The stress system in depression and neurodegeneration - GeneQol

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Review

The stress system in depression and neurodegeneration:Focus on the human hypothalamus

A.-M. Baoa,⁎, G. Meynena,b, D.F. Swaaba

aNetherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The NetherlandsbGGZ Buitenamstel, Hogguerstraat 1183, 1164 EK Amsterdam, The Netherlands

A R T I C L E I N F O

⁎ Corresponding author. Fax: + 31 20 69610006E-mail address: [email protected] (A.

0165-0173/$ – see front matter © 2007 Elsevidoi:10.1016/j.brainresrev.2007.04.005

A B S T R A C T

Article history:Accepted 21 April 2007Available online 27 April 2007

The stress response is mediated by the hypothalamo–pituitary–adrenal (HPA) system.Activity of the corticotropin-releasing hormone (CRH) neurons in the hypothalamicparaventricular nucleus (PVN) forms the basis of the activity of the HPA-axis. The CRHneurons induce adrenocorticotropin (ACTH) release from the pituitary, which subsequentlycauses cortisol release from the adrenal cortex. The CRH neurons co-express vasopressin(AVP) which potentiates the CRH effects. CRH neurons project not only to the medianeminence but also into brain areas where they, e.g., regulate the adrenal innervation of theautonomic system and affect mood. The hypothalamo-neurohypophysial system is alsoinvolved in stress response. It releases AVP from the PVN and the supraoptic nucleus (SON)and oxytocin (OXT) from the PVN via the neurohypophysis into the bloodstream. Thesuprachiasmatic nucleus (SCN), the hypothalamic clock, is responsible for the rhythmicchanges of the stress system. Both centrally released CRH and increased levels of cortisolcontribute to the signs and symptoms of depression. Symptoms of depression can beinduced in experimental animals by intracerebroventricular injection of CRH. Depression isalso a frequent side effect of glucocorticoid treatment and of the symptoms of Cushing'ssyndrome. The AVP neurons in the hypothalamic PVN and SON are also activated indepression, which contributes to the increased release of ACTH from the pituitary.Increased levels of circulating AVP are also associated with the risk for suicide. Theprevalence, incidence andmorbidity risk for depression are higher in females than in malesand fluctuations in sex hormone levels are considered to be involved in the etiology. About40% of the activated CRH neurons in mood disorders co-express nuclear estrogen receptor(ER)-α in the PVN, while estrogen-responsive elements have been found in the CRH genepromoter region, and estrogens stimulate CRH production. An androgen-responsiveelement in the CRH gene promoter region initiates a suppressing effect on CRHexpression. The decreased activity of the SCN is the basis for the disturbances ofcircadian and circannual fluctuations in mood, sleep and hormonal rhythms found indepression. Neuronal loss was also reported in the hippocampus of stressed orcorticosteroid-treated rodents and primates. Because of the inhibitory control of thehippocampus on the HPA-axis, damage to this structure was expected to disinhibit the HPA-axis, and to cause a positive feedforward cascade of increasing glucocorticoid levels over

Keywords:StressHypothalamusDepressionAlzheimer's diseaseHypothalamo–pituitary–adrenal axisCorticotropin-releasing hormoneVasopressinOxytocinAdrenocorticotropinGlucocorticoidSex steroidsThe suprachiasmatic nucleusCircadian rhythm

.-M. Bao).

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time. This ‘glucocorticoid cascade hypothesis’ of stress and hippocampal damage wasproposed to be causally involved in age-related accumulation of hippocampal damage indisorders like Alzheimer's disease and depression. However, in postmortem studies wecould not find the presumed hippocampal damage of steroid overexposure in eitherdepressed patients or in patients treated with synthetic steroids.

