X-Message-Number: 15215
Date: Sat, 30 Dec 2000 21:50:37 +0100
From: 
Subject: NEUROBIOLOGY:	ON REGENERATING THE DAMAGED CENTRAL NERVOUS SYSTEM

a fragment from SCIENCE-WEEK December 29, 2000

[...]

2. NEUROBIOLOGY:
ON REGENERATING THE DAMAGED CENTRAL NERVOUS SYSTEM
     The ability to regenerate at least certain parts of the
organism is found in all living systems, including plants and
animals, unicellular and multicellular. With higher organisms,
however, for example with mammals, the process of regeneration
involves many constraints. Of great concern in clinical medicine
are injuries to the nervous system, injuries which are often
permanently debilitating because of poor or absent regeneration
of neural tissue. Important advances have recently been made in
our understanding of nervous system injury and regeneration, and
there are now indications that significant breakthroughs will
occur in the near future.
     What happens when a nerve cell is injured? Consider the case
when the *axon of the nerve cell is severed. When a *peripheral
nerve fiber is cut, certain events follow in different parts of
the neuron. The distal segment of the nerve fiber, the part on
the far end of the cut, undergoes degeneration, which begins
slowly, requiring days to be completed, and involves the separate
parts of the nerve fiber differently. The axon gradually breaks
up and the segments are digested and absorbed. If there is a
*myelin sheath, it is gradually transformed into a chain of lipid
droplets, the larger of which may in the early stages contain
degenerating fragments of the axon. The fragments of the axon
disappear in a few days; parts of the degenerating myelin sheath,
in the form of droplets, may persist for six months or more. When
a nerve fiber is cut, the parts of the neuron from the break
toward the cell body (the proximal parts) also show
characteristic changes. The cell body undergoes evident changes
in *endoplasmic reticulum and *ribosomes (chromatic changes in
Nissl substance). This changes reaches its peak in 7 to 15 days,
after which there may be recovery, or complete degeneration if
there is too much damage. If the cell body completely
degenerates, the nerve fiber between the cell body and the cut
undergoes degeneration (Wallerian degeneration) just as the
distal segment does. But if the cell body survives, only a small
amount of destruction of the proximal segment occurs, and that
near the cut. Since this is a peripheral nerve, what happen then
is that from each axon near its cut end a number of small sprouts
grow out in all directions. Some of the sprouts grow in the
direction of the former distal axon segment and grow into the
connective tissue matrix that has formed scar tissue. The
haphazard arrangement of connective tissue fibers influences the
amoeboid growing tips of the nerve sprouts. Not all of the fibers
get across the scar, but a few do, and even fewer manage to
regain the original neural pathway.
     The above is a description of a mammalian peripheral nerve
degeneration and regeneration, the process first described at the
beginning of the 20th century. For most of the 20th century,
there was a clear dogma in neurobiology: It was believed that in
the mammalian central nervous system, including in humans, the
nerve fibers of the brain and spinal cord were incapable of
regeneration sufficient to restore function. A most important
corollary of this dogma was that this incapability of sufficient
regeneration (or any regeneration at all) was intrinsic to
central nervous system nerve cells. In 1980, that corollary dogma
was overturned, and it is now understood that the regenerative
capacity of the central nervous system is not intrinsic to
central nervous system nerve cells, but depends on the
circumstances of damage and the immediate environment of the
nerve cells. Regeneration can occur in the damaged central
nervous system, and this new understanding has caused
considerable excitement in the neurobiological and medical
communities.
... ... P.J. Horner and F.H. Gage (Salk Institute, US) present an
extensive review of regeneration in the damaged central nervous
system, the authors making the following points:
     1) The authors point out that in contrast to fish, amphibia,
and the mammalian peripheral nerves and developing central
nerves, adult central mammalian neurons do not regrow functional
axons after damage. This inability of adult central nervous
system neurons to regrow after injury cannot be entirely
attributed to intrinsic differences between adult central nervous
system neurons and all other neurons, since it has been known
since the early years of the 20th century that adult central
nervous system neurons could regrow in a permissive environment.
