Philos Trans R Soc Lond B Biol Sci 275:299–325
123
J Comp Physiol A (2007) 193:1013–1019
Kier WM (1988) The arrangement and function of molluscan muscle.
In: Trueman ER, Clarke MR (eds), Wilbur KM (Editor-in-Chief)
The Mollusca, form and function. Academic, New York, pp 211–
252
Kier WM, Smith KK (1985) Tongues, tentacles and trunks: The biomechanics of movement in muscular-hydrostats. Zool J Linn Soc
83:307–324
Koch UT, Koester J, Weiss KR (1984) Neuronal mediation of cardiovascular eVects of food arousal in Aplysia. J Neurophysiol
51:126–135
Koester J, Koch UT (1984) Neural control of the circulatory system of
Aplysia. Experientia 43:972–980
Kupfermann I (1991) Functional studies of cotransmission. Physiol
Rev 71:683–732
LenhoV HM (1961) Digestion of ingested protein by Hydra as studied
by radioautography and fractionation by diVerential solubilities.
Exp Cell Res 23:335–353
Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP (1993) Nkx-2.5:
a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 119:419–
431
Marcum BA, Campbell RD (1978) Development of Hydra lacking
nerve and interstitial cells. J Cell Sci. 29:17–33
Matthews GG (1997) Neurobiology: molecules, cells, and systems.
Blackwell, New York, pp 23–24
Meinhardt H (1997) Models of biological pattern formation. Academic, New York
Meinhardt H (2002) The radial-symmetric hydra and the evolution of
the bilateral body plan: an old body became a young brain. Bioessays 24:185–191
Mitgutsch C, Hauser F, Grimmelikhuijzen CJP (1999) Expression and
developmental regulation of the Hydra-RFamide and HydraLWamide preprohormone genes in Hydra: evidence for transient
phases of head formation. Dev Biol 207:189–203
Moosler A, Rinehart KL, Grimmelikhuijzen CJP (1996) Isolation of
four novel neuropeptides, the Hydra RFamides I-IV, from Hydra
magnipapillata. Biochem Biophys Res Commun 229:596–602
Nieuwenhuys R, Ten Donkelaar HJ, Nicholson C, Smeets WJAJ
(1998) The central nervous system of vertebrates: an introduction
to structure and function. Springer Heidelberg
Okkema PG, Ha E, Haun C, Chen W, Fire A (1997) The Caenorhabditis elegans Nk-2 homeobox gene ceh-22 activates pharyngeal
muscle gene expression in combination with pha-1 and is required
for normal pharyngeal development. Development 124:3965–
3973
Ono JK, McCaman RE (1984) Immunocytochemical localization and
direct assays of serotonin-containing neurons in Aplysia. Neuroscience 11:549–560
Parry DA, Brown RHJ (1959) The hydraulic mechanism of the spider
leg. J Exp Biol 36:423–433
Pennisi E (2003) Drafting a tree. Science 300:1694
Price DA, Greenberg MJ (1977) Structure of a molluscan cardioexcitatory
neuropeptide. Science 197:670–671
1019
Ram JL, Shukla UA, Ajimal GS (1981) Serotonin has both excitatory
and inhibitory modulatory eVects on feeding muscle in Aplysia.
J Neurobiol 12:613–621
Riddle DL, Blumenthal T, Meyer BJ, Priess JR (1997) C. elegans II:
monograph 33 (Cold Spring Harbor Monograph Series) Cold
Spring Harbor Laboratory Press
Robertson D, Low PA, Polinsky RJ (1996) Primer on the autonomic
nervous system. Academic, San Diego
Ruppert EE, Barnes RD (1996) Invertebrate zoology. Saunders College, Fort Worth
Sakaguchi M, Mizusina A, Kobayakawa Y (1996) Structure, development, and maintenance of the nerve net of the body column in Hydra. J Comp Neurol 373:41–54
Sarnat HB, Netsky MG (2002) When does a ganglion become a brain?
Evolutionary origin of the central nervous system. Semin Pediatr
Neurol 9:240–253
Sawin ER, Ranganathan R, Horvitz HR (2000) C. elegans locomotory
rate is modulated by the environment through a dopaminergic
pathway and by experience through a serotonergic pathway. Neuron 26:619–631
Shimizu H, Fujisawa T (2003) Peduncle of Hydra and the heart of
higher organisms share a common ancestral origin. genesis
36:182–186
Shimizu H, Koizumi O, Fujisawa T (2004) Three digestive movements
in Hydra regulated by the diVuse nerve net in the body column. J
Comp Physiol A 190:623–630
Sugden AM, Jasny BR, Culotta E, Pennisi E (2003) Charting the evolutionary history of life. Science 300:1691
Sugiyama T, Fujisawa T (1977) Genetic analysis of developmental
mechanisms in hydra I sexual reproduction of Hydra magnipapillata and isolation of mutants. Dev Growth DiVer 19:187–200
Takahashi T, Kobayakawa Y, Muneoka Y, Fujisawa Y, Mohri S, Hatta
M, Shimizu H, Fujisawa T, Sugiyama T, Takahara M, Yanagi K,
Koizumi O (2003) IdentiWcation of a new member of the GLWamide peptide family: physiological activity and cellular localization in cnidarian polyps. Comp Biochem Physiol B Biochem Mol
Biol 135:309–324
Takaki M, Neya T, Nakayama S (1987) Functional role of lumbar sympathetic nerves and supraspinal mechanism in the defecation reXex of the cat. Acta Med Okayama 41:249–257
Walker RJ, Franks CJ, Pemberton D, Rogers C, Holden-Dye L (2000)
Physiological and pharmacological studies on nematodes. Acta
Biol Hung 51:379–394
Weinshenker D, Garriga G, Thomas JH (1995) Genetic and pharmacological analysis of neurotransmitters controlling egg laying in
C. elegans. Neuroscience 15:6975–6985
Wolpert L (1971) Positional information and pattern formation. Curr
Top Dev Biol 5:183–224
Yum S, Takahashi T, Koizumi O, Ariura Y, Kobayakawa Y, Mohri S,
Fujisawa T (1998) A novel neuropeptide, Hym-176, induces contraction of the ectodermal muscle in Hydra. Biochem Biophys
Res Commun 248:584–590
123