© 2007 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5321.1. The stress system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532

1.1.1. The HPA-axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5321.1.2. HPA–HPG-axis interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533

1.2. Sex and age differences in the stress system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5331.3. Circadian fluctuations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534

2. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5352.1. The stress system in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535

2.1.1. The CRH hypothesis of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5362.1.2. AVP hypothesis of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5372.1.3. Glucocorticoids in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538

2.2. Causes of HPA-axis hyperactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5382.3. Sex differences and reproductive stages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5382.4. Sex hormone level fluctuations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5392.5. The circadian system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5402.6. Influence of the cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540

3. Alzheimer's disease (AD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5413.1. The stress system in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5413.2. AD and sex hormones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5423.3. Hippocampal damage in AD and depression: is the glucocorticoid cascade hypothesis valid . . . . . . . . . . . . 543

4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546

1. Introduction

1.1. The stress system

1.1.1. The HPA-axisAs pointed out for the first time by Hans Selye in Nature in 1936(Selye, 1998), stress or ‘noxious agents’ initiate a reaction in thebody, which he called the ‘general adaptation syndrome’ (GAS).Selye distinguished three stages that the body passes whenresponding to stress in the GAS: 1) the first stage is an ‘alarmreaction’, in which the body prepares itself for ‘fight or flight’; 2)the second stage of adaptation (provided the organism survivesthe first stage), is one inwhich a resistance to the stress is built;and 3) finally, if the duration of the stress is sufficiently long, thebody enters a stage of exhaustion, a sort of aging, due to ‘wearand tear’. Although the stress response of the body is meant tomaintain stability or homeostasis, long-term activation of thestress system can have a hazardous or even lethal effect on thebody, increasing the risk of obesity, heart disease, depression,and a variety of other illnesses.

The hypothalamo–pituitary–adrenal (HPA) system is the finalcommon pathway in the mediation of the stress response.Briefly, the hypothalamus releases corticotropin-releasing hor-mone (CRH) in response to a stressor, CRH acts on the pituitary

gland, triggering the release of adrenocorticotropin (ACTH) intothe bloodstream,which subsequently causes the hormonal end-product of the HPA-axis, corticosteroid release from the adrenalcortex (mainly cortisol in humans). Cortisol normally exerts anegative feedback effect to shut down the stress response afterthe threat has passed, acting upon the levels of the pituitary andhypothalamus. Cortisol is a major stress hormone that acts onmany organs and brain areas through two types of receptors, i.e.the mineralocorticoid receptor (MR) and the glucocorticoidreceptor (GR), which have a specific and selective distributionin the brain (Reul and de Kloet, 1985). GRs have been found inmultiple brain regions such as the hippocampus, amygdala andprefrontal cortex, which are relevant to cognition. These regionsare also actively involved in feedback regulation of the HPA-axis.Moreover, stimulation by corticosteroids can be exerted at thelevel of the amygdala, the prefrontal cortex and the brain stem(locus coeruleus), interfering with HPA activity and stress effectson memory (Quirarte et al., 1997; Roozendaal, 2002; Fuchs et al.,2004). CRH-expressing neurons in the hypothalamic PVN projectnot only to the median eminence but also to other brain areas,where they regulate the adrenal innervation and thus thesensitivity of the adrenal for ACTH via the autonomic system(Buijs and Kalsbeek, 2001). Besides the role of a crucialneuropeptide which regulates the HPA-axis, CRH also shows

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central effects, including cardiovascular regulation, respiration,appetite control, stress-related behavior and mood, cerebralblood flow regulation and stress-induced analgesia (for reviewsee (Swaab, 2003)). Part of the CRH neurons in the hypothalamicPVN co-express arginine vasopressin (AVP). When releasedtogether into the portal capillaries, AVP strongly potentiatesthe ACTH-releasing activity (Gillies et al., 1982; Rivier and Vale,1983). In addition, circulating AVP from the supraoptic nucleus(SON) may induce ACTH release from the pituitary (Gispen-deWied et al., 1992).