In 1980, P.M Richardson et al replicated the early studies with
new methods that definitely confirmed that adult central nervous
system neurons have regenerative capabilities. This finding
revealed that the failure of central nervous system neurons to
regenerate was not an intrinsic deficit of the neuron, but rather
a characteristic feature of the damaged environment that either
did not support or prevented regeneration. In the past 20 years,
progress has been made in identifying the elements that are
responsible for the differences between the adult central nervous
system and peripheral nervous system environments, and in the
past few years the molecular and cellular bases of regenerative
compared with non-regenerative responses are beginning to be
revealed.
     2) The authors suggest that regeneration strategies
developed from these new discoveries will be applicable to many
central nervous system disorders. Spinal cord injury could be the
most approachable, owing to the well-defined loss of cells and
axons and the relative lack of consequent chronic pathology.
Genetic disorders that result in aberrant axonal pathfinding or
neuronal cell loss may also be amenable to regeneration.
Degenerative diseases where a defined cell type is lost (e.g.,
Parkinson's disease, Alzheimer's disease, amyotrophic lateral
sclerosis) are also good targets, but may be more challenging
because of the potential for continued cell loss or axonal
degeneration. Finally, regeneration strategies may also be
applied to less well-defined disorders where diffuse cell and
axonal loss can occur, such as cerebrovascular disease, tumor,
and infection of the central nervous system.
     3) Concerning recent work, an increasing number of studies
have demonstrated that an adult cut axon in the central nervous
system can be induced to regrow by either increasing the
permissive cues or decreasing the non-permissive cues of the
existing environment. Furthermore, a growing list of reports
indicate that one strategy or another can induce some level of
functional recovery following damage. The authors (Horner and
Gage), however, point out that it is not sufficient to
demonstrate axon elongation and behavioral improvement after
injury to conclude that authentic functional regeneration is
responsible for the outcome. There are many mechanisms that may
account for observed functional recovery that do not require
regeneration, and these non-regenerative mechanisms are common in
most experimental models of traumatic injury and need to be
excluded before invoking functional regeneration as the cause of
repair and recovery. The reason for sorting out the authentic
mechanisms of functional recovery is that without understanding
the underlying basis of regeneration, little progress can be made
beyond the phenomenological observation of recovery from injury.
     4) The authors conclude: "Despite the progress in the last
century of research on regeneration... *Cajal's [1928] flowery
decree, as translated by Raoul May, still resonates: 'Once the
development was ended, the founts of growth and regeneration of
the axons and *dendrites dried up irrevocably. In the adult
centers the nerve paths are something fixed, ended, and
immutable. Everything may die, nothing may be regenerated. It is
for the science of the future to change, if possible, this harsh
decree.' The decree is lifted; the solution remains elusive."
-----------
P.J. Horner and F.H. Gage: Regenerating the damaged central
nervous system.
(Nature 26 Oct 00 407:963)
QY: Fred H. Gage: 
-----------
Text Notes:
... ... *axon: In general, nerve cells have a single long
extension (the "axon") that propagates the electrical output (the
action potential) of the cell. In some types of nerve cells,
axons are extensively branched into a multitude of fine fibers
that make contact (synapses) with other nerve cells.
... ... *peripheral nerve fiber: In mammals, neural tissue
comprising the brain and spinal cord is called the "central
nervous system", while neural tissue outside the brain and spinal
cord is called the "peripheral nervous system". The dichotomy is
more than formal, since anatomical, functional, and in this
context regeneration differences are significant.
... ... *myelin sheath: High signal propagation velocities in
motor and sensory neurons in vertebrates are achieved by
association of the nerve fiber with an enfolding "myelin sheath".
The myelin sheath consists of concentric layers of electrically
insulating lipid material (myelin), but the sheath is
periodically interrupted, and at the points where the sheath
is interrupted so is the electrical insulation interrupted. The
result, predictable from the classical physics of electrical
transmission lines and the electrical parameters of nerve fibers,
is that the propagation of an electrical pulse along such nerve
fibers occurs at a velocity much higher than that found in
unmyelinated fibers. 
... ... *endoplasmic reticulum: The term "endoplasmic reticulum"
refers to a complex system of intracellular flattened sacs, and
it is the site of many important syntheses, including the
production of new surface membrane and the intracellular
transport of various biochemical entities.
