Regulation of adult neurogenesis by stress, sleep
disruption, exercise and inflammation: Implications
for depression and antidepressant action☆
P.J. Lucassena,⁎, P. Meerlob, A.S. Naylorc,d, A.M. van Dame, A.G. Dayerf,
E. Fuchsg,h, C.A. Oomena, B. Czéhg,i
aCentre for Neuroscience, Swammerdam Institute of Life Sciences, University of Amsterdam, P.O. box 94214,
1090 GE Amsterdam, the Netherlands
bCenter for Behavior and Neurosciences, University of Groningen, Haren, the Netherlands
cDepartment of Physiology, Faculty of Medicine and Health Sciences, The University of Auckland, Auckland, New Zealand
dDepartment of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden
eFree University Medical Center, Department of Anatomy & Neurosciences, Amsterdam, the Netherlands
fDepartment of Neurosciences, University Medical Center, University of Geneva, Medical School, Geneva, Switzerland
gClinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
hDFG Research Center Molecular Physiology of the Brain (CMPB), University of Göttingen, Germany
iMolecular Neurobiology, Max-Planck-Institute of Psychiatry, Munich, Germany
Received 6 November 2008; received in revised form 11 August 2009; accepted 18 August 2009
Early life events;
Adult hippocampal neurogenesis, a once unorthodox concept, has changed into one of the most
rapidly growing fields in neuroscience. The present report results from the ECNP targeted expert
meeting in 2007 during which cellular plasticity changes were addressed in the adult brain,
focusing on neurogenesis and apoptosis in hippocampus and frontal cortex. We discuss recent
studies investigating factors that regulate neurogenesis with special emphasis on effects of
stress, sleep disruption, exercise and inflammation, a group of seemingly unrelated factors that
share at least two unifying properties, namely that they all regulate adult hippocampal
neurogenesis and have all been implicated in the pathophysiology of mood disorders.
We conclude that although neurogenesis has been implicated in cognitive function and is
stimulated by antidepressant drugs, its functional impact and contribution to the etiology of
depression remains unclear. A lasting reduction in neurogenesis following severe or chronic stress
exposure, either in adult or early life, may represent impaired hippocampal plasticity and can
contribute to the cognitive symptoms of depression, but is, by itself, unlikely to produce the full
☆This paper has been written on the occasion of the ECNP Targeted Expert Meeting Basic Neuroscience 2007, 12–13 October 2007, Vienna,
⁎ Corresponding author. Tel.: +31 20 525 7719; fax: +31 20 525 7709.
E-mail address: email@example.com (P.J. Lucassen).
0924-977X/$ - see front matter © 2009 Elsevier B.V. and ECNP. All rights reserved.
European Neuropsychopharmacology (2010) 20, 1–17
mood disorder. Normalization of reductions in neurogenesis appears at least partly, implicated in
© 2009 Elsevier B.V. and ECNP. All rights reserved.
1. Introduction: the role of stress and
hippocampal formation in mood disorders
The stress system represents an essential alarm system that
is activated whenever a discrepancy occurs between the
expectation of an organism and the reality it encounters.
Lack of information, loss of control, unpredictability or
psychosocial demands can all produce stress responses. The
same holds for perturbations of a more biological nature, like
blood loss, metabolic crises or inflammation. Various sensory
and cognitive signals then converge to activate a stress
response that triggers several adaptive processes in the body
and brain aimed at restoring homeostasis. If stressful
situations become chronic and uncontrollable, then an
imbalance may occur that can exert deleterious effects on
virtually all organs (de Kloet et al., 2005).
Exposure to a single severe, or repetitive, uncontrollable
stressor may trigger or facilitate the development of
psychopathologies. Major depressive disorder is one among
these illnesses known to result from an interaction between
environmental stressors and genetic/developmental predis-
positions (Kessler, 1997; Kendler et al., 1999). Although
depressive disorders are traditionally considered to have a
neurochemical basis, recent studies suggest that impair-
ments of structural plasticity contribute to their pathophys-
iology as well (Castrén, 2005; Berton and Nestler, 2006).
Many brain structures, ranging from the monoaminergic
pathways to limbic–cortical areas, mediate the different
symptoms of depression. In vivo imaging studies on patients
with emotional disorders have repeatedly indicated that a
dysregulated status of various structures is apparent such as
the prefrontal cortex and subgenual cingulate cortex, as well
as the hippocampus and amygdala (Ressler and Mayberg,
2007). In this review, we will largely focus on the
hippocampal formation, because of the occurrence of adult
neurogenesis in this structure. Hippocampal neurogenesis is
regulated by various factors including stress, disturbed
sleep, exercise and inflammation. Interestingly, these
factors have all been implicated in brain vulnerability and
have been suggested to play a role in the pathophysiology of
mood disorders, like depression. As such, they may share
overlapping mechanisms of action that could e.g. involve
glucocorticoids, cytokines and neurotrophic factors, as will
be further discussed in detail.
In depressed patients, both the morphology and function
of the hippocampus are altered. High resolution in vivo
magnetic resonance imaging studies consistently document
reductions in hippocampal volume (Campbell et al., 2004;
Videbech and Ravnkilde, 2004), but the significance and
etiology of this volume loss is unclear. It has been
hypothesized that hippocampal volume reduction might be
the consequence of repeated periods of major depressive
disorder (Sheline, 2000; Bremner, 2002; MacQueen et al.,
2003). This volume loss translates into disrupted function as
indicated by the cognitive impairments, which are one of the
symptoms of major depression. Indeed, depressed patients
often exhibit deficits in declarative learning and memory and
diminished cognitive flexibility (e.g. Austin et al., 2001).
