Neuroscience 135 (2005) 659 – 678
REVIEW
THE PATHOGENESIS OF CLINICAL DEPRESSION: STRESSOR- AND
CYTOKINE-INDUCED ALTERATIONS OF NEUROPLASTICITY
S. HAYLEY,a* M. O. POULTER,a Z. MERALIb AND
H. ANISMANa,b
a
Institute of Neuroscience, Carleton University, 1125 Colonel By Drive,
Ottawa, Ontario, Canada K1S 5B6
b
University of Ottawa Institute of Mental Health Research, Department of
Psychology, Department of Psychiatry, Ottawa, Ontario, Canada K1Z 7K4
Abstract—Stressful events promote neurochemical changes
that may be involved in the provocation of depressive disor-
der. In addition to neuroendocrine substrates (e.g. cortico-
tropin releasing hormone, and corticoids) and central neuro-
transmitters (serotonin and GABA), alterations of neuronal
plasticity or even neuronal survival may play a role in depres-
sion. Indeed, depression and chronic stressor exposure typ-
ically reduce levels of growth factors, including brain-derived
neurotrophic factor and anti-apoptotic factors (e.g. bcl-2), as
well as impair processes of neuronal branching and neuro-
genesis. Although such effects may result from elevated cor-
ticoids, they may also stem from activation of the inflamma-
tory immune system, particularly the immune signaling cyto-
kines. In fact, several proinflammatory cytokines, such as
interleukin-1, tumor necrosis factor-␣ and interferon-␥, influ-
ence neuronal functioning through processes involving apo-
ptosis, excitotoxicity, oxidative stress and metabolic de-
rangement. Support for the involvement of cytokines in de-
pression comes from studies showing their elevation in
severe depressive illness and following stressor exposure,
and that cytokine immunotherapy (e.g. interferon-␣) elicited
depressive symptoms that were amenable to antidepressant
treatment. It is suggested that stressors and cytokines share
a common ability to impair neuronal plasticity and at the
same time altering neurotransmission, ultimately contribut-
ing to depression. Thus, depressive illness may be consid-
ered a disorder of neuroplasticity as well as one of neuro-
chemical imbalances, and cytokines may act as mediators of
both aspects of this illness. © 2005 IBRO. Published by
Elsevier Ltd. All rights reserved.
Key words: BDNF, CRH, interleukin, 5-HT, neurogenesis, in-
flammatory.
*Corresponding author. Tel: ⫹1-613-520-2600x6314; fax: ⫹1-613-
520-4052.
E-mail address: shayley@ccs.carleton.ca (S. Hayley).
Abbreviations: ACTH, adrenocorticotropin; AVP, arginine vasopressin;
BDNF, brain-derived neurotrophic factor; BDZ, benzodiazepine; CREB,
cAMP responsive element binding protein; CRH, corticotropin releasing
hormone; CSF, cerebral spinal fluid; ERK, extracellular signal-regulated
kinase; HPA, hypothalamic–pituitary–adrenal; IDO, indoleamine 2,3-di-
oxygenase; IFN, interferon; IL-1, interleukin-1; IL-1ra, interleukin-1 recep-
tor antagonist; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide;
MAP, mitogen-activated protein; NE, norepinephrine; NT-3, neurotro-
phin-3; PFC, prefrontal cortex; PKA, cAMP binding to protein kinase A;
PTSD, post traumatic stress disorder; SSRI, selective serotonin reuptake
inhibitor; TNF-␣, tumor necrosis factor-␣; 5-HT, serotonin.
0306-4522/05$30.00⫹0.00 © 2005 IBRO. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuroscience.2005.03.051
659
Contents
Neurochemical underpinning of depressive illness 660
Neurotrophic factors in depression 662
Neuroplasticity and depression 663
Growth factors in relation to depression 663
Neurogenesis and hippocampal atrophy in depression 664
Changes of neuroplasticity in depression 665
Neurotrophins and cytokines 666
Stress– cytokine– depression connection 667
Cytokine effects on neurochemical activity 667
Proactive effects of cytokines and stressors 668
Cytokines in depression 668
Animal models: sickness and depression 668
Clinical evidence for cytokines in depression 669
Neurodegenerative aspects of depression: cytokine
involvement 670
Concluding remarks 670
Acknowledgments 672
References 672
Appreciation of the processes underlying depressive dis-
orders has increased considerably over the past decades,
both in terms of the neurochemical substrates for the dis-
order as well as some of the psychosocial factors that
promote pathology. Few investigators would argue against
the view that stressful events play a prominent role in the
provocation of depression, particularly in the presence of
genetic vulnerability factors (Caspi et al., 2003). Likewise,
a constellation of psychosocial factors (e.g. coping ability,
previous stressful experiences, familial factors) moderates
the effects of stressful events on depression (Anisman and
Matheson, 2005). It is assumed that these factors come
together to affect neuronal processes, culminating in the
provocation or exacerbation of behavioral pathology.
Uncovering the specific neurochemical mechanisms
subserving depressive illnesses is exceedingly complex,
particularly as depression is often considered to be a bio-
chemically heterogeneous disorder. Indeed, subtypes of
depression exist (e.g. typical vs atypical depression; recur-
rent depression; dysthymic disorder) that may involve sev-
eral common neurochemical features, but also several
distinct differences (Gold and Chrousos, 2002; Griffiths et
al., 2000). Furthermore, just as individuals diagnosed with
a particular form of depression may present with some-
what different symptoms, there is reason to believe that the
processes subserving depression in one individual may
differ markedly from those underlying depression in a sec-
ond individual. The view that multiple neurochemical alter-
ations may instigate depression may account for some of
660 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
the interindividual variability of symptoms presented as
well as the variability, and frequent unpredictability in the
efficacy of drug treatments for depression.
The present review is meant to provide a framework by
which chronic stressful events (or acute events that are
associated with chronic rumination) may come to affect
neurochemical processes that impact on depressive ill-
ness. Essentially, it is argued that chronic stressful events
may instigate the activation of a cascade of neurochemical
and/or inflammatory factors that ultimately affect neuronal
functioning and/or survival, thus influencing depression. In
particular, in this working model chronic stressors or cen-
tral cytokine activation may influence limbic corticotropin
releasing hormone (CRH) functioning and the subsequent
provocation of monoamine disturbances (particularly re-
duced serotonin (5-HT) turnover and altered GABA func-
tioning) that favor the emergence of depressive states. The
CRH, 5-HT and cytokine changes are linked to alterations
of growth/anti-apoptotic factors (e.g. brain-derived neuro-
trophic factor (BDNF) and bcl-2), which may, in turn, affect
neuroplasticity, ultimately resulting in depression. It is also
suggested that parallel pathways exist that could influence
depressive outcomes. Although the individual pathways
linking depression to CRH, cytokines, and growth factors is
well-trod ground, in this review we integrate these pro-
cesses with neurotransmitter systems (5-HT, GABA) that
have been implicated in depressive illness.
Neurochemical underpinning of depressive illness
Depressive illness has long been associated with distur-
bances of brain 5-HT, norepinephrine (NE) and dopamine
activity, variations of 5-HT1A and 5-HT2 receptors, as well
as ␣1-NE or ␤-NE receptors (Maes and Meltzer, 1995;
Schatzberg and Schildkraut, 1995). The data concerning
5-HT variations in depression have probably been the
most widely studied. Evidence in favor of the perspective
that 5-HT is involved in depression comes not only from
studies showing that pharmacological manipulation of
5-HT attenuates depression (Blier, 2003), but also from
postmortem and cerebral spinal fluid (CSF) studies indi-
cating low levels of 5-HT and its metabolite, 5-hydroxyin-
doleacetic acid (5-HIAA), in suicide victims and suicide
attempters. Analyses of depressed suicide brains revealed
morphological and functional disturbances within specific
aspects of the prefrontal cortex (PFC; e.g. dorsomedial
and orbital cortex), as part of a wider system of neuronal
processes that may contribute to the emergence of major
depressive illness (Anguelova et al., 2003a,b; Drevets,
2001). The disturbances that characterize the suicide brain
have included reductions of neurons and glial cells (Ra-
jkowska, 2000), a reduction of cyclic AMP (cAMP) binding
to protein kinase A (PKA), and a decrease of PKA activity
(Dwivedi et al., 2002). Depression was also associated
with an increase of 5HT1A and 5HT2A receptors (Arango et
al., 1995; Escriba et al., 2004; Mann et al., 2000; Pandey
et al., 2002; Zanardi et al., 2001), as well as a decrease of
5-HT transporter sites (Arango et al., 1995; Faludi et al.,
2000; Mann et al., 2000). It also appeared that depressed-
suicide brains were associated with altered 5HT2A receptor
and tryptophan hydroxylase gene polymorphisms (Faludi
et al., 2000) and increased frequency of the 5-HT trans-
porter gene long (L) allele (Du et al., 1999). More recent
data indicated that a 5-HT1A repressor gene promoter in
raphe cells was reduced by a promoter polymorphism.
This suggested that the allele that de-represses 5-HT1A
autoreceptor expression [G(⫺1019)] is potentially respon-
sible for the reduced 5-HT neurotransmission, hence pre-
disposing individuals to depression and suicide (Lemonde
et al., 2003).