... ... *ribosomes: A ribosome (not to be confused with riboZYME)
is a small particle, a complex of various ribonucleic acid
component subunits and proteins that functions as the site of
protein synthesis.
... ... *Cajal: Santiago Ramon y Cajal (1852-1934), one of the
founders of microscopic neuroanatomy, was awarded the 1906 Nobel
Prize in Physiology or Medicine for establishing the neuron as
the fundamental unit of the nervous system.
... ... *dendrites: The general input extensions of nerve cells
are called "dendrites", and they may be extensively branched. In
general, dendrites are considered to receive input and axons to
propagate output, but the electrical architecture of most neurons
is complicated, and in many types of nerve cells activation of
the axon produces electrical activity that not only propagates
down the axon but also propagates backward through the cell body
and dendrites.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 29Dec00
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
MEDICAL BIOLOGY:
PROSPECTS FOR NEURAL STEM CELL REPAIR OF INJURED SPINAL CORD
What has happened in vertebrate evolution is that the brain has
evolved from a mere head cluster of nerve cells (a head ganglion)
of the spinal array of ganglia (the spinal cord) to a burgeoned
structure that dominates the spinal cord almost completely.
In terms of both function and anatomy, the human spinal cord can
thus be viewed as a "service" extension of the commanding brain,
the two together constituting the "central nervous system", and
like in the brain, traumatic injury to the spinal cord is usually
irreversible: brain and spinal nerve cells and nerve fibers
usually do not regenerate when damaged. Since many nerve cells
and nerve fibers in the spinal cord are essential to the control
of various voluntary and involuntary muscles of the body below
the head, traumatic injury to the spinal cord can be devastating
in its consequences. An acceleration of research into possible
mechanisms of neuronal regeneration has occurred during the past
several decades, and there is now some hope for applications of
this research to the treatment and repair of spinal cord
injuries.
... ... S.S.W. Han and I. Fischer (Hahnemann University School of
Medicine, US) present a review of current research in this field,
the authors making the following points:
      1) Recent observations that several regions of the
mammalian central nervous system do continue to produce neurons
throughout life suggests there are prospects for repairing an
injured spinal cord. Researchers have developed efficient
methods for culturing the neural *stem cells of rodents,
genetically modifying these cells to produce therapeutic genes,
and then transplanting these cells into animal models of brain
diseases. These same gene therapy and grafting techniques are
being explored as possible methods for restoring function
following traumatic spinal cord injury.
      2) In the developing embryo, *epithelial cells of the
*neural tube generate a variety of precursor cells that migrate
and *differentiate into neurons, *astrocytes, and
*oligodendrocytes. Central nervous system stem cells have now
been discovered in the human central nervous system and appear
to behave similarly to their rodent counterparts, and these stem
cells could potentially be used to promote the generation of new
nerve cells (neurogenesis) following injury and disease.
      3) Transplantation studies have demonstrated that neural
stem cells have the capacity to differentiate in response to the
environment into which they are reintroduced and to integrate
appropriately with the host tissue. Neural stem cells can be
isolated from different areas and propagated for long periods in
culture without losing their ability for varied differentiations
(their "multipotentiality"). When transplanted back into the
central nervous system, these stem cells have the capacity to
migrate, to integrate with the host tissue, and to respond to
local cues for differentiation.
      4) The authors conclude: "Transplantation of neural stem
cells and precursor cells together with gene therapy offers
great promise for spinal cord repair. Specific research goals
include improving neuronal survival, promoting functional
recovery through *axonal regeneration, compensating for
*demyelination, and replacing lost cells. Many issues will need
to be resolved before stem cells can be considered for use in
human subjects, but continued basic research on the properties
of these cells and development of appropriate animal models of
repair will pave the way for successful clinical applications."
-----------
S.S.W. Han and I. Fischer: Neural stem cells and gene therapy:
Prospects for repairing the injured spinal cord.
(J. Amer. Med. Assoc. 3 May 20 283:2300)
QY: S.S.W. Han, MCP Hahnemann University School of
Medicine, Philadelphia, PA US.