CRH and AVP mediate ACTH release via different secondmessenger systems (Won andOrth, 1990;Won et al., 1993, 1990).CRH activates G protein-linked adenylate cyclase, leading tocAMP formation and protein-kinase-A activation. AVP worksthrough a specificAVP receptor subtype termedV1borV3,whichis almost exclusively expressed by pituitary corticotrophs (Reneet al., 2000), and activates only phospholipase C. The V3 receptoris required for a normal pituitary and adrenal response to someacute stressful stimuli, and is necessary for a normal ACTHresponse during chronic stress (Lolait et al., 2006). The number ofCRH and AVP-colocalizing neurons is increased during activa-tion, such as in multiple sclerosis (MS) (Erkut et al., 1995),depression and during the course of aging—at least in males(Raadsheer et al., 1993, 1994b; Bao and Swaab, 2007). V3 receptormRNA levels and coupling of the receptor to phospholipase C arestimulated by glucocorticoids. Consequently, AVP up-regulationmay be critical for sustaining the corticotrophic responsivenessin the presence of high circulating glucocorticoid levels duringchronic stress or depression (Aguilera and Rabadan-Diehl, 2000).Oxytocin (OXT), on the other hand, inhibits ACTH release, afinding that has been confirmed in humans (Legros, 2001) andthat provides an example of the various opposite actions of AVPandOXT. Following different types of corticosteroid treatment indifferent disorders or during the presence of high levels ofendogenous corticosteroids produced by a tumor, we found, inpostmortem tissue, not only that CRH-expressing neurons arehard to detect, but also that AVP expression in the SON and PVNis strongly decreased. OXT neurons were not affected, whichfurther illustrates that, in the human brain, selective negative-feedbackof cortisol ispresent in theCRHcells and incells that co-express AVP (Erkut et al., 2004, 1998). The glucocorticoid-inducedsuppression of AVP-synthesis has been proposed to occur at theposttranscriptional level (Erkut et al., 1998, 2002b).

1.1.2. HPA–HPG-axis interactionStress suppresses the reproductive systemat various levels: CRHprevents the release of the hypothalamic luteinizing hormone-releasing hormone (LHRH=GnRH) which signals a cascade ofhormones that direct reproduction and sexual behavior. Cortisoland related glucocorticoid hormones not only inhibit the releaseof LHRH, but also inhibit LH-induced ovulation and spermrelease. In addition, glucocorticoids inhibit the testes and ovariesdirectly, hindering production of the male and female sex hor-mones (Swaab, 2003). CRH fibers from the PVNdo not only run tothe portal capillaries but also innervate LHRH neurons in theinfundibular nucleus, which may be one of the substrates forCRH control of reproductive functions (Dudas and Merchentha-ler, 2003). On the other hand, the hypothalamic–pituitary–gonadal (HPG) axis also exerts extensive effects on the HPA-axis. Sex hormones partially control CRH gene expression. Both

the nuclear estrogen receptor (ERα) (Bao et al., 2005) and thenuclear androgen receptor (AR) (Bao et al., 2006) are found to becolocalized with CRH neurons in the human hypothalamic PVN.In addition, an up-regulation of CRH and nuclear ERα wasobserved in mood disorders, both in males and females (Baoet al., 2005). There are five perfect half-palindromic estrogen-responsive elements (EREs) in the human CRH gene region,which may confer direct estrogenic regulation of human CRHgene expression (Vamvakopoulos and Chrousos, 1993). Anandrogen-responsive-element (ARE) that initiates a repressingeffect of AR on CRH gene expression in the human CRH genepromoter regionhas also been localized recently (Baoet al., 2006).Ovarian steroids have been found to increase HPA-axis activity,enhance the HPA-axis response to psychological stress, andsensitize theHPG-axis to stress-induced inhibition inhumanandrhesus monkey (Kirschbaum et al., 1996; Roy et al., 1999).