The available data have not uniformly supported a role
for 5-HT dysfunctions in depression (Anguelova et al.,
2003a,b; Stockmeier, 2003), as several studies failed to
show a relationship between suicide/depression and 5-HT
functioning (Lowther et al., 1997; Meyer et al., 1999).
Further, analyses controlling for age of subject, postmor-
tem interval (from the time of suicide), and the time of
tissue storage, revealed that differences of 5-HT1A recep-
tors between depressed suicides and controls were not
evident (Stockmeier, 2003; Stockmeier et al., 1997). Over-
all, it seems that the data from postmortem analyses at-
tempting to specify the specific neurochemical distur-
bances related to depression have been inconsistent
(Gross-Isseroff et al., 1998). Certainly, multiple neuro-
transmitters have been implicated in depression, and it is
possible that some of the inconsistencies reported reflect
the complex interactions that may occur between transmit-
ter systems.
As depicted in Fig. 1, there are considerable data
focusing on the possibility that stressor-elicited hypotha-
lamic–pituitary–adrenal (HPA) hormones (CRH, adreno-
corticotropin (ACTH), cortisol) are associated with depres-
sion, as might CRH within extrahypothalamic sites, notably
the amygdala, PFC and locus coeruleus (Holsboer, 2003;
Nemeroff, 1996). There is reason to believe that CRH and
cortisol are not simply bystanders, but play a provocative
role in depression. Consistent with this position, circulating
cortisol levels, as well as CRH concentrations in cerebro-
spinal fluid are elevated among depressed patients (Arato
et al., 1989; Arborelius et al., 1999; Banki et al., 1992;
Heuser et al., 1998; Nemeroff et al., 1984; Wong et al.,
2000). While there have also been reports indicating a
failure to detect elevated CRH within CSF (Kling et al.,
1991; Pitts et al., 1995), it seems that CRH CSF levels
were particularly elevated in those patients who were
dexamethasone nonsuppressors (Roy et al., 1987). Fur-
ther, pharmacotherapy or electroconvulsive therapy nor-
malized the high levels of CSF CRH associated with de-
pression (Heuser et al., 1998; Nemeroff et al., 1991).
The data concerning concentration of CRH and its
receptors in the brain of depressed patients are relatively
limited. Nevertheless, CRH mRNA expression and/or CRH
immunoreactivity was reported to be elevated in hypotha-
lamic nuclei, locus coeruleus and raphe nuclei of de-
pressed suicides (Austin et al., 2003; Bissette et al., 2003;
Raadsheer et al., 1994, 1995). Despite the frequent as-
sumption that disturbances of frontal cortical processes
may be involved in depressive illnesses, data concerning
CRH-related changes in these regions have been sparse
 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678 661

Fig. 1. Working model depicting potential routes by which chronic stressors could impact depressive state. A chronic stressor could potentially
influence cytokine functioning (note that acutely administered stressors increase cytokine activity, whereas chronic stressors, as depicted in the figure,
functionally reduce cytokine activity), excite CRH release, and inhibit BDNF (black lines); CRH may reciprocally modulate GABAA receptor and inhibit
5-HT neuronal functioning within the PFC, hippocampus and amygdala (depicted by green lines), hence leading to depression; 5-HT may influence
levels of growth and anti-apoptotic factors (BDNF and bcl-2, respectively) favoring impaired cellular plasticity and survival, hence promoting depression
(purple lines); cytokine release, which activate the HPA axis, thereby promoting hormonal variations aligned with depression (red lines); (d: depicted
by orange lines) cytokine release may directly impact cell survival or negatively impinge upon neuroplasticity through apoptotic, oxidative or excitotoxic
processes (orange lines); cytokine activity leading to provocation of toxic metabolites, such as IDO which may directly impair 5-HT functioning, or result
in increased accumulation of kynurenine metabolites (3-OH-kynurenine and hippocampal NMDA), which would then act in a neurotoxic capacity (blue
lines), hence promoting behavioral disturbances. These multiple pathways are not considered to be exclusive of one another.
and inconsistent. While Nemeroff et al. (1988) reported in this regard (Dautzenberg and Hauger, 2002; Nemeroff,
reduced CRH binding sites within the frontal cortex of 1996; Reul and Holsboer, 2002). Data such as these have
depressed suicides, neither Hucks et al. (1997) nor Leake been instrumental in prompting the development of thera-
et al. (1990) observed such effects. However, it has been peutic agents for depression that targeted CRH functioning
found that alterations of CRH levels and receptor mRNA (Nemeroff, 1996; Holsboer, 2003).
expression may occur in selective aspects of the PFC Despite the impressive evidence suggesting a relation-
(Merali et al., 2004a). Specifically, among depressed sui- ship between suicide/depression and both 5-HT and CRH
cide victims CRH levels were elevated in the right fronto- functioning, we emphasize again that the available data
polar (FPC) and dorsomedial PFC (only tissue from the have not been unambiguous. Besides the negative find-
right side was assessed in that work), whereas mRNA for
ings reported by Hucks et al. (1997) and Leake et al.
CRH1, but not CRH2 receptors, was reduced. Presumably,
(1990), it was recently reported (Sibille et al., 2004) that
the CRH1 desensitization develops with excessive CRH
suicide was not associated with unique gene expression
activation (Aguilera et al., 2001; Pozzoli et al., 1996). In-
levels within two regions of the PFC (dorsomedial and
deed, it was reported that acute stressors increased CRH
receptor mRNA expression and CRH content in both post- orbital) with respect to CRH, CRH1, CRH2, CRH binding
mortem and in vivo analyses of rodent central amygdala protein, as well as several 5-HT receptors, tryptophan
(Cook, 2001; Merali et al., 1998, 2004b; Merlo et al., 1995). hydroxylase, and the 5-HT transporter. The investigators
Moreover, in chronically stressed animals, a condition that could not readily determine the source for the inconsisten-
may be more similar to the sustained distress of severe cies between their findings and those of numerous other
depression, a decrease of CRH1 expression was provoked studies, but raised the possibility that either these aspects
within PFC (Iredale et al., 1996). Together, these data of the PFC were not related to depression/suicide, or the
support a role for CRH elevations in depression/suicide, genomic differences from controls were below the detec-
and suggest that the CRH1 subtype is particularly pertinent tion limit for the methodology used.
662 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
In addition to CRH involvement in depression, there is
reason to believe that GABA may also contribute in this
respect, particularly as CRH and 5-HT may influence
GABA activity (Sibille et al., 2000; Steiger and Russek,
2004; Tan et al., 2004), thereby influencing mood disor-
ders (e.g. Merali et al., 2004b). Indeed, several sources of
evidence have implicated GABA functioning in depressive
illness, including (a) increased plasma and CSF GABA
levels in depression, (b) the effects of GABA acting agents
on symptoms of depression/anxiety, and (c) the influence
of antidepressants on GABAergic interneuronal function-
ing (Brambilla et al., 2003; Krystal et al., 2002; Petty, 1995;
Shiah and Yatham, 1998; Tunnicliff and Malatynska,
2003). The potential involvement of GABA in depression
was further reinforced by the finding that reciprocal inner-
vation exists between GABA and 5-HT within brain regions
often associated with depression, including the PFC and
hippocampus (Brambilla et al., 2003). Yet, postmortem
brain analyses concerning the involvement of this trans-
mitter in depression have not yielded compelling data.
While GABA levels within the PFC were inversely related
to severity of depression (Honig et al., 1988), conflicting
results were reported showing that neither GABA levels
(Korpi et al., 1988), GABA-related enzymes (Cheetham et
al., 1988; Sherif et al., 1991), the GABA transporter (Sund-
man-Eriksson and Allard, 2002) nor GABAB binding in the
frontal cortex differed between drug-free depressed sui-
cide victims and controls (Cross et al., 1988; Sundman et
al., 1997). Importantly, however, GABAA/BDZ (benzodiaz-
epine) binding sites were elevated in depressed suicides
(Cheetham et al., 1988), indicating that GABAA receptor
subunit expression is likely changed.
An interesting link between 5-HT and GABA receptors
has been reported, essentially indicating that 5HT1A recep-
tors regulate GABAA receptor expression (Sibille et al.,
2000). Specifically, 5-HT1A knockout mice respond poorly
to BDZ anxiolysis, an effect attributed to a loss of GABA
binding sites, and specifically to ␣1 and ␣2 GABAA subunit
decreases in the CA1 and dentate of the hippocampus.
This link between 5-HT receptor status and GABAA recep-
tor expression corroborates the well-known findings that
depressed patients often respond poorly to BDZ therapy
(Roy-Byrne et al., 1996; Schlegel et al., 1994).
Inasmuch as CRH receptors regulate the responsive-
ness of 5-HT receptors, it is important to consider the
involvement of CRH in the GABA-5HT receptor relation-
ship. It seems that CRH potentiates the enhancement of
GABAA receptor inhibition caused by 5-HT application,
suggesting the occurrence of functional cross-talk between
these receptor systems. In this regard, CRH and GABAA
function/expression may be interrelated in that CRH is
uniquely expressed in GAD positive interneurons in rat
cortex and chronic stressors can affect GABAA receptor
expression (Cullinan and Wolfe, 2000). Likewise, GABAer-
gic agents may affect CRH mRNA expression within limbic
sites (Gilmor et al., 2003; Stout et al., 2001).