-----------
Text Notes:
... ... *stem cells: In general, a stem cell is any precursor
cell, a form prior to cell differentiation. E.g., stem cells in
bone marrow that give rise to blood cells.
... ... *epithelial cells: In animals, "epithelial cells" compose
the cell layers that form the interface between a tissue and the
external environment, for example, the cells of the skin, the
lining of the intestinal tract, and the lung airway passages.
... ... *neural tube: The term "neural tube" refers to the early
embryonic structure (an actual hollow tube of cells formed by the
infolding and closing of a long sheet of cells) that subsequently
gives rise to the entire brain and spinal cord.
... ... *differentiate: In this context, the term
"differentiation" refers to developmental cell specialization
(morphology and biochemistry) resulting from activation of
specific parts of the cell genome. E.g., the differentiation of a
stem cell into a nerve cell.
... ... *astrocytes: (astroglial cell) Neuroglia are non-neuronal
cellular elements of the central and peripheral nervous systems,
and astroglia (astrocytes) are a type of neuroglia. In general,
neuroglia are thought to have important metabolic functions.
... ... *oligodendrocytes: (oligodendroglia) Glial cells
characterized by sheet-like processes that are wrapped around
individual neuron axons to form the myelin sheath of nerve
fibers in the central nervous system. (The myelin sheath of a
nerve fiber is effectively a periodically interrupted insulation
which increases the propagation velocity of nerve impulses. See
note on "demyelination" below.)
... ... *axonal regeneration: In general, nerve cells have a
single long extension (the "axon") that propagates the electrical
output (the action potential) of the cell. In some types of nerve
cells, axons are extensively branched into a multitude of fine
fibers that make contact (synapses) with other nerve cells.
... ... *demyelination: (demyelinization) A number of
neurodegenerative diseases involve progressive demyelination of
various myelinated nerve fibers. High signal propagation
velocities in motor and sensory neurons in vertebrates are
achieved by association of the nerve fiber with an enfolding
sheath called myelin. The myelin sheath consists of concentric
layers of electrically insulating lipid material, but the sheath
is periodically interrupted, and at the points where the sheath
is interrupted so is the electrical insulation interrupted. The
result, predictable from the classical physics of electrical
transmission lines and the electrical parameters of nerve fibers,
is that the propagation of an electrical pulse along such nerve
fibers occurs at a velocity much higher than that found in
unmyelinated fibers. 
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 2Jun00
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
NEUROBIOLOGY: FUNCTIONAL REGENERATION OF SENSORY AXONS IN ADULT
SPINAL CORD
      In vertebrates, the spinal cord is continuous with the
brain, and the two together constitute what is called the
"central nervous system". In addition to other functional
involvements, the spinal cord, and the nerves extending from and
leading into the spinal cord ("spinal nerves"), comprise neuronal
circuits that among other things mediate a number of fast
responses to environmental changes. For example, if you
inadvertently pick up a hot object, the grasping muscles in your
hand may relax and the object drop even before the sensation of
extreme heat or pain reaches your brain and your conscious
perception. This is an example of a "spinal cord reflex", a fast
automatic response to certain types of stimuli, the response
requiring only nerve fibers and nerve cells in the spinal nerves
and spinal cord. In addition to processing such reflexes, the
spinal cord also is the site for integration of nerve impulses
that originate locally in the spinal cord or that arrive from the
periphery and brain. Of great importance is that the spinal cord
is the "highway" traveled by sensory nerve impulses carrying
sensory information to the brain, and by motor nerve impulses
originating in the brain and destined for voluntary muscles via
the spinal nerves. In humans, there are 31 pairs of spinal nerves
arranged with bilateral symmetry to serve the two sides of the
body.
      Sensory input to the spinal cord (and to nerve cells in the
spinal cord) occurs via sensory neurons with a special
morphology. Ordinary neurons have a cell body with short (often
arborized) extensions (dendrites) to receive input, and a long
extension (axon) to propagate output away from the cell body to
either another neuron or to a muscle cell. But most sensory
neurons conveying input to the spinal cord are quite different:
such neurons have a long input extension, as much as 1 meter long
in humans, that propagates nerve impulses at high speed _toward_
the cell body, and a short or long (depending on the specific
type of sensory nerve cell) output extension into the spinal cord
from the sensory neuron cell body located just outside the spinal
cord.