Altered hippocampal function is furthermore likely to
influence the activity of other brain structures, in particular
the prefrontal cortex and the amygdala; key areas in
emotional regulation. Since the hippocampus provides a
negative feedback control of the hypothalamic–pituitary–
adrenocortical (HPA) axis (Ulrich-Lai and Herman, 2009), a
distorted function of the hippocampus may further con-
tribute to HPA axis dysregulation, which is common in almost
50% of depressed patients (Swaab et al., 2005).
2. Stress affects hippocampal function
After it was discovered that glucocorticoid receptors are
abundantly expressed in the hippocampal formation, this
brain area has come into the focus of preclinical stress
research (de Kloet et al., 1975). Since then, a large body of
evidence has been gathered, demonstrating that stress, via
elevated levels of glucocorticoids, affects both hippocampal
structure and function (McEwen, 2006a, Joëls et al., 2007).
Functionally, chronic stress is generally associated with
reductions in hippocampal excitability, long-term potentia-
tion and hippocampal memory, but positive effects of stress
on these parameters have also been described, depending on
the timing and type of stressor (Kim and Diamond, 2002;
Joëls et al., 2007). Morphological consequences of chronic
stress include volume reductions as well as a number of
cellular changes, most notably dendritic retraction and a
suppressed rate of adult neurogenesis (McEwen, 2006a, Joëls
et al., 2007).
Hippocampal volume loss is well documented in stress-
related disorders as well as in patients treated with synthetic
et al., 1992; Sapolsky, 2000; Sheline, 2000; Bremner, 2002;
Gianaros et al., 2007). The traditional explanation for this
glucocorticoids have neurotoxic effects on the hippocampus
subregions has been emphasized (Sapolsky et al., 1990).
However, recent studies which employed more sophisticated
cell counting methods failed to find massive neuronal loss after
in the hippocampus of depressed individuals (Vollmann-
Honsdorf et al., 1997; Sousa et al., 1998; Leverenz et al.,
1999; Lucassen et al., 2001, 2004; Müller et al., 2001;
Stockmeier et al., 2004). The concept that major neuronal
loss cannot explain the hippocampal volume changes observed
after stress is consistent with observations that many of the
stress-induced structural changes are transient and often
spontaneously disappear when animals are subjected to a
recovery period (Heine et al., 2004a,b) or when elevated
corticosteroid levels are normalized again (Starkman et al.,
2 P.J. Lucassen et al.
1992). Therefore, volume changes must be derived from other
factors than cell death. Candidate cellular mechanisms are
(atrophy of) the somatodendritic components, adult neurogen-
esis, glial changes, but factors like shifts in fluid balance cannot
be excluded either (for detailed discussion see Czéh and
The most thoroughly documented stress-inducedstructural
change is the dendritic reorganization that occurs parallel to
postsynaptic densities. Chronic stress or experimentally
increased corticosterone concentrations induce shrinkage of
the apical dendrites of the CA3 and to a lesser extent of CA1
pyramidal cells and dentate granule cells (McEwen, 2006a;
Fuchs et al., 2006; Sousa et al., 2008). The most often
proposed explanation for dendritic remodeling is that the
neurons need to protect themselves from the excitoxic effect
of glutamate by reducing their input surface area. These
changes of neuronal morphology are likely to contribute to
various cognitive deficits that have been described as a result
of chronic stress exposure (Conrad, 2006; Sousa et al., 2008).
Another possible functional outcome of dendritic retraction
may be a disturbance of HPA axis regulation, leading to
unregulated glucocorticoid release (Conrad, 2006).
3. Adult neurogenesis
Adult neurogenesis (AN) refers to the production of new
neurons in an adult brain. AN is a prominent example of adult
neuroplasticity, that occurs in most vertebrate species
including humans (Eriksson et al., 1998, but see Amrein
et al., 2007). In young adult rodents thousands of new
granule neurons are generated everyday (Cameron and
McKay, 2001) though significant differences exist even within
different mouse strains (Kempermann and Gage, 2002). The
process of AN is dynamically regulated by various environ-
mental factors and rapidly declines with age (in rodents:
Kuhn et al., 1997; Heine et al., 2004a; in tree shrews: Simon
et al., 2005; in humans: Manganas et al.,2007). Neurogenesis
also occurs in the subventricular zone (SVZ) of the ventricle
wall in many mammals, and has been reported in human
brain as well (Curtis et al., 2007, Sanai et al., 2007). Several
independent groups have observed low levels of neurogen-
esis also in other brain structures like the amygdala, striatum
and neocortex, but negative results exist as well (Gould et
al., 1999, Bernier et al., 2002, Kornack and Rakic, 2001;
Cameron and Dayer, 2008; Rakic, 2002). Part of the difficulty
in studying AN in regions such as the neocortex could reside
in the fact that new cortical neurons probably belong to
small subclasses of interneurons dispersed over large
neocortical volumes (Cameron and Dayer, 2008).
In contrast to its abundance during embryonic develop-
ment, hippocampal neurogenesis in the adult is much less
frequent. Yet, AN follows a similar complex multi-step
process that starts with the proliferation of progenitor cells,
followed by their morphological and physiological matura-
tion. The latter is often referred to as the “survival” process,
that ends with a fully functional neuron that is integrated
into the pre-existing hippocampal network (Fig. 1) (for
detailed overview see e.g. Kempermann, 2006; Balu and
Lucki, 2009). The existence and numbers of true multipotent
neural stem cells residing in the adult dentate gyrus (DG) is
still a disputed issue. Experimental data report that a
heterogeneous population of precursor cells is located and
proliferates in the subgranular zone, a narrow layer located
between the dentate granule cell layer and hilus. These
precursor cells show a characteristic phenotype of radial
astrocytes (Seri et al., 2001) and can generate new cells.
