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Author's personal copy
Adult Neurogenesis and Acupuncture Stimulation at
, Chang Shik Yin
, Kwang-Sup Soh
, Seung-hoon Choi
Department of Pathology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
Acupuncture and Meridian Science Research Center, College of Oriental Medicine, Kyung Hee University,
Seoul, Republic of Korea
Nano Primo Research Center, Advanced Institute of Convergence Technology, Seoul National University,
Suwon-si, Gyeonggi-do, Republic of Korea
Received: May 25, 2011
Accepted: Jun 21, 2011
primo vascular system;
Although it was believed that the brain was incapable of regeneration after embryonic
development, neurogenesis is now known to occur into adulthood. Adult neurogenesis
has been demonstrated in the subventricular zone of the lateral ventricles and the sub-
granular zone of the dentate gyrus of the hippocampus. Acupuncture has long been used
to treat neurologic conditions, and recent reports suggest that neurogenesis may account
for its beneﬁcial effects. ST36 was the most often used acupoint in previous reports and
was shown to enhance cell proliferation and neuronal differentiation. This acupoint may
be linked to the brain through the primo vascular system, an anatomic structure thought
to correspond to acupuncture meridians. This primitive vascular-like system appears to
be involved in physiologic and pathologic processes by circulating substances throughout
the body. The role of the primo vascular system as the link between the skin and brain
underlying the beneﬁcial effects of acupuncture requires further investigation.
Neurogenesis was traditionally thought to occur primarily
during embryonic development, and neuron loss in adult-
hood due to injury, disease, and aging was considered
permanent. Although neurogenesis is now known to
continue into the postnatal period , a decline in neuro-
genesis and regenerative capacity of the nervous system
contributes to age-related impairment . Since the ﬁrst
study demonstrating neurogenesis in the adult mammalian
brain was published in 1965 , research has focused on the
involvement of neural stem cells  and neurogenesis-
regulating factors  in this process. There is evidence to
suggest that neurogenesis is altered in individuals experi-
encing cognitive decline and neurodegenerative disorders
. Although acupuncture has been widely used for
neurologic disorders in the East, its effectiveness for
treating stroke  and Alzheimer’s disease [8,9] remains
unclear. A recent study demonstrated that acupuncture
induces cell differentiation and neuroblast differentiation
* Corresponding author: Seung-hoon Choi, Department of Pathology, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong,
Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
E-mail: email@example.com (S.-h. Choi).
ª2011 Korean Pharmacopuncture Institute
J Acupunct Meridian Stud 2011;4(3):153e158
J Acupunct Meridian Stud 2011;4(3):153e158
Author's personal copy
in the rat hippocampus , providing evidence for its
utility as a neurogenesis-stimulating therapy. In this review,
we provide an overview of neurogenesis and acupuncture,
and discuss this topic in relation to the primo vascular
system (PVS), a proposed anatomic structure corresponding
to acupuncture meridians [11,12].
2. Adult Neurogenesis in Mammals
Adult neural stem cells can self-renew and differentiate
into all the major types of neural cells of the adult nervous
system, including neurons, astrocytes, and oligodendro-
cytes (Fig. 1). Because the stem cell properties of adult
neural stem cells were shown in vitro, but were not
demonstrated convincingly in vivo until recently, the term
“neural progenitors” is used to describe all dividing cells
with some capacity for differentiation .
The ﬁrst study on adult neurogenesis, published in 1965,
used 3H-thymidine autoradiography to detect neuronal
proliferation in young adult rats . These new cells
exhibited morphologic characteristics of granule neurons
and were detected in the olfactory bulb and dentate gyrus
(DG). Newer methods include the use of bromodeoxyuridine
(BrdU), which is incorporated along with 3H-thymidine into
cells during the S phase of the cell cycle to label prolifer-
ating cells and their progeny . BrdU can be combined
with other immunohistochemical stains to identify speciﬁc
types of proliferating cells, such as neuronal nuclei,
neuron-speciﬁc enolase, and N-methyl-D-aspartate
receptor subunit NR1 .