      Spinal nerves are "mixed nerves", containing both input
(afferent) nerve fibers and output (efferent) nerve fibers. In
humans and other higher vertebrates, the anatomy is such that
near the spinal cord, just before joining it, each spinal nerve
bifurcates into a "dorsal root" and a "ventral root" (in humans,
posterior root and anterior root, respectively). The ventral root
contains output nerve fibers to "effector cells" (in muscles,
glands, etc.), while the dorsal root contains input nerve fibers
propagating peripheral sensory information to the central nervous
system. Each dorsal root, as seen in gross morphology, has a
bulge which contains the numerous cell bodies of the sensory
nerve fibers, and each of these bulges is called a "dorsal root
ganglion".
      When the human spinal cord is injured by physical trauma
(as in an automobile accident), one of common consequences is a
traction-caused ripping of the spinal nerves (spinal nerve roots)
out of the spinal cord at a particular location in the spinal
cord axis ("spinal root avulsion"). Root avulsion usually
produces complete paralysis of those regions of the body
controlled by those particular spinal nerves, with loss of local
motor control and loss of local sensation. Natural repair of
severed connections between the spinal cord and spinal nerves
does not occur in humans, but in the past decade there has been
much progress in understanding the mechanisms of nerve fiber
regeneration, and there is now some hope of defining
interventions that may possibly provoke regeneration in cases of
human spinal nerve avulsion.
... ... M.S. Ramer et al (3 authors at 2 installations, UK) now
report evidence of functional regeneration of sensory axons in
adult mammalian spinal cord. The authors point out that the
arrest of dorsal root axonal regeneration at the transition zone
between the peripheral and central nervous system (e.g., between
the spinal cord and the spinal nerves) has been repeatedly
described since the early 20th century. The authors report their
work indicates that with *neurotrophic support to damaged sensory
neuron axons, this regenerative barrier is surmountable. In adult
rats with experimentally injured dorsal roots, *intrathecal
treatment with *nerve growth factor, *neurotrophin-3, and
*glial-cell-line-derived neurotrophic factor, resulted in
selective regrowth of damaged axons across the dorsal root entry
zone and into the spinal cord, where neurons that ordinarily
receive sensory input (dorsal horn neurons) were found to be
synaptically driven by peripheral nerve stimulation in treated
animals, demonstrating functional reconnection. In behavioral
studies, rats treated with nerve growth factor and glial-
cell-line derived neurotrophic factor recovered sensitivity to
noxious heat and pressure. The authors report that the observed
effects of neurotrophic factors corresponded to their known
actions on distinct subpopulations of sensory neurons. The
authors suggest that neurotrophic factor intervention may serve
as a viable treatment in promoting recovery from root avulsion
injuries. The authors further suggest that apart from dorsal root
injuries, once the nature of traumatic injuries in general in the
human central nervous are better understood, neurotrophic
treatment may have vast therapeutic potential for such tissue
damage.
-----------
M.S. Ramer et al: Functional regeneration of sensory axons into
the adult spinal cord.
(Nature 20 Jan 00 403:312)
QY: Matt S. Ramer []
-----------
Text Notes:
... ... *neurotrophic treatment: (treatment with neurotrophins)
In general, neurotrophins are chemical entities apparently
essential for the viability of nerve cells. These substances are
polypeptides of 200 to 300 amino acids, and a number of different
neurotrophins have been identified.
... ... *intrathecal treatment: In general, treatment involving
injection into a local area surrounding the spinal cord:
injection beneath one or more of the protective sheaths that
cover the spinal cord.
... ... *nerve growth factor: A type of neurotrophin. The various
neurotrophins can be differentiated on the basis of tissue
specificities. Nerve growth factor has apparent specificity for
dorsal root ganglion cells.
... ...*neurotrophin-3: A specific type of neurotrophin: 257
amino acids, molecular weight 29.32 kilodaltons.
