Adult Neuroplasticity: More Than 40 Years of Research

Abstract

Within the last four decades, our view of the mature vertebrate brain has changed significantly. Today it is generally accepted that the adult brain is far from being fixed. A number of factors such as stress, adrenal and gonadal hormones, neurotransmitters, growth factors, certain drugs, environmental stimulation, learning, and aging change neuronal structures and functions. The processes that these factors may induce are morphological alterations in brain areas, changes in neuron morphology, network alterations including changes in neuronal connectivity, the generation of new neurons (neurogenesis), and neurobiochemical changes. Here we review several aspects of neuroplasticity and discuss the functional implications of the neuroplastic capacities of the adult and differentiated brain with reference to the history of their discovery.

Full text

Review Article
Adult Neuroplasticity: More Than 40 Years of Research
Eberhard Fuchs1,2 and Gabriele Flügge1
1German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, 37077 G¨
ottingen, Germany
2Department of Neurology, Medical School, University of G¨
ottingen, 37075 G¨
ottingen, Germany
Correspondence should be addressed to Gabriele Fl¨
ugge; guegg@gwdg.de
Received  January ; Accepted  April ; Published  May 
Academic Editor: Paul Lucassen
Copyright ©  E. Fuchs and G. Fl¨
ugge. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Within the last four decades, our view of the mature vertebrate brain has changed signicantly. Today it is generallyaccepted that the
adult brain is far from being xed. A number of factors such as stress, adrenal and gonadal hormones, neurotransmitters, growth
factors, certain drugs, environmental stimulation, learning, and aging change neuronal structures and functions. e processes
that these factors may induce are morphological alterations in brain areas, changes in neuron morphology, network alterations
including changes in neuronal connectivity, the generation of new neurons (neurogenesis), and neurobiochemical changes. Here
we review several aspects of neuroplasticity and discuss the functional implications of the neuroplastic capacities of the adult and
dierentiated brain with reference to the history of their discovery.
1. Introduction
e term “neuronal plasticity” was already used by the “father
of neuroscience” Santiago Ram´
on y Cajal (-) who
described nonpathological changes in the structure of adult
brains. e term stimulated a controversial discussion as
some neuropathologists favored the “old dogma” that there
isaxednumberofneuronsintheadultbrainthatcannot
be replaced when the cells die (for review see []). In a
wider sense, plasticity of the brain can be regarded as “the
abilitytomakeadaptivechangesrelatedtothestructureand
function of the nervous system” []. Accordingly, “neuronal
plasticity” can stand not only for morphological changes in
brain areas, for alterations in neuronal networks including
changes in neuronal connectivity as well as the generation of
new neurons (neurogenesis), but also for neurobiochemical
changes. We provide here a short overview of dierent
forms of neuroplasticity with reference to the history of their
discovery.
2. Changes in Neuron Morphology
In the late s, the term “neuroplasticity” was introduced
for morphological changes in neurons of adult brains. Using
electron microcopy Raisman [] demonstrated an “anatom-
ical reorganization” of the neuropil in the septal nuclei of
adult rats aer a selective lesion to distinct axons which
terminateontheneuronsinthosenuclei.Sincethen,many
changes in the morphology of neurons in response to various
internal and external stimuli have been described. A strong
external stimulus that evokes numerous neuroplastic changes
is stress. Repeated or chronic stress changes the morphol-
ogy of neurons in various brain areas. Probably the most
thoroughly investigated neuromorphological change is the
stress-induced regression of the geometrical length of apical
dendrites of pyramidal neurons that was rst demonstrated in
the hippocampus []. e hippocampus is part of the limbic-
HPA (hypothalamic-pituitary-adrenal) system and regulates
the stress response. Retraction of dendrites of CA pyramidal
neurons has been repeatedly documented aer chronic stress
as well as aer chronic glucocorticoid administration [–].