Adult neurogenesis occurs in the subventricular zone
(SVZ) of the lateral ventricles and the subgranular zone
(SGZ) of the DG in the hippocampus (Fig. 2). The SVZ is
a paired brain structure that lies adjacent to the lateral
walls of the lateral ventricles . Neural stem cells of the
SVZ migrate to the olfactory bulb via the rostral migratory
stream, where they differentiate into interneurons .
Because neurogenesis in the adult central nervous system
appears to be restricted to the DG and SVZ, studies have
focused on these two areas as targets for neurogenesis-
stimulating treatment [9,17].
The hippocampus, which plays a central role in learning
and memory, demonstrates a high degree of structural
plasticity [18,19]. Among the hippocampal formations, only
the DG continues to develop through adulthood. Progenitor
cells in the germinal zone of the DG continuously generate
granule cells, which integrate into the existing neuronal
circuits . Thus, DG cell proliferation, differentiation,
and survival inﬂuence adult hippocampal neurogenesis .
Impaired hippocampal neuron replacement in adulthood
is associated with a number of neurologic conditions,
including epilepsy , stroke , Alzheimer’s disease
, Parkinson’s disease , and inﬂammation of the
brain . The reduced proliferative activity of brain cells
associated with aging appears to be speciﬁc to granule cells
in the DG . Neurogenesis increases in the hippocampus
and SVZ in the wake of epileptic seizures and ischemic
stroke, but it is not clear whether the new cells survive and
integrate to compensate for the brain injury . Changes
in the local environment, such as a reduction in peptide
growth factors, may also play a role in age-related
impairments. Thus stimulating neurogenesis may be a key
factor in recovering from these conditions.
3. Acupuncture and Neurogenesis
Acupuncture stimulation has been used for more than 2000
years in East Asian countries as an integral part of the
medical armamentarium . Traditional indications cover
a wide range of conditions, and a recent report from
a Consensus Panel on Acupuncture indicated that
acupuncture may be an effective adjunctive therapy for
addiction, stroke rehabilitation, headaches, menstrual
cramps, epicondylitis, ﬁbromyalgia, lower back pain, carpal
tunnel syndrome, and asthma .
Regarding neurologic conditions, acupuncture has been
reported to be an effective therapy for brain disorders such
as sequelae of stroke , Parkinson’s disease , dementia
, and epilepsy ; however, its effectiveness for these
conditions remains controversial [32,33]. Studies conducted
Figure 1 Adult neural stem cells can self-renew and differ-
entiate into all major types of neural cells, including neurons,
astrocytes, and oligodendrocytes.
Figure 2 Adult neurogenesis occurs in two locations of the
brain: the subventricular zone of the lateral ventricles and the
subgranular zone of the dentate gyrus in the hippocampus.
Neural stem cells of the subventricular zone migrate to the
olfactory bulb via the rostral migratory stream, where they
differentiate into interneurons. Therefore, the dentate gyrus
and olfactory bulb are considered two neurogenic areas of the
adult central nervous system.
154 M.-H. Nam et al.
Author's personal copy
in Korea and China suggest that acupuncture may have the
potential to be developed as an adjunct for managing brain
disorders [34,35]. Acupuncture has been investigated using
functional magnetic resonance imaging of the brain [36,37],
electroencephalography , and physiological measure-
ments [39,40], but the precise mechanism underlying its
beneﬁcial effects have not yet been elucidated.
Recent studies using rodent models have suggested that
acupuncture stimulates neurogenesis. In particular, stimu-
lating the following acupoints by acupuncture or electro-
acupuncture appears to induce neuronal proliferation: ST36
[41e43], GV20 , PC6 , HT7 , CV17, CV12, CV6,
SP10 , GV16, GV8 , LI11, SJ5, and GB30 . Neuro-
genesis is regulated by a number of signaling pathways. In
rats, the cAMP response element-binding protein, a down-
stream target of cAMP signaling, is activated by electro-
acupuncture at ST36 and GV20. This transcription factor is
important in the proliferation,differentiation, and survival of
neuronal precursor cells, and directly regulates the expres-
sion of brain-derived neurotrophic factor, which supports the
growth, differentiation, and survival of neurons .
4. Neurogenesis effect of acupuncture
stimulation on ST36
ST36, an acupoint located on the anterior tibia muscle (Fig. 3),
is one of the most important acupoints in clinical acupuncture.