Given the important role for the PFC in subserving
cognitive processes, including hedonia and behavioral
planning (Kalivas and Nakamura, 1999; Tanji and Hoshi,
2001), coupled with its influence on nucleus accumbens
functioning (a region that may be fundamental in the an-
hedonic features of depression; Stevenson et al., 2003),
we assessed the expression of the ␣ (␣1, ␣2, ␣3, ␣4, ␣5), ␦
and ␥2 receptor subunits that compose the GABAA recep-
tor complex in several aspects of the frontal cortex, namely
the frontopolar, dorsomedial and ventrolateral prefrontal
cortices (Merali et al., 2004a). In addition to the CRH
receptor variations described earlier, mRNA expression of
the ␣1, ␣3, ␣4, and ␦ receptor subunits was reduced in the
frontopolar region of suicide victims. Importantly, our par-
tial analysis of the GABAA receptor functional genome
revealed marked cross-correlations with respect to subunit
expression in cortical regions of nondepressed individuals,
suggesting a high degree of coordinated gene regulation
(Merali et al., 2004b). It was of particular significance that
the GABA subunit intercorrelations were markedly attenu-
ated in suicide brains (with the exception of the interrela-
tions between the ␣2, ␣3 and ␣4 subunits). As an illustrative
example, Fig. 2 shows the scatter plots between ␣1 and
each of the other subunits in frontopolar cortex of control
suicide victims. These findings raise the possibility that the
GABAA receptor subunit changes, or the disturbed coordi-
nation between the GABAA receptor subunits, contribute to
depression/suicide or are secondary to the illness/distress
associated with it. Other investigators have similarly ob-
served coordinated GABAA receptor subunit expression
(␣1, ␣2 ␣3, ␤2/␤3, ␥2, ␦) within dentate granule neurons
(Brooks-Kayal et al., 1999; Kern and Sieghart, 1994;
Mertens et al., 1993), and as the genes for these subunits
appear on different chromosomes, the subunit coordina-
tion could not be attributed to factors related to shared
chromosomal localization (e.g. linkage effects).
It is premature to offer strong positions concerning the
processes subserving the interrelations between CRH and
5HT receptors and the coordinated GABAA subunit ex-
pression. The occurrence of changes within these trans-
mitter systems may be entirely independent of one an-
other, with one affecting a particular attribute of the wide
range of behavioral symptoms that occur in depressed
individuals, while another may be associated with other
characteristics of depressed suicides. It is equally possi-
ble, however, that CRH and GABA systems are related to
one another, and together influence the profile of the de-
pressed suicide. In this respect, as already indicated,
GABAergic acting agents affect limbic CRH mRNA expres-
sion (Gilmor et al., 2003; Stout et al., 2001), and may
contribute to the stressor-provoked CRH response (Culli-
nan and Wolfe, 2000). Thus, just as CRH may influence
monoamine (both NE and 5-HT) neuronal activity, which
could potentially impact depressive states (Ruggiero et al.,
1999), it is possible that CRH-GABA interrelations have
such an effect. Alternatively, CRH variations may instigate
5-HT receptor changes, which then influence frontal corti-
cal GABAA functioning (Tan et al., 2004; Yan et al., 2001).
Neurotrophic factors in depression
Analysis of the underpinnings of depression has increas-
ingly focused on deficiencies of neuroplasticity and im-
 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678 663

Fig. 2. Scatter plots showing relations between the ␣1 GABAA receptor subunit mRNA abundance and those of several other subunits (␣2, ␣3, ␣4, ␣5,
␦ and ␥) in the frontopolar cortex of suicide victims (right hand panels) and controls (left hand panels). Note the tight correlations evident between the
subunit abundance in control brains (most of the cross-correlations between these subunits were significant). In the suicide brains these relations were
limited (data from Merali et al., 2004, which reports all the cross-correlations between these subunits).

paired production of trophic factors (Manji et al., 2001).
The target of experimental agents has included treatments
that promote cell survival such as the growth factor, BDNF,
and the anti-apoptotic protein, bcl-2 (Duman, 2004; Hashi-
moto et al., 2004; Manji and Duman, 2001). These have
received particular attention as stressors and depression
have been implicated in alterations of neuronal plasticity or
even injury, whereas antidepressants may act on path-
ways associated with enhanced cellular plasticity and sur-
vival (see Fig. 1). In this regard, it was shown that infusion
of BDNF into the dorsal raphe nucleus provoked an anti-
depressant-like effect in rodents tested in the learned help-
lessness model of depression (Altar, 1999). The fact that
BDNF also promoted sprouting of central 5-HT neurons
(Altar, 1999) supported the view that its antidepressant
effect may stem from structural remodeling of these neu-
rons. Likewise, infusion of BDNF or the related neurotro-
phin-3 (NT-3) protein into the hippocampus produced an-
tidepressant-like effects in the learned helplessness and
forced swim models of depression (Shirayama et al.,
2002). Limited information is available concerning BDNF in
the brain of depressed individuals. However, it was re-
ported that mRNA and protein levels of BDNF and its
receptor (tyrosine kinase B, TrkB) were lower within the
PFC and hippocampus of suicides than in age- and sex-
matched controls (Dwivedi et al., 2003a). Further, varia-
tions of neurotrophins other than BDNF in human patients
were observed in that CSF levels of NT-3 were elevated in
depressed individuals (Hock et al., 2000).
Neuroplasticity and depression
The belief that depression is strictly a disorder of neuro-
chemical imbalances has undergone reconsideration with
the realization that some degree of impaired neuronal
survival or structural abnormalities may be evident in this
disorder (Harrison, 2002; Manji et al., 2001). Essentially,
the “depressed brain” may be unable to produce appropri-
ate adaptive neuronal responses (e.g. such as changes of
synaptic connections or dendritic branching required to
deal with stressors or other environmental challenges),
hence rendering individuals vulnerable to emotional and
cognitive disturbances. When faced with extreme, unre-
lenting stressors, degeneration of neurons may even occur
(Uno et al., 1994), an effect that may be exacerbated in
depressed individuals.
Growth factors in relation to depression. We have
argued that inflammatory immune system factors might
contribute to many of the neurochemical and neuroplastic
deficiencies associated with clinical depression. Of course,
this is still a controversial issue and it is not even univer-
sally accepted that altered neuroplasticity is a prominent
aspect of depression. In this regard, it is unclear whether
variations of neuroplasticity play a causal role in depres-
sive pathology or are simply a product of the chronic
distress associated with ongoing depression (Duman,
2004; Hayley and Anisman, 2004; MacQueen et al., 2003).
Nevertheless, several studies revealed that stressors im-
664 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
pair neuronal branching, growth and survival (Duman,
2004; Gould and McEwen, 1993; Manji et al., 2003), and
given that stressors precipitate depression, the influence of
these processes warrants continued attention. It ought to
be underscored, as well, that the changes of neuroplastic-
ity may stem from BDNF and bcl-2 variations brought
about by 5-HT changes that may have been induced by
stressors (see Fig. 1). Indeed, 5-HT and BDNF influence
one another, such that 5-HT enhances BDNF expression,
and BDNF ensures 5-HT neuron survival. Thus, stressor-
induced variations of 5-HT may ultimately come to influ-
ence neuroplasticity (Mattson et al., 2004).
As mentioned earlier, depression is a biochemically
heterogeneous disorder, with multiple subtypes (e.g. dys-
thymic and major depressive illness; typical and atypical
subtypes), and alterations of plasticity may only be evident
in certain forms of the disorder. These differences notwith-
standing, several imaging studies have revealed that hip-
pocampal volume was reduced among depressed pa-
tients, and postmortem analyses indicated that this out-
come was directly related to illness duration (Bremner et
al., 2000; Campbell et al., 2004; Sheline et al., 2003) and
was most evident in depressed individuals carrying the
long variant of the 5-HT transporter (Frodl et al., 2004).
Furthermore, symptom remission was associated with hip-
pocampal volume (and lateralization), with non-remitted
individuals showing a greater reduction than patients in
remission (Frodl et al., 2004), particularly within the left
hippocampus (Mervaala et al., 2000; MacMaster and Ku-
sumakar, 2004; Vakili et al., 2000). Others have failed to
find such morphological changes, but did report memory
deficits (Vythilingam et al., 2004). It is also possible that
reduced hippocampal volume may be a risk for depres-
sion, rather than a result of the disorder, as has been
shown in the case of post traumatic stress disorder (PTSD)
(Gilbertson et al., 2002).
Although the mechanisms responsible for reduced hip-
pocampal volume have yet to be determined, a variety of
potential processes have been advanced, including re-
duced neurogenesis, diminished dendritic branching, as
well as induction of excitotoxic and apoptotic death mech-
anisms. Such effects have been linked to the excessive
glucocorticoid activity that is frequently evident among de-
pressed individuals and it is possible that cytokine-medi-
ated neuroinflammatory processes may also be involved
(Ma et al., 2002; Sapolsky, 2000; Stepanichev et al.,
2003). It is important to underscore, however, that most
studies of altered brain architecture involved modifications
of hippocampal volume. Yet, this region is only one of
many that may be involved in depressive illness. To be
sure, various aspects of the PFC, amygdala and hypothal-
amus have been implicated in depression, but data regard-
ing atrophy of these regions have not received equivalent
attention (Harrison, 2002).