Dendritic retraction does of course reduce the surface of the
neurons which diminishes the number of synapses. Also neu-
rons in the medial prefrontal cortex retract their dendrites in
response to stress, but the eects depend on the hemisphere
[,]. Studies on the prefrontal cortex showed that neurons
in this brain region are particularly plastic in that they change
their dendritic morphology with the diurnal rhythm [].
Hindawi Publishing Corporation
Neural Plasticity
Volume 2014, Article ID 541870, 10 pages
http://dx.doi.org/10.1155/2014/541870

Neural Plasticity
Such neuroplastic reactions are not a one-way road. In the
amygdala, the dendritic arborization of the pyramidal and
stellate neurons in the basolateral complex was enhanced by
a similar chronic stress paradigm that reduces branching of
dendrites in hippocampal CA pyramidal neurons []. e
brain’s pronounced neuroplastic capacities are also reected
by the fact that the synapses are replaced as soon as the
stress is terminated []. Furthermore, drugs that stimulate
neuroplasticity can prevent the stress-induced retraction of
dendrites in the hippocampal formation []. A form of
functional neuroplasticity is long-term potentiation (LTP),
that is the long-lasting enhancement in signal transmission
between two neurons aer synchronous stimulation [].
3. Neuron Death
e research on neuroplasticity in adult brains was strongly
stimulated by observations that brain neurons may die, for
example, because of trauma or degenerative illnesses such
as Parkinson’s or Alzheimer’s disease []. In the late s,
there were reports that even the stress that an individual
experiences can kill neurons in the brain. is message
was based on studies in wild vervet monkeys that had
been housed in a primate center in Kenya where they died
suddenly. e animals had experienced severe stress because
of social isolation from their group []. e nding that their
brains revealed dead pyramidal neurons in the hippocampus
attracted great public attention as the message was reduced
to “stress kills neurons.” However, it later turned out that in
thisstudyonwildlifeanimalsthepost mortem treatment
of the brain tissue had been not optimal. e time between
death of the animals and xation of the brains for the
neuropathological analysis was obviously too long so that
morphology of the neurons was aected to an extent that had
nothing to do with the previous stress exposure of the living
animals. Since stress raises plasma glucocorticoids (GC),
monkeys were chronically treated with GC in a subsequent
study, and also the brains of these animals revealed changes
in neuron morphology that were interpreted as dead or
dying neurons []. However, these ndings could not be
conrmed by others. Instead, it was recognized that the
morphological analysis of pyramidal neurons is technically
delicate. It became apparent that, aer a subject’s death,
neurons may dramatically change their morphology and turn
into “dark neurons” when the brain tissue has not been
xed adequately for the histological analysis []. When the
chronic stress experiments were repeated under conditions
that acknowledged those technical issues, it turned out that
stress does not kill neurons, which is denitely a good
message for stressed individuals []. Further studies showed
that apoptosis (programmed cell death) in the hippocampal
formation is a relatively rare event and that chronic stress may
even reduce cell death in certain hippocampal subelds while
increasing apoptosis in others []. Since chronic social stress
in animals is regarded as preclinical model for depression
the nding of a lack of neuron death in stressed animals
also shed new light on a hypothesis saying that, in humans,
major depression kills neurons in the brain. Indeed, it was
later found that hippocampal neuron numbers in depressed
subjects do not signicantly dier from the numbers in
healthy individuals []. Also the hypothesis that chronic
GC exposure leads to neuron death had to be revised. A
summary of a range of studies on these issues concluded
that it is unlikely that endogenous GC can cause structural
damage to the hippocampal formation []. Nevertheless it
is an established fact that “adverse inuences” such as stress,
depression, and chronic GC treatments may cause shrinkage
of the hippocampal formation []. However, the underlying
processes are obviously not neuron loss but other changes
in the tissue such as reductions in neuronal dendrites and
further presumptive alterations in the neuropil that have not
been identied in detail yet ([,]; for review see []).