Daughter cells of these progenitors proliferate at high
frequency and are often observed as bromodeoxyuridine
(BrdU)-positive cell clusters; they have been named amplify-
ing neural progenitors (Encinas et al., 2006). The maturing
newborn neurons subsequently extend their axons and
dendrites, a process followed by the formation of spines
and functional synapses (See Fig. 1 for a diagram illustrating
the main aspects of the maturation process).
New neurons display characteristic functional properties
such as a lower threshold for induction of long-term
potentiation (LTP) and robust LTP (Schmidt-Hieber et al.,
2004). Recent data indicate that the subsequent survival of
the newly generated neurons is regulated by their input-
dependent activity (Tashiro et al., 2006). There is a
significant overproduction of newborn cells and neurons
that do not become integrated into the pre-existing network
are rapidly eliminated by apoptotic cell death (Dayer et al.,
2003). This process provides a significant turnover of granule
cells in the dentate gyrus of young rodents. In monkeys this
turnover rate is significantly lower while no quantitative
data are yet available for humans (Cameron and McKay,
2001; Kornack and Rakic, 1999).
Adult neurogenesis in the dentate gyrus is potently
stimulated by exercise and enriched environmental housing
(Kempermann et al., 1997; Brown et al., 2003). It has been
suggested that data on the incidence of AN originating from
laboratory rodents, that generally live in impoverished
conditions, represents an underestimation of the true
occurrence of AN in animals living in natural (complex)
environments. A recent finding, however, appears to
challenge this concept, as cell proliferation and the number
of immature neurons in the hippocampus of adult wild living
rats were found to be within the normal range of captive-
bred rats (Epp et al., 2009).
Theexact functional roleof thenewborn granular neurons
remains to be determined. Based on the fact that the
hippocampus plays a central role in the acquisition and
consolidation of episodic-declarative memories, and in view
of the selective occurrence of AN in this structure, it is
tempting to argue that newborn neurons have a key role in
spatial learning and pattern separation. Indeed there have
been numerous attempts to link these two processes to each
other (see e.g. Bruel-Jungerman et al., 2007; Imayoshi et al.,
2008; Dupret et al., 2007, 2008; Garthe et al., 2009; Oomen
et al., 2009). Primates are thought to have the highest
cognitive capacities among mammals. In case the newly
generated neurons are truly essential for learning, an
unresolved issue is why rats and mice seem to have higher
rates of neurogenesis than primates.
4. Stress and exercise regulate adult
Stress is one of the most potent environmental parameters
known to suppress adult neurogenesis, as shown in several
3 Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation
different species, using various stress paradigms (Mirescu
and Gould, 2006; Lucassen et al., 2009c). Both psychosocial
(Gould et al., 1997; Czéh et al., 2002) and physical stressors
(Malberg and Duman, 2003; Pham et al., 2003; Vollmayr
et al., 2003) all inhibit one or more phases of the
neurogenesis process (Oomen et al., 2007). Both acute and
chronic stress exposures have a potent suppressive effect on
proliferation, thus the duration of the stress does not seem
to be a relevant factor (Gould et al., 1997; Heine et al.,
2004c; Czéh et al., 2002). Furthermore, stress appears to
interfere with all stages of neuronal renewal, and inhibits
both proliferation and survival (Fig. 2) (Czéh et al., 2001,
2002; Mirescu and Gould, 2006; Oomen et al., 2007; Wong
and Herbert, 2004).
Stress-induced reductions in proliferation could result
from apoptosis of progenitor cells, or from cell cycle arrest.
After acute stress, a reduction in proliferation was paralleled
by increased numbers of apoptotic cells, yet no distinction
was made between apoptosis of newborn or mature cells.
Following chronic stress, both proliferation and apoptosis
were reduced, parallel to increases in the cell cycle inhibitor
p27Kip1, indicating that more cells had entered cell cycle
arrest and that the granule cell turnover had thus slowed
down (Heine et al., 2004b,c).
The exact underlying cellular mechanisms mediating the
inhibitory effect of stress are largely unknown. The adrenal
glucocorticoid hormones (GCs; corticosterone in rodents;
cortisol in man) have been pointed out as key players in this
process (Wong and Herbert, 2004; 2005) and both MR and GR,
as well as NMDA receptors have been identified on progenitor
cells. At the same time, several examples exist of a persistent
a later normalization of GC levels (e.g. Czéh et al., 2002;
Mirescu and Gould, 2006). These findings suggest that while
glucocorticoids may be involved in the initial suppression of
cell proliferation, particularly in early life when neurogenesis
is abundant, they are not always necessary for the main-
dentate gyrus (modified from Enikolopov and Overstreet-Wadiche, 2008). Abbreviations used: GFAP: glial fibrillary acidic protein;
Sox2: sex determining region Y (SRY)-box 2; DCX: doublecortin; PSA-NCAM: polysialylated form of the neural cell adhesion molecule;
TuJ1: ß-tubulin III; NeuN: neuronal nuclear antigen.
Schematic diagram illustrating the neuronal differentiation cascade of newborn cells located in the adult hippocampal
4 P.J. Lucassen et al.
mediate the stress-induced inhibition of AN. The stress-
induced increase in glutamate release via NMDA receptor
activation is another leading candidate in this process (Gould
et al., 1997; Nacher and McEwen, 2006).
Stress is also known to affect the levels of various
neurotransmitters that have all been implicated in the
regulation of AN: GABA (Ge et al., 2007), serotonin
(Djavadian, 2004), noradrenalin (Joca et al., 2007) and
cell layer (GCL). B: Newborn granule cells (brown) in the rat DG. Insert in B shows a confocal microscopy image of a double labelled
cell: red reflects mature neurons (NeuN), green–yellow is the proliferation marker bromodeoxyuridine (BrdU) labelling of a newly
generated neuron. C–D: Chronic social stress inhibits both the cell proliferation rate and survival rate of the newly generated cells,
whereas concomitant fluoxetine treatment can counteract this effect of stress. E: A representative image of GFAP-staining in the
dentate gyrus. GFAP (glial fibrillary acidic protein) labels astroglia, insert shows an individual GFAP-positive astrocyte. F: Chronic
stress results in reduced numbers of astroglia in the hippocampus, whereas fluoxetine blocked this effect of stress. Pb0.05 compared
to control; # Pb0.05 compared to stress. For details see Czéh et al. (2006, 2007). (For interpretation of the references to color in this
figure legend, the reader is referred to the web version of this article.)