... ... *glial-cell-line-derived neurotrophic factor: Glial cells
are cells of the central and peripheral nervous system that
metabolically support neurons. Such cells also produce the
multiple membrane layers called myelin and enfold nerve cell
axons with it. The glial cells are found everywhere in the brain
and spinal cord, and one result of a localized injury to the
central nervous system is a local proliferation of glial cells
to form a scar matrix. In this context, the term
"glial-cell-line" refers to a line of laboratory cultured glial
cells.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 14Apr00
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
REGENERATION OF A GERMINAL LAYER IN THE ADULT MAMMALIAN BRAIN
Until recently, one of the dogmas of neurobiology was that the
adult mammalian brain is incapable of regeneration: after injury,
neurons in the central nervous system do not spontaneously
reestablish their connections. During the past decade, however,
progress has been made in identifying various factors and types
of cells that can promote a degree of *axonal regeneration, and
an unanticipated form of *neuroplasticity in the adult mammalian
brain has been demonstrated  -- the continued production of new
neurons in certain brain regions. For example, proliferating
cells apparently persist throughout adult life along the length
of the lateral wall of the internal brain fluid space known as
the "lateral *ventricles". This germinal region, called the
"subventricular zone", generates new neurons destined for the
part of the brain receiving olfactory sensory information
(olfactory bulb). The olfactory bulb is a major mammalian brain
structure, considerably reduced in size in man, but still of
physiological importance [*Note #1]. The subventricular zone is
organized as an extensive network of chains of migrating cells
destined to become neurons (neuroblasts). The newly generated
neuroblasts migrate through the subventricular zone to join a
migrating stream of precursor neurons that leads to the olfactory
bulb, and in the olfactory bulb, the new neurons differentiate
into various types of nerve cells
... ... F. Doetsch et al (3 authors at 2 installations, US ES)
now report that after treatment of the adult mouse brain with an
antimitotic agent (cytosine-beta-D-arabinofuranoside) (i.e., an
agent that stops cell mitosis), subventricular zone neuroblasts
are eliminated, but the subventricular zone network then rapidly
regenerates. In 2 days, precursor cells reappear, followed at 4.5
days by migrating neuroblasts. By 10 days, the subventricular
zone network is fully regenerated, and the orientation and
organization of chains of migrating neuroblasts resemble that of
normal mice. The authors suggest this regeneration reveals an
unexpected plasticity in the adult central nervous system and
should provide a model system to study the early stages of
neurogenesis in the adult brain.
-----------
F. Doetsch et al: Regeneration of a germinal layer in the adult
mammalian brain.
(Proc. Natl. Acad. Sci. US 28 Sep 99 96:11619)
QY: Arturo Alavarz-Buylla []
-----------
Text Notes:
... ... *axonal regeneration: In general, nerve cells have a
single long extension (the "axon") that propagates the electrical
output (the action potential) of the cell. In some types of nerve
cells, axons are extensively branched into a multitude of fine
fibers that make contact (synapses) with other nerve cells. 
... ... *neuroplasticity: In neurobiology, the term "plasticity"
is the name given to the capacity of neural tissue to adjust to
change. One variant of this concerns the dependence of the
"wiring" of the nervous system on its input. Another variant
concerns the degree to which one region can under certain
conditions assume the function of another region. A 3rd meaning,
used in this report, refers to the ability of the nervous system
to repair itself after damage, i.e., to regenerate both cells and
connections between cells.
... ... *ventricles: The ventricles are spaces in the vertebrate
brain that comprise the remnants of the embryonic neural tube.
These spaces are filled with cerebrospinal fluid (CSF), a clear
colorless fluid that flows continuously in the brain and spinal
cord, the fluid containing proteins, glucose, and various
electrolytes.
... ... **Note #1: The olfactory sensory tissue system (olfactory
epithelium) comprises approximately 10 square centimeters in a
70-kilogram human and 20 square centimeters in a 3-kilogram cat.