Neurogenesis and hippocampal atrophy in depression.
Consistent with a stress model of depression, rodents
exposed to a chronic stressor regimen or corticosterone
treatments displayed impaired hippocampal neurogenesis
(Coyle and Duman, 2003). Consistent with the view that
neurogenesis may be relevant to depression, this impair-
ment was reversed by chronic antidepressant treatment or
by a single session of electroconvulsive shock (Jacobs,
2002). Human postmortem analyses likewise indicated
that neurogenesis was diminished within the hippocampus
of patients suffering from major depression (Kempermann
and Kronenberg, 2003). As alluded to earlier, such an
outcome could come about through several mechanisms,
including the possibility that the altered turnover of 5-HT
ordinarily associated with stressors may provoke distur-
bances of growth factors important in neurogenesis (see
Fig. 1) (Mattson et al., 2004).
Reduced hippocampal volume associated with clinical
depression may be related to the direct actions of glu-
cocorticoids, which are frequently elevated in relatively
severe cases of depression or in response to chronic
stressors (Sapolsky et al., 1985). Specifically, corticoids
impair glucose transport into hippocampal pyramidal neu-
rons, thus resulting in an energetic compromise of these
cells (McEwen, 2001). Glucocorticoids may potentiate el-
evations of free cytosolic calcium, and hence may either
directly impair neuronal survival or render cells vulnerable
to other insults. In addition, corticoids can exacerbate
these vulnerabilities through excitotoxic processes involv-
ing elevations of NMDA and/or AMPA glutamate receptors
(McEwen, 2001). Consistent with this perspective, adre-
nalectomy attenuated the stressor-induced increase of glu-
tamate typically observed in the hippocampus and PFC
(Moghaddam et al., 1994). In addition to excitotoxic pro-
cesses, excessive levels of the hormone may contribute to
free radical accumulation, largely by reducing the capacity
of antioxidant enzymes (Sapolsky, 2000). Ultimately, such
corticoid-mediated effects may lead to either hippocampal
neuronal demise or the regression of pyramidal neuron
dendritic branching (Sapolsky, 2000). Either situation
would elicit a reduction of hippocampal volume like that
observed in chronically depressed patients.
Further support for the damaging effects of stressors
and glucocorticoids comes from studies in monkeys dem-
onstrating that hippocampal implantation of cortisol pellets
for 1 year provoked morphological changes in the hip-
pocampal CA3/CA2 subfields, including irregular cell lay-
ers, soma shrinkage and dendritic atrophy (Sapolsky et al.,
1990). Likewise, in rats, intermittent restraint exacerbated
the hippocampal neuronal loss, as well as expression of
the degenerative marker, tau protein, seen after kainic acid
treatment (Stein-Behrens et al., 1994). Moreover, chronic
corticosterone treatment increased hippocampal neuronal
loss, whereas glial cells displayed abnormal morphology
(Sapolsky et al., 1985). The hippocampal cell loss was also
evident in response to chronic psychosocial stressors.
Specifically, subordinate male tree shrews chronically ex-
posed to a dominant animal displayed reduced apical den-
drite length of hippocampal pyramidal neurons and fewer
dendritic branching points (Magarinos et al., 1996). Simi-
larly, pyramidal neurons within the PFC displayed reduced
apical dendritic branching and length in response to a
chronic restraint stressor regimen (Cook and Wellman,
 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
2004). Paralleling these findings, humans suffering pro-
tracted trauma or PTSD displayed reduced volume of the
cerebral cortex as revealed in imaging studies (Grossman
et al., 2002; Yehuda, 2002). Of course, as already indi-
cated, the latter data are correlational and the possibility
cannot be excluded that among individuals with a dimin-
ished hippocampus, traumatic events may be more likely
to result in PTSD (Gilbertson et al., 2002).
Although corticoids are capable of inhibiting neurogen-
esis (Manji et al., 2003), factors other than these hormones
may be responsible for the observed effects in depression.
In particular, chronic electroshock treatment was associ-
ated with increased neurogenesis, even in the presence of
elevated corticoid levels (Hellsten et al., 2002). It was
similarly reported that the antidepressant, fluoxetine, nor-
malized hippocampal neurogenesis in animals exposed to
inescapable electric footshock, independent of any actions
upon corticosterone (Malberg and Duman, 2003; Malberg
et al., 2000). The finding that drugs that inhibited either
CRH1 or arginine vasopressin (AVP)1b receptors pre-
vented the reduced neurogenesis associated with a
chronic mild stressor (Alonso et al., 2004) points to an
important role for these neuropeptides in the hippocampal
changes evident in affective illness.
Changes of neuroplasticity in depression. Indirect
evidence has pointed to the possibility that apoptotic pro-
cesses might be operative in depression. Specifically,
postmortem analysis revealed modest, in situ end-labeling
for DNA fragmentation in 11 of 15 depressed cases (Lu-
cassen et al., 2001). However, data are unavailable con-
cerning the expression of the prototypical apoptotic initia-
tors, Fas, p53, Bax and downstream caspases in clinical
depression. Importantly, however, it will be recalled that
animal studies indicated that stressor exposure reduced
expression of the anti-apoptotic factor, bcl-2 (Manji and
Chen, 2002; Manji et al., 2003), and exposure to a severe
stressor exacerbated infarct size in response to ischemia
through the suppression of bcl-2 expression (Manji et al.,
2003).
Reductions of BDNF and bcl-2 expression elicited by
stressors have been linked to altered levels of neurotrophic
factors and induction of mitogen-activated protein (MAP)
kinase pathways (Manji and Chen, 2002). In this respect, it
was shown that BDNF was reduced in the serum of de-
pressed patients and the reduction correlated negatively
with the degree of clinical impairment (Shimizu et al.,
2003). Moreover, several clinically beneficial treatments,
including selective serotonin reuptake inhibitors (SSRIs),
tricyclics and electroconvulsive therapy, increased BDNF
expression (Shirayama et al., 2002). In rodents, it was
similarly observed that both acute and chronic immobiliza-
tion reduced BDNF in the hippocampal dentate gyrus
(Smith et al., 1995), and a psychological stressor (explicit
or contextual cues previously paired with footshock) like-
wise reduced BDNF mRNA (Rasmusson et al., 2002).
Inasmuch as the reduced BDNF associated with stressors
was not evident in adrenalectomized animals, the reduced
levels of the neurotrophin were not attributable to stressor-
665
provoked corticosterone release (Smith et al., 1995). Inter-
estingly, however, the reduced BDNF associated with re-
straint was prevented by antidepressant treatment (Duman
et al., 1999). An upregulation of BDNF expression was
also associated with improved performance (i.e. reduced
immobility) among rats in the forced swim test, a paradigm
that has been used to screen antidepressant agents
(Shirayama et al., 2002). While there is certainly evidence
that stressors generally reduce hippocampal or hypotha-
lamic BDNF levels, the observed effects may vary in a
biphasic fashion with the duration of the stressor (Givalois
et al., 2004; Marmigere et al., 2003; Rage et al., 2002), in
that brief stressors of moderate severity may increase
BDNF expression, whereas more extended insults may
have the opposite effect.
The mitogen activated protein (MAP) kinase signaling
pathways may be important for BDNF and bcl-2 function-
ing (Ying et al., 2002; Eom et al., 2004) and may thus play
a role in depression. The three MAP kinase pathways, (1)
extracellular signal-regulated kinase (ERK), (2) c-Jun N-
terminal kinase (JNK; also know as stress-activated pro-
tein kinase) and (3) p38, are thought to play an important
role in cellular responses to environmental events through
the transmission of synaptic signals to the nucleus (Curtis
and Finkbeiner, 1999). These pathways comprise a series
of enzymes that sequentially phosphorylate one another to
promote transcriptional activation and synthesis of proteins
important for cellular survival/death as well as inflamma-
tory processes.
Consistent with a role for MAP kinase pathways in
depression, it was shown that olfactory bulbectomy (which
elicits depressive-like behaviors in rodents) provoked long-
term expression of the immediate early gene, c-Jun, within
the amygdala (Wrynn et al., 2000). c-Jun acts as a final
messenger for the JNK pathway and controls the expres-
sion of several genes that promote either adaptive neuro-
plastic changes to environmental challenges (e.g. thermal
or osmotic stress) or apoptotic responses to highly toxic
insults, including trophic factor withdrawal, traumatic brain
injury or neurotoxin exposure (Cowan and Storey, 2003;
Crocker et al., 2001; Hayley et al., 2004b; Saporito et al.,
2002). Rodents subjected to electroconvulsive shock,
which is used in the treatment of depression, displayed
augmented JNK expression within the amygdala and hip-
pocampus (Brecht et al., 1999). In these same animals,
this treatment initially enhanced phosphorylation (activa-
tion) of c-Jun within the amygdala and hypothalamus, but
diminished with progressive treatment (Brecht et al.,
1999), possibly reflecting ongoing neuroplastic changes
corresponding to the clinical efficacy of electroconvulsive
therapy. As well, protein and mRNA for the MAP kinase,
ERK, were reduced in the hippocampus and PFC of de-
pressed suicide victims (Dwivedi et al., 2001). However,
treatment with the antidepressant, fluoxetine, provoked
expression of the neurotrophic factors, glial-derived neu-
rotrophic factor (GDNF) and deiodinase 3, through activa-
tion of the ERK and p38 kinase pathways, whereas BDNF
expression was dependent on alternate signaling path-
ways (Mercier et al., 2004). Thus, the possibility exists that
666 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
MAP kinases may serve as an interface between signals
regulating neuronal survival and plasticity and those asso-
ciated with emotional state.