A: Adult hippocampal neurogenesis occurs in the subgranular zone (SGZ) of the dentate gyrus (DG) adjacent to the granule
5 Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation
dopamine (Domínguez-Escriba et al., 2006), to name a few
examples. Other neurotransmitter systems, such as the
cannabinoids, opioids, nitric oxide and various neuropep-
tides may contribute as well (see e.g. Balu and Lucki, 2009).
Importantly, stress also reduces the expression of several
growth and neurotrophic factors, such as brain-derived
neurotrophic factor (BDNF), insulin-like growth factor-1
(IGF-1), nerve growth factor (NGF), epidermal growth factor
(EGF), and vascular endothelial growth factor (VEGF), that
all can influence neurogenesis (see e.g. Schmidt and Duman,
2007). The role of gonadal steroids should not be neglected
either (Galea, 2008). The proximity of the precursors to
blood vessels further suggests a strong interaction with the
vasculature and it is this population that is particularly
sensitive to stress (Heine et al., 2005). Also, astrocytes are
important in this respect as they support the survival of
developing neurons, possess glucocorticoid receptors and are
significantly affected by some but not all types of stress
(Fig. 2) (Czéh et al., 2006; Banasr et al., in press; Oomen
et al., 2009).
When studying the effects of stress on adult neurogenesis
in laboratory conditions it is important to realize that many
variables influence the outcome of such studies, as inter-
individual and gender differences in stress coping, handling,
time of day at sacrifice and previous exposure to stressful
learning tasks can all be of influence (e.g. Holmes et al.,
2004; Ehninger and Kempermann, 2003). An interesting
contradiction also exists regarding the generally positive
effect of exercise on AN (Van Praag et al., 1999). Exercise is
generally associated with beneficial changes, also in its
effects on mood (Ernst et al., 2006; Brene et al., 2007). In
rats, short term voluntary running for 9 days potently
stimulated neurogenesis whereas long-term running for
24 days induced a strong down-regulation of progenitor
proliferation rate to approximately 50% of non-running
controls (Fig. 3). These latter findings were paralleled by a
gradual activation of the HPA axis and the opioid system
(Droste et al., 2003; Naylor et al., 2005; Lou et al., 2008).
Furthermore, by decreasing or modulating the daily running
distance of long-term running animals, the HPA axis
activation was prevented and a return to normal prolifera-
tion levels was found (Naylor et al., 2005; Lou et al., 2008).
Hence, prolonged running can develop into a stressor,
overruling the positive effects of exercise on AN, and may
even induce dependency-like behavior (Droste et al., 2003).
This suggests that positive stimuli for AN can only be
effective when HPA axis activation is minimal.
5. The long lasting effects of perinatal
but can be changed by early development. In humans, early
lifestressors areamongthestrongestpredisposing factorsfor
major depression in later life. Aversive experiences, both in
utero or neonatally, like early maternal separation or abuse,
can result in sustained HPA axis activation and lasting
alterations in the stress response that may predispose
individuals to adult onset depression, anxiety disorder, or
both (Heim et al., 2008).
In experimental conditions, exposure of pregnant animals
to stress affects critical periods of fetal brain development
that can persistently alter structural, emotional and neu-
roendocrine parameters in the offspring which results in
altered anxiety-like behavior, increased HPA axis reactivity
and memory deficits in adult life (Welberg and Seckl, 2001;
Kofman, 2002; Weinstock, 2008). Subjecting pregnant rats or
non-human primates to stress induces long lasting reductions
in adult neurogenesis in the offspring (Lemaire et al., 2000;
Coe et al., 2003; Lucassen et al., 2009a,b, but see Tauber
et al., 2008).
For rat (and non-human primate) newborns, the most
important environmental factor during early development is
the mother. Rat pups that receive more maternal care during
this period are generally less anxious later in life and show
enhanced survival of newborn cells in the dentate gyrus
(Bredy et al., 2003). Variations in maternal care determine
HPA axis properties through epigenetic modulation (Liu
et al., 2000) while the amount of maternal care received
by the offspring differs between the sexes (Oomen et al.,
2009). Of interest, maternal deprivation, or low levels of
maternal care, reduces hippocampal neurogenesis in some
(Mirescu et al., 2004, Bredy et al., 2003), but not all studies
(Greisen et al., 2005). Apparently, the experimental out-
come critically depends on the timing of deprivation and
Parallel to the changes in adult neurogenesis following
early maternal separation, an altered incidence of cell death
of voluntary running on adult hippocampal neurogenesis.
Whereas short term running for 9 days potently increases
neurogenesis levels (N400%), prolonged running for 24 days
induces a strong reduction in neurogenesis to approximately 50%
of control levels. These changes are paralleled by the develop-
ment of an activated HPA axis and a gradual rise in corticoster-
one levels, as represented by the size of the red ovals (see Naylor
et al., 2005; Droste et al., 2003). (For interpretation of the
references to color in this figure legend, the reader is referred to
the web version of this article.)
Schematic representation of the differential effects
6 P.J. Lucassen et al.
occurs as well (Mirescu et al., 2004; Zhang et al., 2002).