Simulation of ST36 is carried out for a wide range of conditions
affecting digestive system, cardiovascular system, and
immune system, and nervous system. Furthermore, ST36 is
one of the seven acupoints usedfor stroke treatment ,and
has been widely used for brain disorders [30,51e53].
Recent studies have reported that acupuncture stimu-
lation may enhance adult neurogenesis at the SVZ and DG in
the brain (Table 1). In 2001, Kim et al provided the ﬁrst
evidence for the increased generation of DG progenitor
cells after acupuncture treatment in ischemic gerbils (aged
11e13 weeks). Manual acupuncture at ST36 signiﬁcantly
increased the number of BrdU-positive cells after ischemic
injury . Subsequently, acupuncture stimulation at ST36
was reported to enhance cell proliferation in the DG a rat
model of diabetes . In SAMP8 mice, which serve as
a model for Alzheimer’s disease, simulation of ST36, as well
as CV17, CV12, CV6, and SP10, induced cell proliferation in
different brain regions . In healthy rats, acupuncture and
electroacupuncture stimulation at ST36 and GV20 signiﬁ-
cantly increased cell proliferation in the SGZ of the DG ,
and electroacupuncture stimulation at ST36, LI11, SJ5, and
GB30 produced a sustained effect on progenitor cell
proliferation and promoted cell differentiation in young
rats . However, one study reported a beneﬁcial effect
on neurogenesis with acupuncture stimulation at HT7, but
no effect at ST36 .
Several proteins found in the brain appear to be
increased by acupuncture therapy. Furthermore, stimula-
tion at ST36 upregulated the expression of neuropeptide Y,
which promotes the proliferation of neuronal precursor
cells [42,54]. In addition, modulation of brain-derived
neurotrophic factor expression appeared to mediate the
effects of electroacupuncture stimulation at ST36, which
attenuated the neuropathologic effects of stress in rats
. Upregulation of brain-derived neurotrophic factor and
activation of the cAMP response element-binding protein in
the DG were also demonstrated in rats that exhibited
increased neuroblast plasticity after electroacupuncture at
ST36 and GV20 . In this study, neurogenesis was
detected by immunostaining against Ki67, a marker of cell
proliferation, and doublecortin, which is speciﬁcally
expressed in neuronal precursors in the developing and
adult central nervous system [10,49].
5. Discussion: Neurogenesis Effect of ST36 and
the Primo Vascular System
Three reports have been published showing that acupunc-
ture stimulation at ST36 enhances cell proliferation in the
DG of the hippocampus [41e43]. Four additional studies
claimed that simultaneous stimulation at several acupoints
(including ST36) increased cell proliferation in the SGZ of
the DG [9,10,48,49]. Although one study  did not ﬁnd
a beneﬁcial effect with ST36, further investigation into the
mechanism behind the effects of acupuncture at ST36 on
adult neurogenesis is warranted.
An important ﬁrst step in understanding the role of ST36
in neurogenesis is investigating the anatomy and physiology
of acupoints, in particular, identifying and characterizing
the anatomic structure connecting the acupoint ST36 and
the brain. Recently, the PVS was proposed as the anatomic
Figure 3 ST36, one of the most important and most
frequently stimulated acupoints, is located on the tibialis
anterior muscle. This ﬁgure originated from World Health
Organization Standard Acupuncture Point Locations.
Role of ST36 and the PVS in adult neurogenesis 155
Author's personal copy
Table 1 Summary of Papers on Adult Neurogenesis by Acupuncture at ST36
Study Year Animal model Acupoints Stimulation Results
Kim et al  2001 Mongolian gerbils (11e13 weeks)
with transient global ischemia
ST36 Acupuncture; 20 min, 2 times/day for 9 days Acupuncture increased cell proliferation in
the dentate gyrus of ischemic gerbils.
Kim et al  2002 Sprague Dawley rats (6 weeks) with
ST36 Acupuncture; 20 min, 2 times/day for 7 days Acupuncture at ST36 enhanced proliferation
of neuronal precursor cells in the dentate
Yun et al  2002 Male Sprague Dawley rats (6 weeks) ST36 Electroacupuncture; 2 Hz, 1e2 mA, 0.3 ms
Electroacupuncture restored brain-derived
neurotrophic factor expression attenuated
by immobilization stress.