In accordance with the position that MAP kinases may
influence or interact with cytokines, and conversely cyto-
kines may affect MAP kinases, it was reported that the p38
MAP kinase pathway might be responsible for the central
induction of tumor necrosis factor-␣ (TNF-␣) and interleu-
kin-1 (IL-1)␤ following traumatic ischemic injury (Piao et
al., 2003). In peripheral tissues, it was likewise observed
that in response to infection (Mycobacterium avium) mac-
rophages produce high levels of TNF-␣ through p38 and
CREB signaling (Roach et al., 2005). Conversely, several
studies also indicated that IL-1␤ influences central expres-
sion of p38, ERK, and JNK central signaling (Lai et al.,
2003; Maher et al., 2004; Minogue et al., 2003). Likewise,
some of the effects of IL-1, including long term potentia-
tion, as well as the neurodegenerative effects of the cyto-
kine, appear to be linked to alterations of JNK and ERK
signaling pathways (Minogue et al., 2003; Wang et al.,
2004).
In addition to MAP kinases, the transcription factor,
cAMP response element binding protein (CREB) may con-
tribute to the regulation of mood state and neuroplasticity
(D’Sa and Duman, 2002). Evidence for the role of CREB in
hippocampal plasticity comes from the finding that CREB
activity, which is regulated upstream by PKA, modulated
hippocampal long-term potentiation (Nguyen and Woo,
2003). Moreover, endogenous PKA activity was reduced in
the PFC of depressed suicide victims, particularly with
respect to the RIIbeta and the catalytic Cbeta regulatory
subunits (Dwivedi et al., 2004a). Likewise, in the dorsome-
dial PFC (granular frontal) of depressed suicides, mRNA
and protein levels of CREB as well as PKA were dimin-
ished (Dwivedi et al., 2003a,b). Postmortem analysis of
antidepressant drug-free patients that had suffered from
major depression also revealed reduced levels of CREB in
both its basal and activated (phosphorylated) state in the
orbitofrontal cortex (Yamada et al., 2003). Further, al-
though limited information is available concerning the in-
fluence of antidepressants on CREB within brain, success-
ful antidepressant-induced clinical responses were asso-
ciated with increased CREB phosphorylation (activation) in
peripheral T lymphocytes (Koch et al., 2002).
In contrast to these findings, increased cortical levels
of CREB have also been reported in suicide victims; how-
ever, these comprised a mixed group of major depressive
and bipolar disorder patients (Odagaki et al., 2001) and as
already indicated, subtypes of the disorder may involve
different signaling mechanisms. In a more recent and de-
tailed analysis, Sibille et al. (2004) observed that within the
dosrsomedial and orbital PFC, neither CREB nor BDNF
gene expression differed between controls and depressed
suicides. As described earlier with respect to CRH and
5-HT, the possibility exists that the absence of gene ex-
pression differences may have been limited to these brain
regions, or the genomic assays were not sufficiently sen-
sitive to detect subtle differences that may exist. Of course,
it is also conceivable, as indicated by Sibille et al. (2004),
that the CREB, BDNF, 5-HT and CRH differences between
controls and depressed suicides that have been reported
by others reflect post-transcriptional effects.
Paralleling some of the findings in human studies,
repeated exposure to inescapable footshock that elicited
behavioral impairments in rats tested in the learned help-
lessness model of depression, was associated with dimin-
ished [(3)H]cAMP binding, PKA activity, and expression of
PKA RIIbeta and Calpha and Cbeta subunits, much like
those observed in the suicide brains (Dwivedi et al.,
2004b). Further, overexpression of CREB within the amyg-
dala, which may be important for anxiety associated with
depression, was associated with an antidepressant-like
response in the learned helplessness model of depression
(Wallace et al., 2004). Importantly, as well, the reduced
CREB expression reported in rodents exposed to a chronic
stressor was up-regulated by 5-HT acting antidepressant
treatments (Lai et al., 2003; Shen et al., 2004). Thus, in our
scheme, CREB activation may arise through increased
5-HT activity (Fig. 1) that would facilitate BDNF production
and ultimately modulate plasticity and hence positive mood
change.
Neurotrophins and cytokines
Cytokines, such as IL-1, IL-2, IL-6 and TNF-␣, serve as
growth factors in peripheral immune cells. These signaling
molecules and their receptors have also been identified
within the brain, increase in response to traumatic brain
injury and neurological disturbances (Roth et al., 2004;
Rothwell, 1999; Vezzani et al., 2000; Wang and Shuaib,
2002), and may contribute to depressive states (Maes,
1999). Depending on a number of factors (e.g. cytokine
concentrations, timing of application, endogenous vs ex-
ogenous source), cytokines may act either in a reparatory
capacity or promote neuronal damage (Stoll et al., 2000;
Allan and Rothwell, 2001). We suggest that the proinflam-
matory cytokines, IL-1, IL-6, TNF-␣ and IFN-␣/␥ promote
deleterious neuronal consequences through activation of
neuroinflammatory cascades involving microglial release
of oxidative species. As depicted in Fig. 1, stressors may
directly or indirectly (through HPA activity) come to af-
fect cytokine functioning, thereby influencing depression
through several downstream processes.
Psychogenic insults affect circulating cytokine levels,
which may influence the organism’s ability to respond to
inflammatory or immunological challenges. The nature of
the stressor effects (i.e. immunoenhancement or immuno-
disturbance) depends on factors such as stressor chronic-
ity (Dhabhar, 2000), and it seems that stressors may pref-
erentially affect certain cytokines (Zhang et al., 1998). It is
of particular relevance to the present argument that just as
acute stressors influence peripheral cytokine activity, such
challenges may also increase cytokine mRNA expression
in brain and increase cytokine protein levels (Miyahara et
al., 2000; Nguyen et al., 1998). In this regard, it was
reported that a neurogenic stressor increased levels of IL-1
in the hypothalamus (Shintani et al., 1995) and in the
hippocampus and nucleus tractus solitarius (Nguyen et al.,
1998). Moreover, pretreatment with the interleukin-1 re-
 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
ceptor antagonist (IL-1ra) prevented the hormonal and
hypothalamic monoamine alterations otherwise elicited by
a psychogenic stressor (Shintani et al., 1995). Together,
these findings raise the possibility that the effects of stres-
sors on central monoamine activity may be mediated
through central cytokine actions.
Ultimately, neurotrophic factors such as BDNF may be
affected by cytokines (possibly through their actions on
5-HT, see Fig. 1), and conversely, certain brain cytokines
(e.g. IL-1␤) may be influenced by BDNF. Moreover, primed
T helper lymphocytes that release anti-inflammatory cyto-
kines, including IL-4 and IL-10, also induce BDNF expres-
sion (Ziemssen et al., 2002). Moreover, intra-hippocampal
infusion of an IL-1 antagonist prevented the reduction of
BDNF mRNA within the dentate gyrus and CA3 region
following social isolation. (Barrientos et al., 2004). In light
of such findings it ought to be considered that cytokines
may influence mood states as a result of processes related
to neuroplasticity, just as interplay between cytokines and
neurotrophins has been implicated in neurodegenerative
illnesses, such as Parkinson’s (Nagatsu et al., 2000). In-
deed, it may well be that the reported high comorbidity
between depression and Parkinson’s disease (McDonald
et al., 2003), may involve similar processes, namely acti-
vation of proinflammatory cytokines and/or inhibition of
anti-inflammatory factors (McDonald et al., 2003). The
same holds true of the high comorbidity that exists be-
tween depression and heart disease (particularly arthero-
sclerosis) where high levels of proinflammatory cytokines
have been detected along with c-reactive protein (Frasure-
Smith et al., 2002).
Certain cytokines, such as IL-6, are considered neuro-
trophic factors as they play a significant role in the preven-
tion of apoptosis and in the differentiation and regeneration
within the CNS (Obara and Nakahata, 2002). Alternatively,
cytokines may have neurotrophic actions through their
effects on BDNF (Murphy et al., 2000). Within peripheral
blood mononuclear cells BDNF also influenced mRNA
expression of TNF-␣, IL-4, as well as transforming growth
factor-␤ (Bayas et al., 2003). Whether such interactions
also occur in brain is uncertain, although it was reported
that systemic lipopolysaccharide (LPS) administration, at
doses that potently increase cytokine activity did not influ-
ence BDNF expression within the dentate gyrus (Shaw et
al., 2001). Yet, it will be recalled that intrahippocampal
pretreatment with IL-1ra prevented the reduction of BDNF
in the CA1, CA2 and dentate gyrus otherwise elicited by
social isolation (Barrientos et al., 2003). Together, these
data are consistent with the view that cytokines may act in
concert with BDNF in affecting cognitive or emotional
processes.
Stress– cytokine– depression connection
As indicated earlier, through their effects on neuroendo-
crine and neurotransmitter functioning, stressors may be
fundamental in the provocation of affective disorders.