Notably, changes in neurogenesis after maternal deprivation
occur in a sex-dependent manner (Oomen et al., 2009) and
some could be normalized by fluoxetine treatment (Lee et
al., 2001). Gonadal steroids are likely factors that determine
such sex-dependent changes. Estrogens are thought to exert
a protective role here. They can exert non-genomic effects
directly and indirectly on the newly generated cells in
neonatal and adult rat dentate gyrus while specific estrogen
receptors have been found on immature doublecortin-
positive neurons (Herrick et al., 2006). Evidence suggests
that acute estradiol initially enhances and subsequently
suppresses cell proliferation in the dentate gyrus of adult
female rodents but may have limited effects in male rodents
(Galea, 2008). Testosterone on the other hand, promotes
differentiation and survival of the newborn neurons, but not
cell proliferation, in adult male rodents (Galea, 2008).
Hence, gonadal steroids contribute to the development of
sex differences in neurogenesis and may modulate differ-
ential effects after perinatal stress exposure.
6. Sleep disruption as a stressor
Sleep is a very general feature of all mammals and plays an
important role e.g. in homeostatic functions (Tononi and
Cirelli, 2006). Chronic sleep disruption can be regarded as a
physiological stressor, as it impairs brain functions, increases
the sympathetic tone, blood pressure and evening cortisol
levels, raises the levels of pro-inflammatory cytokines, and
also elevates insulin and blood glucose (McEwen, 2006b;
Meerlo et al., 2008). Disturbed sleep is not only a common
symptom of mood disorders, but may also sensitize individ-
uals to the development of depression. Consistent with this,
primary insomnia often precedes and predicts depressive
episodes (Riemann and Voderholzer, 2003). Experimental
studies in rats have now shown that chronic sleep curtail-
ment gradually leads to neurobiological and neuroendocrine
changes similar to those found in depression (Roman et al.,
2005a; Novati et al., 2008). Preclinical studies demonstrate
that chronically disrupted and restricted sleep can interfere
with adult neurogenesis (Roman et al., 2005b; Mirescu et al.,
2006; Guzman-Marin et al., 2007; Mueller et al., 2008). On
the basis of these findings, it has been hypothesized that
chronically disrupted sleep, by inhibiting neurogenesis, may
contribute to the etiology of depression (Meerlo et al.,
effect on the basal rate of cell proliferation and survival
(Roman et al., 2005b; Guzman-Marin et al., 2007), yet, one
study showed that even a mild restriction of sleep may
prevent the increase in AN that occurs after hippocampal-
dependent learning (Hairston et al., 2005). Since sleep
deprivation also disturbs hippocampal-dependent memory
formation (Stickgold and Walker, 2005), it could thus be that
sleep loss may also interfere with cognition by affecting
stages of dentate neurogenesis.
The mechanisms by which sleep disruption affects
hippocampal neurogenesis are not fully understood. It has
been proposed that this inhibitory effect of prolonged sleep
deprivation on AN might be an indirect result of stress
(Mirescu et al., 2006). Indeed, sleep loss can be considered
stressful and is sometimes associated with mildly elevated
GC levels (Meerlo et al., 2008). Also, prolonged sleep
disruption gradually causes alterations in HPA axis regulation
similar to those seen in depression (Meerlo et al., 2002;
Novati et al., 2008). One study has suggested that lowering
circulating GC concentrations may prevent the sleep
deprivation-induced suppression of hippocampal neurogen-
esis (Mirescu et al., 2006). On the other hand, a number of
studies with adrenalectomized rats have clearly shown that
prolonged sleep loss can inhibit neurogenesis by ways that
are independent of adrenal glucocorticoid hormones (Fig. 4)
(Guzman-Marin et al., 2007; Mueller et al., 2008).
Besides glucocorticoids, many other factors are affected
by sleep deprivation or sleep disruption, and some of these
may provide a link between insufficient sleep and reductions
in adult neurogenesis. For example, serotonin promotes
neurogenesis, in part via the serotonin-1A receptor (Banasr
et al., 2004). Interesting in this respect is that chronic sleep
restriction reduced the sensitivity of the serotonin-1A
receptor system (Roman et al., 2005a). This reduction
animals that were subjected to forced walking but had sufficient time to sleep (SFC). Whereas 1 day of SF had no effect on cell
proliferation, the numbers of BrdU-positive cells in the dorsal DG were significantly reduced after 4 or 7 days of SF. B: Effects of 4 days
SF on cell proliferation in adrenalectomized (ADX) rats that received basal corticosterone in their drinking water. Independent of
changes in corticosterone, a 55% reduction in the number of BrdU-positive cells was found after SF compared with ADX SF controls.
Pb0.01 compared to controls. After Guzman-Marin et al. (2007), with permission.
A: Hippocampal cell proliferation in rats subjected to sleep fragmentation (SF) by forced treadmill walking and in control
7 Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation
develops during the course of prolonged sleep restriction,
consistent with the finding that also the suppression of adult
neurogenesis generally occurs only after a prolonged period
of sleep disturbance. Reductions in AN following sleep
deprivation might also be related to increased levels of
pro-inflammatory cytokines (see next chapter). Both inter-
leukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are
increased after sleep restriction (Irwin et al., 2006, Haack et
al., 2007). Plasma IL-6 levels are also increased in patients
with primary insomnia (Burgos et al., 2006). Exposure to both
IL-6 and TNF-α decreases neurogenesis in vitro suggesting
that these cytokines may mediate at least some of the
detrimental effects of neuroinflammation on hippocampal
neurogenesis in vivo (Monje et al., 2003). In summary, the
mechanisms by which prolonged sleep disturbance affects
adult neurogenesis include several complex factors that are
also relevant for the etiology of mood disorders (Meerlo et
al., 2009; Lucassen et al., 2009b).
7. Inflammation as a stressor and the role
As already noted above, the effect of stress and sleep
disruption on hippocampal neurogenesis may in part be
mediated by pro-inflammatory cytokines. The HPA axis is
activated not only by stress, but also during disease
processes, and by pro-inflammatory cytokines such as IL-6
or exogenous interferon alpha (Cassidy and O'Keane, 2000).