-------------------
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 3Dec99
[For more information: http://scienceweek.com/search/search.htm]
-------------------
Related Background:
ON NEW NERVE CELLS IN THE ADULT HUMAN BRAIN
During most of this century, one of the dogmas in neurobiology
was that in the adult human brain new connections between neurons
may arise, but never new neurons. The dogma, in other words, was
that in the adult human brain new nerve cells are not produced,
and the neurons present at birth are the neurons present in the
adult, albeit a maximum number of nerve cells at birth, since a)
the number of neurons in the healthy adult human brain apparently
decreases with age beginning at about age 35; and b) various
neurodegenerative diseases can markedly reduce the population of
neurons in either specific regions of the brain or globally
nearly everywhere in the brain. In recent years, this dogma, the
idea that new nerve cells are not produced in the adult human
brain, has effectively crumbled for at least one specific and
important brain locus called the "hippocampus", which is a region
of the cerebral cortex in the *medial part of the temporal lobe.
In humans, among other functions, the hippocampus is apparently
involved in short-term memory, and analysis of the neurological
correlates of learning behavior in animals indicates that the
hippocampus is also involved in memory in other species.
... ... G. Kempermann and F.H. Gage (2 installations, DE US)
present a review of past and current research in adult
neurogenesis in humans, the authors making the following points:
     1) In 1965, Altman and Das reported neurogenesis in the
hippocampus of rats, in a subregion of the hippocampus called the
"dentate gyrus". But this data was not viewed as evidence of
significant neurogenesis in adult mammals, primarily because the
methods available then could not accurately estimate the number
of new neurons nor demonstrate definitively that the new cells
were indeed nerve cells. In addition, the concept of *stem cells
in the brain had not yet been introduced, and the belief was that
for new neurons to appear, the only source would be replication
(i.e., mitosis) of adult neurons. There was also no evidence that
neurogenesis occurred in non-human primates, and so the relevance
of the rat data for the human brain seemed remote.
     2) In the mid 1980s, Nottebohm discovered that neurogenesis
occurred in adult canaries in brain centers responsible for song
learning, and that the process accelerated during the seasons in
which the adult birds acquired their songs. Nottebohm and his co-
workers then demonstrated that neurogenesis also occurred in the
hippocampus of adult chickadees, particularly during seasons when
the birds had to keep track of dispersed food storage sites.
     3) In 1997, Gould and McEwan reported that some neurogenesis
occurs in the hippocampus of the primate-like tree shrew, and in
1998, these authors found the same phenomenon in marmoset
monkeys, which are classified as actual primates.
     4) Because of research difficulties, demonstration of
neurogenesis in the adult human brain had to await special
techniques. In 1998, Peter S. Eriksson reported the use of
bromodeoxyruridine as a marker for neurogenesis and the first
evidence for neurogenesis in the hippocampus of adult humans. The
use of this marker depended on its already established use as a
tumor marker in cancer patients. Bromodeoxyuridine is a marker
that becomes integrated only into the DNA of cells preparing to
divide, and the marker was in use with terminally ill patients
with cancer of the tongue or larynx. Eriksson obtained consent
from a number of patients to investigate their brains after
death, and when 5 patients died, all 5 brains displayed new
neurons in the dentate gyrus subregion of the hippocampus. At the
same time as this study was reported, other research groups
reported nerve cell production in the hippocampus of adult rhesus
monkeys, which are primates closer to humans than marmoset
monkeys.
     5) In their review, the authors refer to their own work,
noting that beginning in 1997, they have demonstrated that adult
mice given enriched living conditions generate substantial
increases in dentate gyrus hippocampal neurons over that found in
genetically identical control animals.
     6) The authors suggest that studies of neurogenesis in the
adult human brain, while difficult, may lead to better treatments
for a variety of neurological diseases. The authors conclude:
"The expected benefits of unlocking the brain's regenerative
potential justify all the effort that will be required."
-----------
G. Kempermann and F.H. Gage: New nerve cells in the adult brain.
(Scientific American May 1999)
QY: Gerd Kempermann, University of Regensburg, DE.
-----------
Text Notes: 
... ... *medial part of the temporal lobe: The temporal lobes are
roughly the lower sides of the brain, above the ears and behind
the temporal bones of the skull, but when the human brain is
viewed from the side, as it usually is in common gross
depictions, the large and functionally important ventral and
infolded parts of the temporal lobes are not visible. In general,
the larger anatomical regions of the human brain are best
visualized as highly corrugated lobular structures extensively
folded and densely packed to fit inside the volume-limiting
protective skull. Isolated verbal descriptions of the
architecture are of limited use: anatomical graphics are the best
sources for visualization of gross brain structures.