Thus, in relating depression to cytokines or to growth
factors, it would seem propitious to consider whether stres-
sors affect these physiological messengers, and whether
667
cytokines are capable of eliciting depressive-like states.
Indeed, systemic cytokine challenges may induce many of
the neurochemical alterations ordinarily associated with
processive stressors (i.e. psychogenic or neurogenic
stressors that involve appraisal of a situation, thus entailing
higher order cortical processing) (Anisman and Merali,
1999; Anisman et al., 2003). In particular, like psychogenic
stressors, IL-1, IL-6 and TNF-␣ provoke a constellation of
behavioral, neuroendocrine and central neurotransmitter
changes that have been implicated in depression. These
include increased plasma levels of glucocorticoids and
ACTH, coupled with augmented turnover of monoamines
within hypothalamic and extrahypothalamic regions (Anis-
man et al., 2003; Hayley et al., 2003). Moreover, as de-
scribed earlier, interplay may exist between neurotrophic
factors and cytokines, which may affect depressive illness
either through the neurochemical changes imparted or by
affecting neurogenesis and cell survival (Fig. 1).
Cytokine effects on neurochemical activity. Like psy-
chogenic and neurogenic stressors, systemic IL-1␤ in-
creased 5-HT utilization within the paraventricular nucleus
of the hypothalamus (PVN), central amygdala, and mPFC.
Moreover, in vivo studies indicated that IL-1␤ administered
systemically or directly into the brain increased hypotha-
lamic NE release as well as that of 5-HT at several limbic
sites (Kamikawa et al., 1998; Linthorst et al., 1995; Merali
et al., 1997; Shintani et al., 1993; Song et al., 1999). The
data concerning the effects of TNF-␣ are less extensive
than those regarding IL-1, but its systemic administration
increased NE and 5-HT utilization in several brain regions
thought to contribute to depression and anxiety (Ando and
Dunn, 1999; Brebner et al., 2000; Hayley et al., 1999).
In addition to the similarities between the effects of
stressors and cytokines, these treatments may synergisti-
cally increase monoamine release from limbic neurons
(Merali et al., 1997; Song et al., 1999). One can likewise
imagine, that the impact of cytokine elevations in humans
might be influenced by the presence of ongoing life stres-
sors or by subsyndromal levels of depression. As such,
analyses of the relationship between inflammatory pro-
cesses and depressive state may benefit from assessing
the moderating role of psychosocial factors.
While our position has been that the neurochemical
alterations imparted by cytokines may influence affective
state (Anisman and Merali, 1999), we emphasize again
that this should not be interpreted to suggest that the
effects of systemic and psychogenic stressors are identi-
cal, nor does it imply that they will have comparable emo-
tional or cognitive repercussions. It would certainly not be
expected that systemic insults, such as immune chal-
lenges, would provoke cognitive disturbances akin to those
elicited by psychogenic challenges, although the influence
of systemic insults may be sensitive to contextual or ex-
periential (e.g. stressor) factors. Furthermore, cytokines
may stimulate HPA activity and other central functions
through pathways different from those utilized by psycho-
genic (e.g. predator exposure, restraint) or neurogenic
(e.g. painful stimuli) stressors (Buller et al., 2001; Dayas et
668 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
al., 1999, 2001; Herman and Cullinan, 1997). Thus, just as
multiple pathways may exist by which stressors come to
affect mood state (Fig. 1), different stressors may activate
diverse neural circuits, and hence may not be equally
effective in promoting depressive symptoms.
At this juncture, it is essential to underscore that the
bulk of the available data have been limited to the effects
of acute cytokine/immune manipulations and limited infor-
mation is available concerning the influence of chronic
activation of the inflammatory immune system. Among
other things, chronic cytokine elevations (as in the case of
IL-2) may result in variations of blood– brain barrier perme-
ability (Banks et al., 2004), thus permitting cytokines (and
other large molecules) greater accessibility to brain sites.
Furthermore, as in the case of stressors (Anisman and
Matheson, 2004), it may be more relevant to assess the
effects of chronic cytokine elevations or repeated cytokine
treatments on depressive symptoms, as viral and bacterial
encounters typically occur on a chronic or subchronic ba-
sis. Under such conditions, the excessive wear and tear on
physiological systems may be sufficiently great (allostatic
overload), thus rendering the organism less well prepared
to contend with further insults (McEwen, 2001).
Proactive effects of cytokines and stressors. Sys-
temic and central cytokine administration increases the
response to stressors or further cytokine exposure (Anis-
man et al., 2003; Hayley et al., 2003; Schmidt et al., 1996;
Tilders and Schmidt, 1999; Tilders et al., 1993). For in-
stance, stressors not only increased central IL-1␤ levels,
but also augmented the effects of subsequent central ad-
ministration of LPS on brain IL-1 levels. In contrast, among
rats pretreated with IL-1ra the effects of the stressor treat-
ment were attenuated (Johnson et al., 2004). In addition to
the sensitization of cytokine processes in brain, stressors,
IL-1␤ and TNF-␣ time-dependently increased the co-ex-
pression of CRH and AVP within the external zone of the
median eminence, although the time course varied across
treatments. Thus, the co-release of CRH and AVP upon
subsequent challenge with stressor or cytokine treatments
synergistically stimulated ACTH secretion from the anterior
pituitary (Hayley et al., 1999, 2002; Schmidt et al., 1996;
Tilders and Schmidt, 1999). On the basis of such findings
the possibility exists that exposure to stressful events (in-
cluding activation of the inflammatory immune system)
may dispose animals to greater vulnerability to stressor-
related pathology. The time course for these vulnerabilities
is not fully known, nor is it clear whether there are periods
during which animals are particularly vulnerable to the
development of sensitized responses. However, numerous
reports have indicated that adverse events encountered
early in life may augment the adult response to stressors,
whereas positive events (e.g. high levels of maternal care)
may have the effect of buffering against the effects of later
stressors (Meaney, 2001). While any number of factors
could potentially influence these processes, it is significant
that early life stimulation related to maternal care in-
creased BDNF mRNA expression and may thus have con-
tributed to the stressor resilience seen in adulthood (Liu et
al., 2000).
Just as limited maternal attention (extended separation
from the dam or low levels of licking and grooming by the
dam) favored elevated neuroendocrine responses to stres-
sors encountered in adulthood (Meaney, 2001), rat pups
exposed to a bacterial endotoxin, subsequently (as adults)
exhibited increased stressor-elicited corticosterone and
neuroimmune responses (Shanks et al., 2000; Boisse et
al., 2004). Whether this neuroendocrine plasticity involves
the same systems as those governing the stress sensiti-
zation is uncertain, but it does seem to involve at least
some of the same circuitry. Of particular relevance to the
present report is that early life immunological insults, like
other stressors, could potentially affect vulnerability to de-
pression owing to the greater reactivity of stress-relevant
circuits, particularly those related to CRH and monoamine
activity.
It is uncertain whether sensitization processes associ-
ated with stressors or cytokines affect BDNF, bcl-2 or other
normally protective factors, although there are inferential
data consistent with this possibility. Specifically, adminis-
tration of BDNF into the ventral tegmentum may elicit a
behavioral sensitization characterized by progressively
greater motor activity with repeated treatments (Pierce et
al., 1999; Guillin et al., 2001). As well, BDNF induced a
behavioral sensitization to L-DOPA by triggering overex-
pression of the D3 receptor within the basal ganglia (Guillin
et al., 2001; Sokoloff et al., 2002).
Cytokines in depression
Animal models: sickness and depression. Adminis-
tration of cytokines, such as IL-1␤, or activation of macro-
phages and other inflammatory immune cells by systemic
LPS treatment, provokes behavioral symptoms (reduced
locomotion, increased sleep, curled body posture, ptosis,
piloerection) collectively referred to as sickness behavior
(Maier and Watkins, 1998; Dantzer, 2001). Although these
behaviors are thought to be of adaptive significance, as
they may serve to minimize energy expenditure, they are
also reminiscent of the neurovegetative features of depres-
sion, albeit in themselves they do not reflect the core
symptoms of depression. However, in addition to the sick-
ness behaviors, cytokines disrupt operant responding
for reinforcement and elicit reduced social exploration
(Dantzer, 2001; Merali et al., 2003). Although such effects
may be secondary to the malaise induced by cytokines,
rather than characteristics of depression per se, these
same features may reflect changes in motivational state
(e.g. anhedonia). In fact, studies employing progressive
ratio schedules of reinforcement (i.e. these tap into the
degree to which an animal is willing to respond in order to
gain a reward) indicated that cytokines act on incentive
motivational forces (drive) independent of effects related to
malaise (Larson et al., 2002; Merali et al., 2003). More-
over, antidepressant treatment attenuated the decreased
responding for a palatable snack ordinarily elicited by
IL-1␤, but without influencing the reduced chow intake
provoked by the cytokine (Merali et al., 2003).
 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
As in the case of food-motivated behavior, it has been
shown that LPS may affect responding for rewarding brain
stimulation (in this instance electrodes were positioned
within the lateral hypothalamus) (Borowski et al., 1998). As
this paradigm does not involve food reward, the reduced
responding cannot be ascribed to anorexia, but instead
likely reflects disturbances of incentive motivation. How-
ever, it did appear that the effectiveness of LPS in disrupt-
ing responding was related to the intensity of the stimula-
tion, possibly suggesting that the effects of the treatment
reflected the cost:benefit relationship. Together, these
data, and other related findings have supported the view
that beyond the neurovegetative effects of inflammatory
immune activation, the treatments may promote anhedo-
nia, a fundamental feature of depressive illness.