4. Neurogenesis in Adult Vertebrates
e most appealing phenomenon of neuroplasticity appears
to be adult neurogenesis, that is the generation of new
neurons in adult brains. Neurogenesis takes of course place
in the developing central nervous system, but in view of
the fact that certain illnesses such as Parkinson’s disease and
multiple sclerosis occur in adulthood the interesting question
is whether also adult brains are able to replace lost neurons.
In contrast to most cells of the body such as those in the
gut, the skin, or the blood which are constantly renewed, the
brain—and in particular the mammalian brain—has always
been regarded as a nonrenewable organ. Most neurons of the
adult central nervous system appear as terminally dieren-
tiated. Although the adult brain can sometimes functionally
compensate for damage by generating new connections
among surviving neurons, it does not have a large capacity
to repair itself because most brain regions are devoid of stem
cells that are necessary for neuronal regeneration. is lack
of neuroplasticity was rst described by Santiago Ram´
on
y Cajal who stated that “In adult centers the nerve paths
are something xed, ended, immutable. Everything may die,
nothing may be regenerated. It is for science of the future to
change, if possible, this harsh decree” [].
e “no new neurons” dogma was already challenged
almost ve decades ago. Using autoradiography with the triti-
ated DNA nucleoside 3H-thymidine, Altman [,]gained
rst evidence for the production of glia cells and possibly also
of neurons in the brains of young adult rats and adult cats.
In subsequent studies, -day-old rats received 3H-thymidine
and the tritium radioactivity was visualized  months later
in cells of the subgranular zone in the dentate gyrus [].
Unfortunately, autoradiography with 3H-thymidine is a very
delicate method and it is not easy to pick up the low
number of neurons that is generated daily in, for example, the
dentate gyrus of adult mammals. Accordingly, 3H-thymidine
autoradiographs produced at that time could not generally
convince the scientic community that adult neurogenesis
really exists. us only a limited number of experiments
followed the initial studies mentioned above. However, the
neuronal character of newly generated cells in the rodent
dentate gyrus was conrmed and further substantiated by
demonstrating that these newborn cells receive synaptic input

Neural Plasticity 
and extend axons into the mossy ber pathway that projects
to the CA subeld [–]. Another landmark was in the
early s, when substantial neurogenesis was demonstrated
in a vocal control nucleus of the adult canary brain [],
and a functional link between behavior, song learning, and
the production of new neurons was established []. e
nding that, in songbirds (canaries, zebra nches), males
have larger song control nuclei in their brains as compared
to females indicated that the number of neurons in those
adult birds may change with the season []. Indeed, the
neuron number in song control nuclei increases in spring
time when male zebra nches begin to sing, and newborn
neurons were also found in the HVC (hyperstriatum ventrale,
pars caudalis) of adult canaries []. Studies on the HVC in
birds showed that steroid hormones play important roles in
these processes of neuroplasticity, in particular the gonadal
hormone testosterone [,].
In line with these ndings Cajal’s statement on the xed
number of neurons in adu lt brains was further challenged as it
became clear that even in mammals, parts of the adult central
nervous system are able to replace neurons. In the olfactory
epithelium of the mammalian nose, sensory neurons are con-
tinuously generated throughout the lifespan, as rst shown in
adult squirrel monkeys []. is electron microscopic study
clearly showed large numbers of newborn sensory neurons
thatareproducedeverydayintheolfactoryepitheliumof
theadultanimals.Lateritwasfoundthatalsoneuronsinthe
olfactory bulb (OB) of adult mammals can be replaced. e
new OB neurons derive from the subventricular zone at the
lateral ventricle where neuroblasts are generated that migrate
through the rostral migratory stream to the OB (Figure ).
e neuroblasts dierentiate to functional neurons, in that
case granule cells, which formsynapses with mitral cells ([,
]; for review see []). However, OB neurogenesis is easier
to detect than hippocampal neurogenesis and it took several
years until there was reliable evidence that hippocampal
neurogenesis does exist in adult mammals.