1.2. Sex and age differences in the stress system

Sex-related differences in the stress response are well-knownfrom the animal experimental literature, but in humans thefindings seemed inconsistent, probably, at least partly, due to thedifferentmethods used to stimulate the HPA-axis and to the ageof the subjects. Gender-related differences in sex hormone levelsfurther confound the specific role of the gender in HPA-axisresponsivity. Over the past decade, however, the situation hasbecome much clearer as a result of the development of psy-chological tests that generate adequate HPA-axis responses, forexample the Trier Social Stress Test (Kirschbaum et al., 1993;Dickerson and Kemeny, 2004; Kudielka and Kirschbaum, 2005).The conclusion of these studies is that sex differences in thebasal, unstressedstatearesubtlebutbecomegreatlypronouncedfollowing a psychological stressor. Although there are excep-tions, in general between puberty andmenopause, the HPA-axisand autonomic responses tend to be lower in women comparedto men of the same age (Kajantie and Phillips, 2006). Recently,Rocaetal. have found that, comparedwithage-matchedwomen,young to middle-aged (18–45 years) men showed increasedstimulatedACTHandcortisol, to either pharmacological (CRH) orphysiological (exercise) stressors during pharmacological sup-pression of the gonadal axis. In addition, the secretion of cortisolafter exercise and the initial secretion (0–30 min) of ACTH toeither of the stressorswere significantly larger inmen comparedto women. These data demonstrate that sex differences in theHPA-axis exist even in the absence of characteristic sex dif-ferences in reproductive steroids (Roca et al., 2005).

It has also been found that elderlymenactivate theHPA-axisto a greater extent than women in response to psychologicalstress (Traustadottir et al., 2003;Kudielka etal., 1998;Uhart et al.,2006). Our group has also recently found gender differences inthe number of CRH expressing neurons in the human hypotha-lamic PVN, namely: 1) there is a significant age-related increaseof CRH neurons in men, but not in women; and 2) men havesignificant more CRH neurons than women from the age of24 years onward (Fig. 1). We also showed that an abnormalhormone status, induced by castration, ovariectomy or sexhormone-producing tumor, was accompanied by changes inCRH neuron number (Fig. 2) (Bao and Swaab, 2007). The in-creased number of CRH neurons in the human PVN may beinterpreted as a sign of activation of the CRH neurons, because

Fig. 2 – The total number of corticotropin-releasing hormone(CRH)-immunoreactive neurons in the hypothalamicparaventricular nucleus (PVN) of control males and subjectswith abnormal sex hormone status. Values of control-male-group (E, solid line), castrated-male-group (D, dashed line), and‘extended group’, i.e. the castrated-male-group (D) plus an


in situ hybridization of CRH mRNA analyzed in the samepatients gave the same results under such varied chroniccircumstances as depression, hypertension and MS (Huitingaet al., 2004; Goncharuk et al., 2002; Raadsheer et al., 1995). More-over, duringaging, cortisol levels in thecerebral spinal fluid (CSF)and in plasma are found to increase progressively between theages of 20 and 80 years (Laughlin and Barrett-Connor, 2000).

Age-relatedactivationofCRHneurons couldbedue to a seriesof factors, such as a decreased function of the hippocampus,which suppresses the activity of theHPA-axis andwhich ismoresensitive to the process of aging than the PVN (Giordano et al.,2005;Miller andO'Callaghan,2005)(seebelow). In this respect, it isof interest that a sex difference has also been reported inhippocampal aging, e.g., a significant age-related decline ofhippocampal volumewas found inmenbutnot inwomen (Bouixet al., 2005; Pruessner et al., 2001). Increasing insensitivity of theHPA-axis to the feedback of cortisol may be another factorinvolved in the activation of the HPA-axis during aging(Goncharova and Lapin, 2002). Baseline AVP levels were foundto be significantly higher in elderly subjects compared withyoung subjects (Rubin et al., 2002), whichmay also stimulate theHPA-axis. In addition, a sex difference was reported in AVPplasma levels. Men have higher AVP levels than women (vanLonden et al., 1997; Asplund and Aberg, 1991), which agrees withthe observation that the posterior lobe of the pituitary, whereAVP and OXT are released into the circulation, is larger in boysthan in girls (Takano et al., 1999). These sex differences areexplained by the higher metabolic activity we found in AVP

Fig. 1 – The total number of corticotropin-releasing hormone(CRH)-immunoreactive neurons in the hypothalamicparaventricular nucleus (PVN) of control males (E) and females(●). The control males had significantly (p = 0.004) more CRHneurons thancontrol females fromage24onwardsandshoweda significantly positive correlation (the solid line) between ageand the total number of CRHneurons. The control female groupdid not show significant correlation (the dashed line) betweenage and the total number of CRH neurons. (From Bao andSwaab, 2007, Fig. 2, with permission.)