Clinical evidence for cytokines in depression. De-
pressed patients, particularly those presenting with melan-
cholic illness, exhibit disturbances of several aspects of
immune functioning, including altered circulating lympho-
cyte subsets, reduced mitogen-stimulated lymphocyte pro-
liferation, and impaired natural killer cytotoxicity, although
equivocal results have been reported (Irwin, 1999; Maes,
1999). Yet, depression was also associated with immune
activation reminiscent of an acute phase response, includ-
ing increased plasma concentrations of complement pro-
teins, C3 and C4, IgM, and positive acute phase proteins,
haptoglobin, ␣1-antitrypsin, ␣1 and ␣2 macroglobulin, and
reduced negative acute phase proteins (Maes, 1999; Ro-
thermundt et al., 2001).
Commensurate with the view that depressive illness
might be secondary to activation of the inflammatory im-
mune system (Maes, 1999), severe depressive illness was
accompanied by elevated circulating cytokines or their
soluble receptors, including IL-2, soluble IL-2 receptors
(sIL-2R), IL-1␤, IL-1ra, IL-6, soluble IL-6 receptor (sIL-6R),
and ␥-interferon (IFN) (Anisman et al., 1999; Maes, 1999;
Mullar and Ackenheil, 1998; Nassberger and Traskman-
Bendz, 1993; Sluzewska, 1999). Moreover, increased pro-
duction of IL-1␤, IL-6 and TNF-␣ was evident in mitogen-
stimulated lymphocytes, and the magnitude of these effects
was related to severity of illness (Maes, 1999), and chronicity
of illness in the case of IL-1␤ (Anisman et al., 1999).
In addition to cytokine differences between depressed
and non-depressed individuals, cytokines or immune chal-
lenges in humans may provoke depressive-like symptom-
atology. For instance, healthy volunteers that received a
low dose of LPS or vaccinated with live attenuated rubella
virus displayed depressed mood up to 10 weeks following
the challenge, and protracted periods of anxiety and mem-
ory deficits were elicited by endotoxin (Yirmiya et al.,
1999). Furthermore, among patients undergoing IL-2 or
IFN-␣ immunotherapy for hepatitis C or certain forms of
cancer, marked cognitive disturbances and neurovegeta-
tive symptoms frequently emerged (Valentine et al., 1995;
Dieperink et al., 2000, 2003). Generally, these neuropsy-
chiatric symptoms included fatigue, sleep disturbances,
irritability, appetite suppression and depressed mood. In
fact, the affective symptoms that often emerged were di-
669
agnosed as reflecting major depression, sometimes of
sufficient severity to necessitate discontinuation of therapy
(Denicoff et al., 1987; Meyers and Valentine, 1995;
Miyaoka et al., 1999; Musselman et al., 2001; Maes et al.,
2001; Bonaccorso et al., 2002a,b; Capuron et al., 2000,
2002; Wichers and Maes, 2002; Maes and Bonaccorso,
2004). Not surprisingly, patients that exhibited subsyndro-
mal levels of depression prior to cytokine therapy were
those most likely to develop the most pronounced depres-
sive illness in response to the cytokine (Capuron et al.,
2004).
It is of both practical and theoretical importance that
depressive symptoms elicited by IFN-␣ were attenuated
among patients that received conventional SSRI antide-
pressant treatments, including sertraline, citalopram and
paroxetine (Schramm et al., 2000; Musselman et al., 2001;
Hauser et al., 2002; Kraus et al., 2002). Moreover, the
course of symptom evolution, as well as the amelioration of
symptoms in relation to antidepressant medication, sug-
gests that the neurovegetative and mood-related symp-
toms introduced by immunotherapy are independent of
one another. Specifically, the neurovegetative symptoms
elicited by IFN-␣ (e.g. anorexia, fatigue and pain) fre-
quently appeared within 2 weeks of treatment commence-
ment, whereas depressed mood, anxiety and cognitive
dysfunction tended to appear later. The latter symptoms
were also more responsive to antidepressant medication
than were the neurovegetative symptoms (Capuron et
al., 2002). These findings raise the possibility that the
cytokine effects involve more than a single process, and
as such it is reasonable to expect that depression
to systemic challenges that activate the inflammatory
immune system might likewise induce disparate symp-
toms.
As described earlier, cytokine-elicited depression may
evolve owing to effects on biogenic amines, or by their
potential impact on BDNF and bcl-2 expression, thereby
affecting cellular viability and hence functioning. However,
Maes et al. (2001), Capuron et al., (2003) and Bonaccorso
et al. (2002a,b) provided an alternative scenario as to how
cytokines might influence neurochemical functioning, while
taking into account the effects on cell survival. Specifically,
as illustrated in Fig. 1, these investigators indicated that
IFN-␣ as well as several proinflammatory cytokines
(TNF-␣, IL-1␤, IFN-␥) increased the activity of the 5-HT
transporter, which may reduce extracellular 5-HT levels.
As will be recalled, IFN-␣ increases indoleamine 2,3-dioxy-
genase (IDO) which is responsible for the catabolism of
tryptophan to kynurenine (Menkes and MacDonald, 2000).
Thus, elevations of this enzyme may diminish the avail-
ability of tryptophan and hence reduce brain 5-HT con-
centrations. In fact, depressive affect that followed cy-
tokine therapy was accompanied by reduced tryptophan
and elevated levels of kynurenine (Bonaccorso et al.,
2002a,b). Yet, despite the inverse relationship between
tryptophan and depressive symptoms, one cannot con-
clude a causal relationship from these data. Among
other things, metabolites of kynurenine, such as 3-hy-
droxy-kynurenine and quinolinic acid, through the induc-
670 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
tion of reactive oxygen species or stimulation of hip-
pocampal NMDA receptors, may promote tissue dam-
age leading to depression (Wichers and Maes, 2004).
Furthermore, as described in Fig. 1, it is possible that
cytokines, through their actions on 5-HT and BDNF
(which co-regulate one another) may contribute to the
pathogenesis of depression as well as age-related neu-
rodegenerative disorders (Mattson et al., 2004).
Neurodegenerative aspects of depression: cytokine in-
volvement. Cytokines and other neuroinflammatory fac-
tors are in a position to influence cellular viability, and there
is a substantial literature exploring the potential effects of
cytokines on neurodegeneration. Certainly, this field has
been controversial, and it will be recalled that some find-
ings indicate that cytokines act in a reparatory capacity,
whereas other studies suggest that cytokines function in a
neurodestructive manner (Allan and Rothwell, 2001).
These differential effects may be related to cytokine con-
centrations and genetic background of the host organism,
as well as timing of exposure to the cytokine relative to
various to insults. These differences not withstanding, con-
siderable evidence has indicated that proinflammatory cy-
tokines, notably TNF-␣ and IL-1␤, provoke neuronal loss
through several possible mechanisms. In particular, cyto-
kines, such as TNF-␣, may induce apoptotic conse-
quences due to their actions on intracellular caspase-re-
lated pathways (Varfolomeev and Ashkenazi, 2004), or
they may affect cell survival through extracellular mecha-
nisms, including excitotoxic processes that involve gluta-
mate activity (Silverstein et al., 1997; Rothwell, 1999;
Allan, 2002). Additionally, the proinflammatory cytokine,
IFN-␥, as well as endotoxins may elicit the release of free
radicals from microglia (Pawate et al., 2004), thereby pro-
moting oxidative injury. Finally, as described earlier, cyto-
kines might mediate neurodegeneration through the pro-
motion of metabolic toxins, such as 3-hydroxy-kynurenine
and quinolinc acid, which themselves are increased in
depression (Wichers and Maes, 2004). These kynurenine
metabolites can synergistically induce free radical gener-
ation and have been implicated in a number of neurode-
generative diseases, including Huntington’s and Parkin-
son’s, and have been implicated in AIDS dementia (Wich-
ers and Maes, 2004).
It will be recalled that macrophage-derived inflamma-
tory factors were hypothesized to influence mood states
(Smith, 1991). The common myeloid lineage and the strik-
ing similarity of functioning between peripheral macro-
phages and brain microglia raise the possibility of common
involvement of these cell types in depression. Indeed,
microglia are the primary central reservoirs of proinflam-
matory cytokines, and like macrophages, they act as anti-
gen presenting cells within the brain (Hanisch, 2002).
Thus, these cells may function to orchestrate central im-
mune responses that may have deleterious consequences
on local tissue. In this regard, microglia release several
cytokines (IL-1, IL-6, IL-8, TNF-␣ and IFN-␥) in response to
various stressful and traumatic stimuli (e.g. seizure, stroke,
head injury) and over the course of neurodegenerative
disorders (e.g. Parkinsonism, Alzheimer’s disease, multi-
ple sclerosis), and may thus contribute to cognitive and
mood processes associated with these illnesses (Pocock
and Liddle, 2001; Hanisch, 2002; Vezzani et al., 2002).