During inflammation, cells of the immune system produce
pro-inflammatory cytokines such as interleukin-1 (IL-1) and
IL-6, which elicit various (patho)physiological reactions, that
together coordinate the “nonspecific symptoms of sickness”
and activate the HPA axis (Berkenbosch et al., 1987);
elevated GC levels are generally immunosuppressive and
then prevent the immune system from overshooting (Dunn,
2006). Thus, a clear bi-directional communication exists
between the immune and neuroendocrine systems (Rhen and
Interleukins are also produced within the brain during
ischemia, dementia, multiple sclerosis and epilepsy (Skaper,
2007; Ravizza et al., 2008). In most of these conditions,
microglial cells produce interleukins that are generally
considered detrimental for neuronal viability, although
interleukins have also been implicated in processes such as
brain plasticity (Johansson et al., 2008; Spulber et al., 2008).
Hence, neuroinflammation, defined by microglial activation
and the presence of pro-inflammatory mediators, represents
a stressor that may affect AN. More recent evidence,
however, suggests that microglia can have a dual role and,
dependingon their state of activation, they can either inhibit
or stimulate AN both in the intact and injured brain (Ekdahl
et al., 2009). It is also conceivable that various functionally
divergent subpopulations of microglia exist, some having
pro-, others antineurogenic effects (Ekdahl et al., 2009).
Inflammation and cytokine expression largely inhibit AN
directly (Vallieres et al., 2002; Monje et al., 2003) while
immune modulators like transforming growth factor (TGF)-β
(Wachs et al., 2006) have a concentration-dependent pro-
neurogenic potential in the adult brain (Battista et al.,
2006). Other pro-inflammatory cytokines such as TNF-α (Iosif
et al., 2006) or interferon-α decrease AN through modulation
of IL-1 (Kaneko et al., 2006). In addition, impairment of IL-1β
action prevents the attenuated rate of AN in response to
stress, supporting the idea that pro-inflammatory mediators
and local cues in the brain play a role in restricting AN (Koo
and Duman, 2008).
Conversely, factors capable of affecting cell genesis can
also influence microglial activation. As part of the neuroin-
flammatory response, activated microglia modulates the
neurogenic niche and, dependent on whether they are
activated by IL-4 or by IFN-γ, microglia cells can differen-
tially induce oligodendrogenesis and neurogenesis, respec-
tively (Butovsky et al., 2006). Reducing neuroinflammation
by specific drugs was further shown to restore or increase AN
in different pathological models (Ekdahl et al., 2009; Monje
et al., 2003) while T-cells even seem to influence hippo-
campal plasticity through effects on progenitor cells (Ziv
et al., 2006).
Finally, it should be noted that psychological stress
stimulates pro-inflammatory cytokine production in patients
experiencing stress and anxiety. Also in depressed patients,
increases in macrophage activity and in the production of
pro-inflammatory cytokines have been consistently reported
(Dantzer et al., 2008).
8. Stress affects cytogenesis not only in the
hippocampus but also in the prefrontal cortex
The hippocampal formation is in the focus of this review, but
it is clear that the hippocampus is not the only limbic
structure where neuroplasticity is affected by stress or
antidepressant treatment (Sairanen et al., 2007; Maya
Vetencourt et al., 2008). Functional impairments of the
hippocampus are obviously not solely responsible for the
symptoms observed in depression. Amongst others, the
prefrontal cortex and amygdala are important structures in
this respect (Ressler and Mayberg, 2007).
The prefrontal cortex (PFC) is implicated in a number of
higher cognitive functions as well as in processing emotions
and regulation of the stress response (Cerqueira et al., 2008;
Holmes and Wellman, 2009). In the medial prefrontal cortex
(mPFC) of experimental animals, stress-induced morpholo-
gical changes have been revealed that are comparable to
what is seen in the hippocampus with some significant
differences (Czéh et al., 2008). In the mPFC, stress leads to
the regression of apical dendrites of pyramidal neurons (Cook
and Wellman, 2004; Radley et al., 2004; Cerqueira et al.,
2008) and inhibits adult cell proliferation (Czéh et al., 2007;
Banasr et al., 2007). However, phenotypic analysis of the
newborn cells in the mPFC reveals that most of them develop
into glia and only a minority into neurons (Cameron and
Dayer, 2008). Accordingly, for the mPFC the inhibitory effect
of stress essentially involves adult gliogenesis. Human
studies reporting on volume reduction and glial cell loss in
prefrontal areas of patients with mood disorders (Drevets,
2001; Rajkowska and Miguel-Hidalgo, 2007) are of particular
interest in this respect.
Ongoing, low-frequent neurogenesis has been reported
also in the cortex of adult rats and non-human primates
(Dayer et al., 2005; Gould et al., 1999), but these findings
raised substantial skepticism (Kornack and Rakic, 2001), and
the question of whether AN actually occurs to a considerable
8 P.J. Lucassen et al.
extent in the cortex is still debated (Gould, 2007; Cameron
and Dayer, 2008; Imayoshi et al., 2008). It is worth to note
here, that in humans, neocortical neurogenesis has been
shown to be restricted to prenatal developmental stages
(Bhardwaj et al., 2006), and cytogenesis has not yet been
documented in the adult human neocortex (Manganas et al.,
2007). Interestingly, the expression of doublecortin, an
endogenous marker for immature neurons (Couillard-Despres
et al., 2005) has also been observed in a subpopulation of
mature glia cells in the human cortex (Verwer et al., 2007)
and in considerable numbers in the adult primate amygdala
and piriform cortex (Bernier et al., 2002). So far, there is no
evidence that stress or antidepressant treatment could
affect adult cortical neurogenesis, but this possibility should
The studies demonstrating opposing effects of stress and
antidepressant treatments on cytogenesis in the mPFC reveal
that the majority of the newly generated cells express the
chondroitin sulfate proteoglycan NG2 (Neuron-glia 2) (Fig. 5)
(Czéh et al., 2007; Banasr et al., 2007). NG2 identifies a glial
cell population that is widely and uniformly distributed
throughout gray and white matter of the mature CNS,
representing 5–8% of the total glial cell population (Butt
et al., 2005). The exact functional role of this glia type is still
largely unknown, especially because NG2-positive cells most
probably represent functionally heterogeneous populations.