ovariectomized female-to-male (F–M) transsexual (q, dashedline), are delineated by a minimum convex polygon,respectively. Note that the total number of CRH neurons in thePVN of the 5 castrated males (n= 5, age = 67) is significantly(p = 0.008) lower than that of the matched old control males(n = 5, age = 66). Such a significant difference remained(p = 0.009) when the ovariectomized F–M transsexual wasincluded in the ‘extended group’ (n = 6, age = 51) comparedwiththematched controlmales (n = 6, age = 50). The total numbers ofCRH neurons in the three M–F castrated-with-estrogen-replacementM–F transsexuals (○) were significantly larger thanthose in the castration group (p = 0.036) and the ‘extendedgroup’ (p = 0.024), while there was no significant differencewhen compared with age-matched control males (age 50–70,n= 6, p = 0.905; or age 50–78, n = 5, p = 1.000). The 31-year-oldmale with an estrogen-producing adrenal tumor (□) had a veryhigh total number (16832) of CRH neurons in the PVN. M–Ftranssexual: male-to-female transsexual; F–M transsexual:female-to-male transsexual; Feminizing tumor: estrogen-producing adrenal tumor. (From Bao and Swaab, 2007, Fig. 3,with permission.)

neurons in the SON in young men as compared to women, asdetermined by the size of the Golgi apparatus (Ishunina et al.,1999).

1.3. Circadian fluctuations

The stress response is strongly influenced by the time of day. Thehypothalamicsuprachiasmaticnucleus (SCN), thebiological clock,is responsible for the rhythmic changes of the stress system. The

Table 1 – Findings supporting the involvement of thestress system in depression

CRH hypothesis⋅ CRH neuron number in PVN increased (Raadsheer et al.,1994a; Bao et al., 2005).⋅ AVP colocalization in CRH neurons in PVN increased(Raadsheer et al., 1994a).⋅ CRH mRNA in the PVN increased (Raadsheer et al., 1995).⋅ CRH in CSF increased (Banki et al., 1992).⋅ CRH-R1 SNP (Liu et al., 2006b).⋅ Anti-depressants decrease CSF CRH (Heuser et al., 1998).⋅ CRH-R1 antagonists: anti-depressants (O'Brien et al., 2001a;Keck and Holsboer, 2001).⋅ CRH i.c.v. in rat induces symptoms (Holsboer, 2001).⋅ Transgenic mouse overproducing CRH: anxious(Stenzel-Poore et al., 1994).


SCN innervates brain areas in the human hypothalamic region(Dai et al., 1997, 1998a,b) imposing its rhythm also onto the bodyvia threedifferent routesof communication: 1)Via thesecretionofhormones; 2) via the parasympathetic autonomous nervoussystem and 3) via the sympathetic autonomous nervous system.The SCN uses separate connections via either the sympathetic orthe parasympathetic system, not only to prepare the body for theimpending change in activity cycle but also to sensitize the bodyand its organs for the hormones that are associated with such achange (Buijs et al., 2006). We have also found CRH fibers in thearea of the SCN (Bao et al., 2005; Bao and Swaab, 2007), whichsuggests the existence of a bi-directional direct anatomicalconnection between the SCN and the PVN. The function of suchan anatomical connection in health and disease deserves furtherstudy.

Vasopressin hypothesis⋅ AVP and OXT neuron numbers increased (Purba et al., 1996).⋅ AVP mRNA increased in SON, and in melancholic depressionin both PVN and SON (Meynen et al., 2006).⋅ Elevated AVP plasma levels in depression (van Londen et al.,1997), normalizing when patients improve (van Londen, 2003).⋅ Colocalization of AVP and CRH increased (Raadsheer et al.,1994a).⋅ Depressed patients who attempted suicide had higher plasmaAVP levels compared to those who did not (Inder et al., 1997).⋅ Anxious-retarded (melancholic) depression: relation with plasmaAVP and cortisol (de Winter et al., 2003).⋅ Animal model: after antidepressant, decrease of elevated AVPmRNA in PVN (Keck et al., 2003).⋅ SNP in AVP V1b receptor protects against recurrent MD(van West et al., 2004).⋅ AVP-deficient Brattleboro rats: AVP involved indevelopment of depression-like behavior (Mlynarik et al., 2006).