Park et al  2002 Sprague Dawley rats (14 days) ST36, HT7 Acupuncture; once per day for 1 week,
depth, both sides, twisting the needle
for 30 s, and removing immediately
Acupuncture at HT7 stimulated cell
proliferation in the dentate gyrus.
Acupuncture at ST36 did not produce
a signiﬁcant effect.
Gao et al  2011 Sprague Dawley rats (14 days) ST36, LI11, SJ5,
Electroacupuncture (2 Hz, 0.7 mV);
once per day for 1 week
Electroacupuncture produced a sustained
effect on progenitor cell proliferation
and promoted differentiation into
Hwang et al  2010 Male Wistar rats (13 weeks) ST36, GV20 Acupuncture; 20 min, once per day
for 3 weeks at 5-mm depth
waves of 5/20 Hz, 2e4 mA); 20 min, once
per day for 3 weeks at 5-mm depth
Both acupuncture and electroacupuncture
enhanced cell proliferation, but the effect
of electroacupuncture on neuroblast
differentiation in the dentate gyrus was
greater than that of acupuncture.
Hwang et al  2010 Male Wistar rats (13 weeks) ST36, GV20 Electroacupuncture (dense-dispersed
waves of 5/20 Hz, 2e4 mA) 20 min, once
per day for 3 weeks at 5-mm depth
Electroacupuncture enhanced cell
proliferation and neuroblast
differentiation in the dentate gyrus.
Cheng et al  2008 Male SAMP8 mice (4 months) ST36, CV17, CV12,
Acupuncture; once per day for 15 days
with a rest on day 8
Acupuncture treatment stimulated cell
proliferation in the dentate gyrus of
this autogenic senile strain.
* Maternal separation is known to increase the risk of emotional problems later in life; HT7 is used to treat neuropsychiatric disorders in
156 M.-H. Nam et al.
Author's personal copy
structure of acupuncture meridians . This idea was
originally put forth by Bong-Han Kim in the early 1960s ,
but was ignored until recently because the Japanese
anatomist Fujiwara was the only researcher able to conﬁrm
this discovery .
The PVS forms a network throughout the body in which
so-called primo ﬂuid ﬂows. This circulatory system has
several subsystems, one of which is the superﬁcial PVS in
the skin, thought to correspond to acupuncture meridians
and acupoints . The growth of the PVS around tumor
tissues has been characterized [58,59], as well as its
possible role as an additional pathway of cancer metastasis
. The PVS has also been observed in the brain ventri-
cles, the central canal of the spinal cord , the
subarachnoid space of the brain , and along the
epineurium of the sciatic nerve . These observations
are consistent with Bong-Han Kim’s claim that a primo
vessel from the primo node at ST36 has a course along the
sciatic nerve . Primo vessels in the spinal nerves are
thought link the complex PVS network to the spinal cord
and brain, . If ST36 is connected to the brain via the
PVS, the neurogenesis effect may be mediated by the
circulating ﬂuid, which contains primo microcells [64,65]
that function like the very small embryonic-like stem cells
discovered by Ratajczak . Bong-Han Kim claimed that
primo microcells may be involved in tissue regeneration,
similar to the role of pluripotent stem cells . Thus,
appropriate stimulation at ST36 may promote adult neu-
rogenesis by improving the ﬂow of primo microcells to the
brain. This hypothesis can be tested by investigating the
putative PVS path from the ST36 to the brain, followed by
characterizing the substances ﬂowing along this path and
their therapeutic effects.
Adult neurogenesis, which may be a key process in recov-
ering from brain disorders, occurs in two distinct regions of
the brain: the SVZ of the lateral ventricles and the SGZ of
the DG. Numerous studies have reported that acupuncture
stimulation at ST36 appears to enhance adult neurogenesis.
Circulation through the PVS may be the underlying mech-
anism of this beneﬁcial effect of acupuncture stimulation.
This work was supported by the Association of Korean
Oriental Medicine and Pilot Project 2011 of Advanced
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