In particular, neurogenesis could long not be demon-
strated in the brains of adult nonhuman primates such
as rhesus monkeys thereby leading to the assumption that
neuronal replication is not tolerated in primates. In an initial
study, Rakic [] investigated neurogenesis in adult rhesus
monkeys using 3H-thymidine, examining major structures
andsubdivisionsofthebrainincludingthevisual,motor,and
the association neocortex, hippocampus andOB. Rakic found
“not a single heavily labeled cell with the morphological
characteristics of a neuron in any brain in any adult animal”
and concluded that “all neurons of the rhesus monkey brain
are generated during prenatal and early postnatal life” [,
]. Furthermore, Rakic argued that “a stable population of
neurons may be a biological necessity in an organism whose
survival relies on learned behavior acquired over a long
period of time.” ese statements had a profound inuence
on the development of the research eld in that they formed
the basis for researchers of the time to show little interest to
detect neurogenesis in the adult mammalian brain.
A revolution in the eld of neurogenesis research took
place when the thymidine analog -bromo-󸀠-deoxyuridine
(BrdU) and corresponding antibodies were introduced for
labeling newborn neurons by immunohistochemistry [].
Using this new—and in comparison to autoradiography—
simpleandfasttechnique,itbecameclearthatadulthip-
pocampal neurogenesis in mammals is not restricted to
rodents but has been conserved throughout mammalian
evolution. e formation of new granule neurons was, for
example, demonstrated in the dentate gyrus of adult rats and
tree shrews [,]; the later species is regarded as phylo-
genetically located between insectivores and primates [].
Evidence of neurogenesis in the adult primate brain derived
from studies in marmoset monkeys [], a small nonhuman
primate from South America, and in macaques which are
typical representatives of the nonhuman Old-World primates
[,]. Finally, the existence of neurogenesis in the adult
human brain was shown in cancer patients who were injected
with BrdU to monitor tumor cell proliferation. Some of these
patients died from their illness and small samples of their
hippocampi were evaluated for the presence of BrdU-labeled
neurons. Since BrdU had been systemically administered, all
dividing cells were supposed to be labeled. Indeed, newborn
neurons were detected in the dentate gyrus granule cell
layer of all individuals []. ese data unequivocally showed
that adult neurogenesis is a common phenomenon across
mammalian species. It thus became generally accepted that
adult neurogenesis not only does occur in the olfactory
bulb and the gyrus dentatus of the hippocampal formation
of mammals but can also be detected in “higher” brain
regions such as the neocortex [,]. However, there are
still open questions regarding the extent of neurogenesis in
homologous brain regions of dierent mammalian species
(see below).
To detect neurogenesis in brains of adult humans the
group of J. Fris´
en took advantage of the increased concentra-
tion of 14C in the atmosphere aer nuclear bomb tests [].
Aer a nuclear explosion, this radioisotope is increasingly
incorporated into dividing cells of living organisms, including
humans. rough the determination of 14C, the authors
found that about  new neurons are generated daily in
the hippocampal formation of adult humans. Interestingly,
the 14C analysis of human brains revealed adult neurogenesis
in the striatum, adjacent to a site at the lateral ventricle
where neuronal precursor cells are generated, and there
are indications that the neuroblasts in the human striatum
dierentiate to interneurons []. Surprisingly, no newborn
neurons could be detected with the 14C technique in the
adulthumanOB.esemostrecentndingsclearlyshowthat
species and brain-region specic processes of neurogenesis
await further elucidation.