Interestingly, there is some evidence that NG2-positive cells
have the ability to differentiate into neurons, both under in
vitro andin vivoconditions, i.e. they mayhavestem-cell-like
properties (Lin and Bergles, 2004). Since stress affects the
proliferation of these cells, and because a fraction of these
new GABAergic neurons (Cameron and Dayer, 2008), this
process might also be affected by stress. The hypothesis that
glial cell loss, either by cell death or by inhibition of adult
of glial cells in the mPFC resulted in comparable depressive-
like behavior as exposing animals to chronic unpredictable
stress (Banasr and Duman, 2008).
Hemispheric specialization of the prefrontal cortex in
the stress response is also present in other mammals including
rodents (Gratton and Sullivan, 2005). A number of studies on
rats have now shown that whereas the right mPFC integrates
emotional and physiological responses to long-term stressful
situations, the left mPFC is more involved in the regulation of
immediate stress responses (Sullivan and Gratton, 2002;
Cerqueira et al., 2008). Interestingly, a recent study found
an intrinsic hemispheric asymmetry in the incidence of
cytogenesis in the adult mPFC, i.e. in the left mPFC, both
the proliferation rate and survival of the newborn cells were
always higher (Fig. 5). Furthermore, chronic stress had a
greater suppressive effect on cytogenesis in the left PFC,
resulting in a reversed asymmetry (Fig. 5) (Czéh et al., 2007).
asymmetry. The higher occurrence of gliogenesis in the left
PFC may indicate the left “dominance” of this region in
normal, unchallenged animals. The stress-induced reversal of
this lateralization resulted in higher incidence of cytogenesis
in the right mPFC, which may reflect hyperactivation of this
area during chronic stress. It is tempting to relate these
preclinical findings to the neuropsychological models of
emotional processing which hypothesize that positive (or
approach-related) emotions are lateralized towards the left
hemisphere, whereas negative (or withdrawal-related) emo-
2004). In humans, electroencephalographic (EEG) studies
relate decreased left hemisphere activation to depressive
conditions, and associate hyperfunction in the right hemi-
sphere with anxiety disorders (Sullivan and Gratton, 2002;
Shenal et al., 2003). Depressed mood has further been
associated with hypometabolism and volumetric reduction
also of the left PFC (Drevets et al., 1997; Drevets, 2000). The
significance of hemispheric lateralization in the regulation of
emotional reactivity and stress responses is not yet under-
stood, but it is clear that this lateralization phenomenon
transcends species and is not restricted to the PFC.
relevant for depression?
Recently, the ‘neurogenic theory’ of depression has been put
forward linking a suppressed rate of adult hippocampal
neurogenesis to (the vulnerability for) depression. This idea
postulates that a reduced production of new neurons in the
hippocampus contributes to the pathogenesis of depression
and that successful antidepressant treatment requires an
enhancement in hippocampal neurogenesis (Duman, 2004;
Sahay and Hen, 2007). The most important building blocks of
this theory were the following findings: 1) stress inhibits
adult hippocampal neurogenesis (in animals) and is a risk
factor for depression in predisposed humans; 2) depressed
patients often have cognitive deficits and smaller hippo-
campal volumes which might be the result of suppressed
neurogenesis or altered cellular turnover rates; 3) antide-
pressant treatment stimulates neurogenesis and reverses the
inhibitory effect of stress; 4) most antidepressant drugs do
not exert their therapeutic effects until after 3–4 weeks of
administration, which parallels the time course of the
maturation of the newly generated neurons; 5) ablation of
hippocampal neurogenesis blocks the behavioral effects of
antidepressant treatment (in mice) (Malberg et al., 2000;
Czéh et al., 2001; Oomen et al., 2007; Santarelli et al., 2003;
Warner-Schmidt and Duman, 2006; Sahay and Hen, 2007).
There are, however, several findings which do not fit into
this concept: 1) depletion of neurogenesis by means other than
like” state in animals (Airan et al., 2007); 2) reductions in
hippocampal volume and in adult neurogenesis are not specific
for depression and have also been implicated in various other
psychiatric disorders (e.g. schizophrenia, dementia, addiction
Revest et al., 2009). Also, both neurogenesis-dependent and -
independent mechanisms of antidepressant action have been
demonstrated (Sahay and Hen, 2007; David et al., 2009) that
may involve growth factors and/or inflammatory mediators
a functional theory that explains how exactly newborn neurons
in the adult hippocampus could contribute to the regulation of
mood, or to a specific symptom of depression. Instead, it has
9 Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation
the cognitive impairments common in the above listed
psychiatric disorders (Kempermann et al., 2008).
Given the technical limitations to visualize neurogenesis
in the live brain of humans, convincing evidence for the
central role of reduced neurogenesis in depression would
have to come from a direct examination of this process in
hippocampal tissue of depressed patients. To date, there are
only two studies that addressed this question. One has been
chronic social defeat stress on adult cytogenesis has been investigated in this cortical region. B: Majority of the newborn cells in the rat
prefrontal cortex differentiate into NG2-positive glia. A confocal microscopy image of a double labelled newly generated glial cell: red
reflects the glial marker NG2, green–yellow is the proliferation marker BrdU labelling a newly generated cell. C–D: Chronic social
stress inhibits both the cell proliferation rate and survival rate of the newly generated cells. Statistics: one-way ANOVA followed by
Student–Newman–Keuls post hoc analysis. E–F: The same data set rearranged in a way that facilitates the hemispheric comparison.