... ... *stem cells: In general, the term "stem" cells
refers to undifferentiated cells that upon differentiation can
give rise to various specialized cell lines such as blood cells,
skin cells, nerve cells, etc. Adult bone marrow, for example,
contains stem cells that are the precursors of the various
specialized types of blood cells.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 18Jun99
-------------------
Related Background:
REGENERATION OF AXONS IN CENTRAL NERVOUS SYSTEM WHITE MATTER
When examining the gross anatomy of the mammalian brain and
spinal cord, a striking feature is the presence of large regions
with an opalescent ivory color. The color is due to myelin, the
substance that sheaths many nerve fibers in the central nervous
system. In the vertebrate central nervous system, the axons of
nerve cells involved in physiological functions that require
rapid signaling (for example, the neural control of voluntary
muscle) are wrapped in myelin with a special consequence. The
myelin sheath consists of concentric layers of electrically
insulating lipid material, but the sheath is periodically
interrupted, and at the points where the sheath is interrupted so
is the electrical insulation interrupted. The result, predictable
from the classical physics of electrical transmission lines and
the electrical parameters of nerve fibers, is that the
propagation of an electrical pulse along such nerve fibers occurs
at a velocity much higher than that found in unmyelinated fibers.
Glial cells are cells of the central and peripheral nervous
system that metabolically support neurons and produce the
multiple membrane layers called myelin and enfold nerve cell
axons with it. The glial cells are found everywhere in the brain
and spinal cord, and one result of a localized injury to the
central nervous system is a local proliferation of glial cells to
form a scar matrix. Concerning brain and spinal cord injury, it
has always been a canon of neurobiology that adult central
nervous system neurons cannot regenerate after injury to re-
establish the connections to other cells necessary for proper
functioning. Davies et al (6 authors at 2 installations, US UK),
using microtransplantation techniques, now report that adult
central nervous system white matter can support long-distance
regeneration of adult axons provided the reactive glial
extracellular matrix at the site of the lesion can be bypassed.
The authors suggest this is the first time this glial barrier to
axon regeneration has been noted.
QY: Jerry Silver []
(Nature 18/25 Dec 97) (Science-Week 9 Jan 98)
-------------------
Related Background:
REGENERATION OF MOTOR NEURONS: IDENTIFICATION OF A MITOGEN
Motor neurons are nerve cells that transmit nerve signals from
the brain or spinal cord to muscle or gland tissue, and sensory
neurons are nerve cells that carry signals from various parts of
the body to the brain or spinal cord. High signal propagation
velocities in motor and sensory neurons in vertebrates are
achieved by association of the nerve fiber with an enfolding
sheath called myelin. The myelin sheath consists of concentric
layers of electrically insulating lipid material, but the sheath
is periodically interrupted, and at the points where the sheath
is interrupted so is the electrical insulation interrupted. The
result, predictable from the classical physics of electrical
transmission lines and the electrical parameters of nerve fibers,
is that the propagation of an electrical pulse along such nerve
fibers occurs at a velocity much higher than that found in
unmyelinated fibers. Glial cells are the cells of the central and
peripheral nervous system that produce the multiple membrane
layers called myelin and enfold nerve cell axons with it, and
Schwann cells are a particular type of glial cell. A mitogen is
any compound that stimulates mitotic cell division. Livesey et al
(6 authors at 3 installations, UK CA) report the identification
of an extracellular signaling molecule, previously described as
the pancreatic secreted protein Reg-2, that is expressed solely
in regenerating and developing rat motor and sensory neurons,
with Reg-2 a potent Schwann cell mitogen in vitro. In vivo, Reg-2
is apparently transported along regrowing axons, and inhibition
of Reg-2 significantly retards the regeneration of axons
containing the protein. The authors suggest that Reg-2 is an
essential component of the neuron-glia interactions underlying
development and regeneration of mammalian motor neurons.
QY: Frederick J. Livesey []
(Nature 11 Dec 97) (Science-Week 2 Jan 98)
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