Adult neurogenesis does occur not only in mammals
and birds but also in amphibians, reptiles, and bony shes
(for references see []). Despite this omnipresence of adult
neurogenesis within vertebrates, comparative studies have
revealed signicant dierences between classes. So far it
appearsthatinmostmammals,thegenerationofnew
neurons in adult brains takes place in two regions, the
subventricular zone and the dentate gyrus, and the number

Neural Plasticity
(2) Neurogenesis
in the dentate
gyrus (DG)
Hip
OB
e
abcd
(1) Generation of stem
subventricular
zone (SVZ)
cells in the
Stimulation
by olfactory
learning
Positive modulators:
Environmental stimuli
Learning
Exercise (running)
Estrogens
Antidepressants
···
Negative modulators:
Acute and chronic stress
NMDA receptor activation
Aging
Glucocorticoids
···
DG
SVZ
RMS
II
F : A schematic view on adult neurogenesis. Neuronal progenitor cells are generated in the subventricular zone (SVZ) and in the dentate
gyrus (DG) of the hippocampal formation (Hip). () In the SVZ, neuroepithelial progenitor cells are generated that migrate through the RMS
(rostral migratory stream) to the olfactory bulb (OB). ey dierentiate to mature neurons and are integrated as functional elements into the
neuronal olfactory circuitry. () In the DG, quiescent neural progenitors (a) become amplifying neural progenitors (b) that dierentiate rst
to neuroblasts (c), then to immature neurons (d), and nally to functionally mature granule neurons (e).
of newly generated neurons is small compared to the total
number of brain cells (Figure ). However, there are also
reports from studies in mice that new neurons can be
generated in the adult substantia nigra, although with “a slow
physiological turnover of neurons” []. In contrast, in sh
a huge number of neurons are continuously produced in
many areas of the adult brain []. Also important to mention
that in comparison with shes, reptiles and birds, the rate of
neurogenesis in adult mammals decreases with age [].
5. Regulators of Adult Neurogenesis
e existence of neurogenesis in adult brains gives hope that
even damaged brain regions can be functionally repaired.
Indeed, injury to the adult brain such as ischemic insults stim-
ulates the proliferation of subventricular zone cells and thus
the formation of neuronal precursor cells. ese neuroblasts
migrate along blood vessels to the damaged region (for review
see []). However, only a small percentage can survive,
in part because inammatory processes that occur in the
ischemic brain region inhibit neurogenesis and the successful
integration of new cells into a functional neuronal network
[]. Anti-inammatory drugs can restore neurogenesis, as
shown in rodent models of peripheral inammation and aer
irradiation [].
Knowledge about the regulation of adult neurogenesis is
denitely a prerequisite for future therapeutic interventions
that may take advantage of the generation of new neurons in
adult brains. Kempermann [] emphasized that there is an
“immense spectrum of neurogenic regulators” which reect
“the sensitivity of adult neurogenesis to many dierent types
of stimuli.” Respective regulatory elements that are so far
known include single molecules as well as environmental
conditions that lead to changes in a large number of fac-
tors which themselves inuence neurogenesis. Among the
molecular factors that were rst identied as regulators of
adult neurogenesis are sex steroids such as estrogen which
can at least transiently stimulate neurogenesis in the dentate
gyrus []. Steroid hormones have pleiotropic eects on the
expression of many genes among which are also genes which
themselves encode regulators of neurogenesis. Accordingly,
in female mammals, eects of steroid hormones on adult
neurogenesis depend on the estrous cycle and other stages
related to reproductive biology []. It is not surprising that
growth factors such as BDNF (brain-derived neurotrophic
factor) and VEGF (peripheral vascular endothelial growth
factor) regulate adult neurogenesis [–]. Also the neuro-
transmitter glutamate and astroglia have an impact on adult
neurogenesis, probably by generating a distinct microen-
vironment that may favor the generation/dierentiation of
neuroblasts [–]. e large number of factors that regulate
adult neurogenesis has been reviewed before [].
Eects of stress on neurogenesis in the dentate gyrus
(the so-called hippocampal neurogenesis) have been studied
by several groups. Chronic social stress in tree shrews
and other adverse stress experiences in marmoset monkeys
reduced hippocampal neurogenesis [,,]. e eects
of social and other forms of stress depend on the stressor’s
intensity and its duration, and they may be reversible [].