Cytogenesis in the medial prefrontal cortex showed intrinsic hemispheric asymmetry. In control animals, both the cell proliferative
activity (E) and survival rate of newborn cells (F) were always higher in the left hemisphere, whereas chronic stress (stress) reversed
this asymmetry. Statistics: paired t-test. For details see Czéh et al. (2007). (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)
A: The medial prefrontal cortical areas are displayed on a series of plates, modified from a rat brain atlas. The effect of
10 P.J. Lucassen et al.
published by Reif et al. (2006), in which the authors compared
the level of neural stem-cell proliferation in post mortem
brain samples from patients with major depression, bipolar
affective disorder, schizophrenia, and control subjects. They
could not find any evidence of reduced neurogenesis in the
hippocampi of depressed patients. Furthermore, antidepres-
Unexpectedly,significantlyreducednumbers of newly formed
cells were found only in schizophrenic patients. However, this
study was based on a relatively small sample size and further
studies are warranted.
The other more recent post mortem study is by Boldrini
et al. (2009). This compared the number of progenitor and
dividing cells in 7 controls, 5 untreated patients with major
depressive disorder and 7 depressed patients under antide-
serotonin reuptake inhibitors (SSRIs) and three of them with
depressed subjects the number of nestin-positive progenitors
was significantly decreased, while the number of Ki-67-
reactive dividing cells was 50% less than in controls, but this
difference was statistically not significant. Furthermore, both
the SSRI and TCA treatment increased the number of nestin-
positive progenitors and TCAs had a robust stimulatory effect
on the number of Ki-67-reactive dividing cells. But the SSRIs
had no effect on the number of dividing cells. However, one
has to keep in mind that the studies by Reif et al. (2006) and
and further studies with larger samples are warranted. In this
regard one approach which might address this issue more
precisely could be the visualization of neurogenesis in live
subjects using advanced in vivo imaging techniques.
In summary, to date there is no clear convincing clinical
evidence that an altered rate of adult dentate neurogenesis is
critical to the etiology of major depression. Although adult
neurogenesis may not be essential for the development of
depression, it may be required for clinically effective anti-
depressant treatment (Sahay & Hen, 2007; Surget et al., 2008).
Hence, stimulation of neurogenesis has been regarded as a
promising strategy for identifying new antidepressant targets.
Accordingly, when tested in chronic stress paradigms, several
candidate antidepressant compounds, like corticotrophin-
releasing factor (CRF1), vasopressin (V1b) or glucocorticoid
receptor antagonist (Alonso et al., 2004; Oomen et al., 2007;
Surget et al., 2008), tianeptine (Czéh et al., 2001) or selective
neurokinin-1 (NK1) receptor antagonists (Czéh et al., 2005)
could indeed normalize inhibitory effects of stress on prolifera-
approaches, like vagus nerve and deep brain stimulation have
been tested as well (Revesz et al., 2008; Toda et al., 2008).
Future studies will have to reveal whether screening
compounds for their neurogenic potential is a meaningful
approach in drug discovery. Today we know that AN can be
stimulated by almost all currently available antidepressant
located in the SGZ with extensions passing through the GCL. Lower panels display BrdU- and DCX-positive cell numbers in rats
subjected to 21 days of chronic unpredictable stress. The significant reduction in both BrdU- (21 day old cells) and DCX-positive cell
numbers after chronic stress or corticosterone treatment is normalized by 4 days of high dose treatment with the GR antagonist
mifepristone, whereas the drug alone has no effect (see Mayer et al., 2006 and Oomen et al., 2007 for details).
Top panels show examples of BrdU+ and doublecortin (DCX)+ immunostained cells in the DG. DCX-positive somata are
11 Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation
treatments including selective serotonin reuptake inhibitors
(SSRIs), tricyclic antidepressants (TCAs), electroconvulsive
therapy (ECT), atypical antipsychotics and behavioral ther-
apy (Sahay and Hen, 2007; Warner-Schmidt and Duman 2006;
Pollak et al., 2008).
10. Concluding remarks
Stress, glucocorticoids, inflammation and sleep deprivation all
interfere with one or more of the phases of the neurogenetic
process. However, this inhibitory effect can normalize after a
recovery period, voluntary exercise or antidepressant treat-
ment. While adult neurogenesis has been implicated in
cognitive functions, as well as in the regulation of mood and
its functional impact and contribution to the etiology of
depression remains unclear. Admittedly, we still lack a
functional theory that explains how exactly newborn neurons
the regulation of mood, or to specific symptoms of depression,
besides the cognitive deficits, which are not specific to mood
disorders. In view of the currently available evidence, a
reduced rate of neurogenesis may be indicative of impaired
hippocampal plasticity, but by itself alone, reduced AN is
unlikely to produce depression. Lasting reductions in turnover
rate of DG granule cells, however, alter the average age and
overall composition of the DG cell population and will thereby
influence the properties and functioning of the hippocampal
circuit. Whether stress-induced reductions in adult neurogen-
esis occur in humans, awaits further investigations.
Role of the funding source
The ECNP provided funding for the Targeted Expert Meeting held in
Vienna, on 12 October 2007, on the basis of which this report has
All authors have been sufficiently involved in this paper.
Conflict of interest
All the authors declare no conflict of interest.
PJL is supported by the Volkswagen Stiftung Germany, the University
of Amsterdam, the European Union (MCTS NEURAD), Corcept Inc.
and the Nederlandse Hersen Stichting. We are grateful to Dr. J.
Müller-Keuker (MPI Molecular Biomedicine, Münster) for her help in
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