Glucocorticoid hypothesis⋅ Increased level of corticosteroids and decreased level ofCRH in atypical depression (Gold et al., 1995; Gold andChrousos, 2002).⋅ Side effect of glucocorticoid treatment: depression(Mitchell and O'Keane, 1998).⋅ Atypical depression found in a large proportion of Cushing'ssyndrome (Gold et al., 1995; Dorn et al., 1995).⋅ SNPs GR gene NR3C1 (van West et al., 2006).⋅ Inhibitors of cortisol production (metyrapone,aminoglutethamide, ketoconazole): anti-depressants(Reus et al., 1997; Murphy, 1997).⋅ GR-antagonist (mifepristone (RU486)) for psychoticdepression (Gold et al., 2002; Belanoff et al., 2002).

AVP: arginine vasopressin/vasopressin; CRH: corticotropin-releas-ing hormone; CRH-R: CRH receptor; CSF: cerebral spinal fluid; GR:glucocorticoid receptor; NR3C1: Nuclear Receptor Subfamily 3,Group C, Member 1; OXT: oxytocin; PVN: paraventricular nucleus;SNPs: single-nucleotide polymorphisms; SON: supraoptic nucleus.

2. Depression

2.1. The stress system in depression

TheHPA-axis is considered to be the ‘final commonpathway’ fora major part of the depressive symptomatology. A large part ofthe environmental and genetic risk factors for depression appearto correlatewith increasedHPA-axis activity in adulthood.Whenpatients or animals in models for depression are treated withantidepressants, electroconvulsive therapy,orwhenpatientsshowspontaneous remission, theHPA-axis function returns tonormal(Nemeroff, 1996). Stressful life events such as child abuse andearly maternal separation form risk factors for later depressionand anxiety disorder (for review see Swaab et al., 2005). Prenatalenvironmental stressors of a chemical nature, such as nicotineexposure due to smoking of the pregnant mother, may sensitizea subject for developing depression in later life, especiallychildren who were either light or heavy at birth (Clark et al.,1996; Clark, 1998). Childhood abuse is an early stressor that maypredispose individuals to adult onset depression accompaniedby a permanent hyperactivity of the HPA system (Tarullo andGunnar, 2006). In addition, small size at birth is associated withan alteration in the set-point of the HPA-axis and an increasedcortisol responsiveness and risk of depression in adulthood(Phillips, 2001; Thompson et al., 2001).

In addition to these robust and well-established indicationsfor a hypothalamic hyperdrive, there are various othermeasuresthat point to a causal and primary role for an increasedHPA-axisactivity in depression (Pariante, 2003). First, it is generally knownthat stressful life events are among the most potent factors thatcan triggerdepressiveepisodes (Kendler et al., 1999; Paykel, 2001).Second, elevated plasma and salivary cortisol and cortisonelevels, increased urinary free cortisol excretion, disturbed dexa-methasone suppression, decreased corticosteroid receptor func-tion, an enhanced adrenal response to ACTH, a blunted pituitaryACTH response to CRH as well as adrenal and pituitary enlarge-ment have been found in patients suffering from depression(Scott andDinan, 1998; Krishnan et al., 1991b; O'Brien et al., 1996;Rubinetal., 1996;Modell etal., 1997;Maesetal., 1998;Weberetal.,2000; Holsboer, 2000). The combined dexamethasone/CRH testdoes not only identify, with high sensitivity, a dysfunction of theHPA-axis in depression; the elevated cortisol response in the testalso correlateswitha 4–6-foldhigher risk for relapse compared to

individuals who had a depression but subsequently showed anormal cortisol response (Zobel et al., 2001). Moreover, studies inhigh-risk probands of patients with major depression haveshown that abnormalities in HPA-axis function already existprior to the onset of the clinical symptoms, suggesting that suchabnormalities not only correlate but can, in fact, also precipitatedepressive episodes (Holsboer, 2000). Increased ACTH secretionoccurred in depressed in-patients regardless of cortisolemicstatus, confirming central HPA-axis overdrive in severe depres-