Prenatal stress in rhesus monkeys has persistent eects as
a reduction in neurogenesis was observed in the adolescent
individuals []. In newborn marmoset monkeys which
were intrauterinely exposed to the synthetic glucocorticoid
dexamethasone, the proliferation of putative precursor cells
but not the dierentiation into mature cells was impaired
[]. Interestingly, this decreased proliferation rate observed
in newborn monkeys was no longer detectable in their -
year-old siblings suggesting no long-lasting eect of prenatal
hyperexposure to dexamethasone on neuronal proliferation
and dierentiation in the dentate gyrus of marmoset mon-
keys [].
Several authors attributed the eects of stress on neuro-
genesis to the actions of glucocorticoids which are elevated in

Neural Plasticity 
(a) (b)
(c) (d)
F : Electron micrographs of pyramidal neuron nuclei in the hippocampus of control and stressed male tree shrews: (a), control
CA; (b), stress CA; (c), control CA; (d), stress CA. Note the homogeneous nucleoplasma (NP) in the controls and the large number
of heterochromatin clusters (arrow) in nuclei of CA pyramidal neurons in stressed animals. NL: nucleolus. Calibration bar:  𝜇m.
the blood of stressed individuals. Corticosteroids do indeed
regulate neurogenesis and the glucocorticoid receptor antag-
onist mifepristone prevented the stress-induced reduction in
hippocampal neurogenesis []. Also the mineralocorticoid
receptor appears to play a particular role as indicated by the
fact that a genetic disruption of the receptor impaired adult
hippocampal neurogenesis in mice []. However, elements
of the glucocorticoid system are not the only regulatory
factors of adult neurogenesis in stress. Instead, as pointed
out above, other components of the stress cascade such as
enhanced excitatory neurotransmission (increased glutamate
release) play also a role. In several preclinical models of
depression using stress to induce depressive-like symptoms
in animals, certain antidepressants restored the neurogenesis
that had been impaired by the stress (see, e.g., [,]). ere
are indications that antidepressants activate the glucocorti-
coid receptor which may increase hippocampal neurogenesis
[]. However, it remains an enigma whether endogenous or
synthetic substances exist that can boost adult neurogenesis
via this receptor system.
e formation of new neurons is regulated by substances
derived from blood vessels and is targeted by an enormous
number of factors [,]. Coinciding with this view are
reports demonstrating that adult neurogenesis is enhanced by
physical activity such as running [], by learning [], or by
environmental enrichment [–].
6. Functional Role of Adult Neurogenesis
Soon aer the discovery of adult neurogenesis it was hypoth-
esized that hippocampal neurogenesis (i.e., the neurogenesis
in the subgranular zone of the dentate gyrus, a region of
the hippocampal formation) plays a crucial role in learning
and memory []. However, experimental results on the
role of dierent forms of memory in adult rodents (e.g.,
spatial learning versus associative memory) were in part

Neural Plasticity
20
15
10
5
Control Stress Cortisol
CA1CA3
Relative number/nucleus
20
15
10
5
Relative number/nucleus
∗∗∗
∗∗∗
Control Stress Cortisol
F : Relative number of heterochromatin clusters in electron micrographs from nuclei of pyramidal cells in CA and CA. Data are
mean ±SEM (𝑃 ≤ 0.0001).
contradictory. In a comprehensive review, Koehl and Abrous
[] came to the conclusion that adult neurogenesis in
rodents is involved “when the task requires the establishment
of relationships among multiple environmental cues...for the
exible use of acquired information.” Whether this is true
for all mammals remains to be determined as a low rate or
even absence of neurogenesis was found in the hippocampal
formation of adult bats []andinwhales[], species with
an excellent spatial working memory. In the OB, adult-born
new neurons are integrated into the neuronal circuits that are
responsible for olfaction and olfactory memory, respectively
(for review see []).
e fact that in animal models of depression certain
antidepressants restored normal neurogenesis that had been
impaired by stress led to the hypothesis that the bene-
cial eects of antidepressants depend on the restoration of
normal neurogenesis []. e volume of the hippocampal
formation is reduced in patients with major depression, and
antidepressants can normalize hippocampal volume [].