Concluding remarks
As depicted in Fig. 1, multiple factors may contribute to
depression by impairing neuronal plasticity and disturbing
neurochemical functioning in key mood regulatory brain
regions. In this review we suggested that cytokines play an
integral role in provoking these two outcomes through their
pleiotropic effects upon several physiological systems, in-
cluding (1) HPA axis activity and CRH activity at limbic
sites, (2) monoamine utilization, (3) microglial release of
oxidative species, (4) apoptotic pathways and (5) MAP
kinase and CREB signaling. Essentially, we argued that
stressors and other environmental insults augment proin-
flammatory cytokine expression while concomitantly low-
ering levels of normally beneficial growth or neuroprotec-
tive factors. Such effects trigger a cascade of molecular
events involving promotion of inflammatory and apoptotic
pathways, which may ultimately impair cellular plasticity or
even survival and hence lead to abnormal neurotransmis-
sion favoring the evolution of depression.
To be sure, the processes that subserve stressor-
provoked depression remain to be fully elucidated. How-
ever, evidence exists supporting a role for 5-HT and CRH
involvement in depression, and that 5-HT variations may
inhibit GABAA receptor subunit expression, thereby pro-
moting depressive symptoms. As well, through its action
on ACTH and glucocorticoids, CRH may influence cytokine
functioning and its downstream processes, including 5-HT
changes as well as neuroplasticity. In addition to the path-
ways depicted in the figure, corticoids may also result in
increased deoxycorticosterone release and the production
of its metabolite, tetrahydroxydeoxycorticosterone (THDOC),
which has a positive effect on GABAA functioning (Reddy,
2003).
Beyond the potential role for CRH and monoamine
disturbances, variations of growth factors and anti-apop-
totic factors, as well as cytokines, might contribute to de-
pression. Stressors, it will be recalled, reduce hippocampal
BDNF and bcl-2, possibly through effects on corticoste-
rone release, although other neural circuits may also lead
to such an outcome. Stressors also increase cytokine ex-
pression in brain, which could promote CRH release,
hence eliciting 5-HT neuronal alterations. Alternatively, cy-
tokines may cause the reduction of 5-HT levels through
activation of indoleamine-pyrrole 2, 3-dioxygenase (IDO),
the enzyme responsible for the catabolism of tryptophan to
kynurenine. As depicted in Fig. 1, kynurenine metabolites
(3-hydroxy-kynurenine and quinolinic acid) affect reactive
oxygen species or stimulate hippocampal NMDA recep-
tors, hence promoting tissue damage, possibly leading to
depression (Wichers and Maes, 2004).
Ultimately, in considering the processes that subserve
depressive illness it is essential to account for some of the
phenomenological aspects of the disorder. Symptoms of
depression differ markedly across individuals (although
 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
common features are typically present), and subtypes of
depression exist that may involve different neurochemical
substrates. Subtypes of depression are characterized by
different symptom profiles, may be differentially responsive
to various classes of antidepressant therapy, and may
involve different neurochemical substrates. For instance,
while typical depression involves reduced eating and
sleep, in atypical depressive disorder reversed neuroveg-
etative features predominate (i.e. increased eating, partic-
ularly carbohydrate craving, increased sleep, fatigue; Gold
and Chrousos, 2002). Likewise, melancholic depression
may involve processes in addition to those seen in less
severe forms of depressive illness, and chronic depres-
sion, even of moderate severity (dysthymia), may be as-
sociated with biological processes that are less prominent
in more acute illness (Griffiths et al., 2000). Whereas mel-
ancholic depression may be related to CRH neuronal hy-
perfunctioning, atypical depression was aligned with down-
regulated HPA activity, including CRH deficiency (Anisman
et al., 1999; Gold and Chrousos, 2002). Furthermore, as
cytokine immunotherapy (using IFN-␣) gives rise to de-
pression where neurovegetative symptoms appear in ad-
vance of the affective features, and are more resistant to
antidepressant treatment than are the mood disturbances
(Capuron et al., 2002), it might be considered that cytokine
activation has its primary effect on typical depression,
while the neurovegetative changes are a reflection of sick-
ness provoked by the cytokine.
The elevated CRH associated with melancholic (typi-
cal) depression is consistent with the potent HPA stimulat-
ing actions of pro-inflammatory cytokines. In a similar fash-
ion, the argument can be advanced that high levels of
comorbid anxiety may be related to elevated CRH func-
tioning in central amygdala or bed nucleus of the stria
terminalis (Walker and Davis, 1997), or altered functioning
of CRH and hence NE activity in locus coeruleus-related
processes (Asbach et al., 2001; Brady, 1994). Further-
more, the presence of dopamine disturbances, particularly
within tegmental and accumbal regions, may be linked to
depressive episodes where anhedonia is an essential fea-
ture, especially as this transmitter has been aligned with
reward processes (Wise, 2004). Likewise, given the role of
frontal cortical 5-HT in cognitive processes, behavioral
planning (Kalivas and Nakamura, 1999; Tanji and Hoshi,
2001) and impulsive behaviors (Evenden, 1999), it is pos-
sible that disturbances of this transmitter might be associ-
ated with suicide (Purselle and Nemeroff, 2003). One can
be less certain about the specific symptoms associated
with BDNF and bcl-2 variations, as most of the available
data have been obtained from studies of the hippocampus,
but there is reason to suppose that growth factors are
affected in other brain regions (e.g. animal studies re-
vealed stressor effects on BDNF in cortical regions; Hashi-
moto et al., 2004) and could potentially influence a variety
of neurotransmitter systems. Certainly, some of the sug-
gestions offered here are highly provisional. Nevertheless,
the array of neurochemical processes linked to depressive
illness suggests that while common underlying processes
may be associated with all types of depression (and in all
671
individuals), interindividual and subtype differences may
exist with respect to the presence of certain neurochemical
disturbances.
It will be recalled that depression is comorbid with a
variety of pathological states. These range from other psy-
chiatric disorders (e.g. posttraumatic stress disorder;
Brady et al., 2000) or psychological symptoms (e.g. anxi-
ety) through to heart disease (Frasure-Smith et al., 2002)
and neurodegenerative disorders, such as Parkinsonism
(McDonald et al., 2003). It is unlikely that the psychological
distress associated with these illnesses provoked the de-
pression, as the affective disorder frequently preceded the
physical illness (e.g. Grippo et al., 2003a). Instead, it has
been argued that the comorbidities stem from processes
common across disorders, and indeed each of these ill-
nesses can be linked to inflammatory processes (Maes,
1999; Gao et al., 2003; Rattazzi et al., 2003; Grippo et al.,
2003a,b; Hayley et al., 2004). In effect, it is possible that
cytokines or related factors are a common denominator for
these diverse pathologies.
A third feature of depression that needs to be ad-
dressed is the view that this disorder may be a life-long
illness given its very high rate of recurrence (50 –70% in 5
years; Keller, 2002). Coupled with this, is the fact that 5-HT
and NE acting antidepressants have positive treatment
effects (despite the high rates of placebo response) in only
about two thirds of patients. To account for these aspects
of the disorder it could be argued that certain individuals
are more emotionally reactive to stressful events, or pos-
sess a pre-morbid depressive personality, hence making
them prone to depression given the presence of environ-
mental triggers. Alternatively, it can be argued that neuro-
nal and neurochemical changes akin to those described in
this review are responsible for the persistence of depres-
sion. In particular, as indicated earlier, stressful experi-
ences (including those encountered early in life) and acti-
vation of the inflammatory immune system may result in
phenotypic changes of CRH neurons within the median
eminence, so that they come to co-express AVP (Tilders
and Schmidt, 1999; Hayley et al., 2001). The conjoint
release of these peptides may promote greater HPA acti-
vation and may thus contribute to depression. Importantly,
the CRH/AVP co-expression is fairly long lasting and
hence may influence mood changes long after the initial
stressor experience (Tilders and Schmidt, 1999). In fact, it
has been suggested that certain illnesses, such as dyst-
hymia (low grade, chronic depression), are associated with
a change of basal CRH/AVP levels so that these individ-
uals are particularly vulnerable to major depressive illness
(i.e. double depression) (Griffiths et al., 2000).
Yet another alternative to accommodate the persis-
tence of the depressive vulnerability concerns potential
effects of stressors, as well as cytokines, on neuroplastic-
ity. As already indicated, such insults, by virtue of effects
on BDNF and bcl-2, or by affecting the kyneurenine path-
way or other oxidative/excitotoxic processes, may result in
altered dendritic branching or suppression of neurogen-
esis. From this perspective, antidepressants may be af-
fecting depressive states by altering factors responsible for
672 S. Hayley et al. / Neuroscience 135 (2005) 659 – 678
neuroplasticity (e.g. 5-HT functioning) without actually af-
fecting those factors that lead to the 5-HT alterations (e.g.
CRH/AVP), and hence may be masking symptoms rather
than treating the disease. Thus, with treatment cessation,
and the persistence of the initial neurochemical dysfunc-
tion, major depression has an increased likelihood of re-
emerging. Ultimately, it may be profitable to focus on com-
bined therapeutic strategies that involve factors (e.g. cyto-
kines) that come to affect neuroplasticity, or those that
influence the way in which stressors come to affect neu-
rotransmitter or neurohormone functioning.
Acknowledgments—Supported by funds from the Natural Science
and Engineering Research Council of Canada (NSERC) and by
the Canadian Institutes of Health Research (CIHR). S.H. and H.A.
are CIHR Canada Research Chairs.
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