However,thehippocampalshrinkageisprobablynotduetoa
decrease in neurogenesis but rather to morecomplex changes
in the neural network which involve dendritic, axonal, and
possibly also glial alterations []. Kempermann et al. []
proposed that “failing adult hippocampal neurogenesis may
not explain major depression, addiction or schizophrenia,
but contributes to the hippocampal aspects of the diseases.”
A comparison of the neural stem-cell proliferation in post
mortem brain samples from patients with major depres-
sion, bipolar aective disorder, schizophrenia, and control
subjects revealed no evidence of reduced neurogenesis in
the dentate gyrus of depressed individuals. Furthermore,
antidepressant treatment did not increase neural stem-cell
proliferation. Unexpectedly, signicantly reduced numbers
of newly formed cells were found only in schizophrenic
patients []. Concerning impaired neurogenesis as presump-
tive cause of depression a group of experts summarized that
“a lasting reduction in neurogenesis” ... (is) “unlikely to
produce the full mood disorder” []. However, more recent
reports based on post mortem studies showed decreased
numbers of neuronal progenitor cells in the dentate gyrus
of depressed patients and a selective enhancing eect of
antidepressant treatment in the anterior and middle den-
tate gyrus of depressed individuals [–]. To overcome
the manifold limitations of post mortem studies, a future
approach to address the question of adult neurogenesis in
humans more precisely (possibly in longitudinal studies)
could be the visualization of this process in live subjects
using advanced in vivo imaging techniques. Moreover, this
approach could help answer the open questions on the role of
neurogenesis in cognitive functions and its functional impact
and contribution to the etiology of depression.
7. Chromatin Changes
When searching for dead neurons in the hippocampal for-
mation of male tree shrews, standard histology showed that
chronicsocialstressdoesnotleadtoneuronaldeathbut
changes the appearance of the nuclei in the hippocampal neu-
rons []. Closer investigations revealed that chronic stress
increases the formation of heterochromatin in the nuclei of
the hippocampal neurons []. In this study, the nuclear
ultrastructure of hippocampal pyramidal neurons in male
tree shrews that had been exposed to daily social stress during
four weeks according to a standard stress paradigm was
analyzed. Electron microscopic analysis revealed that in the
stressed animals the nucleoplasma of CA pyramidal neurons
displayed numerous heterochromatin clusters (Figure ).
Heterochromatin is a form of condensed chromatin whose
occurrence indicates that transcription of genes is reduced
in those cells. Quantication of the clusters revealing areas
larger than  𝜇m2in the hippocampal region CA showed

Neural Plasticity 
that there was more heterochromatin in stressed animals
compared to controls. In contrast, in area CA, the stress had
no eect on the density of heterochromatin clusters (Figure ;
[]). Although in those days it was totally unknown which
genes in the hippocampal nuclei were “silenced” by the
chronic stress, these morphological data indicated already
what was later called “epigenetics,” the phenomenon that
environmental factors change the structure of chromatin,
inuence transcription, and induce changes in the genome
[]. Since glucocorticoid hormones are oen regarded as
important factors that convey many eects of chronic stress,
it was tested whether a chronic cortisol treatment would
havethesameeectsonthechromatinasthechronicsocial
stress. Interestingly, chronic cortisol changed the number of
heterochromatin clusters only in hippocampal region CA,
but not in CA, the region that is targeted by stress (Figure ).
ese results indicate a site and treatment specic reaction
to stress and glucocorticoid treatment in the hippocampal
formation. e obvious dierences between chronic stress
and chronic glucocorticoid treatment must be kept in mind
because they possibly reect dierent cellular pathways acti-
vated by the two treatments.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
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