Fig. 4 – Total hybridization signal for humancorticotropin-releasing hormone (CRH) mRNA (arbitrary units)in the paraventricular nucleus (PVN). Bars indicate medianvalues per patient group. The PVN of the Alzheimer patients(n = 10) contained significantly more (MW; U=23.0, W=0.78,Z =−2.0, p = 0.04) CRH mRNA than that of comparison subjects(n = 10). The amount of radioactivity in depressed patients(n = 7) was significantly higher than in comparison cases (MW;U=7.0, W=91.0, Z = −2.7, p = 0.006) and Alzheimer's diseasepatients (MW; U=23.0, W=0.78, Z = −2.0, p = 0.05). (FromRaadsheer et al., 1995, Fig. 2, with permission.)

Fig. 3 – The total number of CRH-expressing neurons in thePVN of human subjects at different ages. ●, 10 control subjects;D, 6 bipolar or major depressed patients;□, 2 ‘non-majordepressed’ subjectswith either an organicmood syndromeor adepressive episode not otherwise specified. Note the highnumber of neurons expressing CRH in bipolar and majordepressed patients. (From Raadsheer et al., 1994a, Fig. 2, withpermission.)


sion (Carroll et al., 2007). Recent studies in patients withpsychotic depression also support the concept that treatmentaimed directly at interfering with the consequences of HPA-axisabnormalities, such as treatment with high doses of GR-antagonist, would reverse the clinical symptoms (Belanoffet al., 2002).

2.1.1. The CRH hypothesis of depressionSeveral findings have pointed towards a central role of CRH inthe neurobiology of depression. CRH neurons are stronglyactivated in depression. First, a fourfold increase in thenumber of CRH neurons in the PVN has been found. Second,the number of CRH neurons co-expressing AVP is increased,and third, the amount of CRHmRNA in the PVN is increased indepressed subjects compared to controls (Raadsheer et al.,1994a, 1995) (see Table 1; Figs. 3 and 4). The central effects ofincreased amounts of CRH may be responsible for at leastsome of the signs and symptoms of depression. The observa-tion that a significant improvement in mood occurred inpatients with treatment-resistant depression who receiveddexamethasone while remaining on their antidepressant(sertraline or fluoxetine) treatment supports the concept ofhyperactive CRH neurons playing a causal role in the symp-tomatology of depression (Dinan et al., 1997). An importantargument for a crucial role for central effects of CRH in de-pression is that similar symptoms such as decreased foodintake, decreased sexual activity, disturbed sleep and motorbehavior, and increased anxiety can all be induced inexperimental animals by intracerebroventricular injection ofCRH (Holsboer, 2001). The recently found single-nucleotidepolymorphisms (SNPs) in CRH receptor1 (CRHR1) gene,

associated with increased susceptibility to major depression(Liu et al., 2006b), is an argument for the direct involvement ofCRH in the symptomatology of depression. Antidepressantdrugs attenuate the synthesis of CRH by stimulation and/orupregulation of corticosteroid receptor expression (Barden,1996). In addition, the CRH concentrations in CSF in healthyvolunteers and depressed patients decrease due to antide-pressant drugs (Heuser et al., 1998), although it should benoted that CSF-CRH is also derived from other brain areas,such as the cortex (see below). Moreover, a transgenic mousemodel with an overproduction of CRH appeared to haveincreased anxiogenic behavior, i.e. symptoms that are usuallyrelated with major depression, that could be counteracted byinjection of a CRH antagonist (Stenzel-Poore et al., 1994).Lastly, CRH-receptor antagonists may be effective in thetreatment of depression (Grammatopoulos and Chrousos,2002; Keck and Holsboer, 2001). Together, the argumentsmentioned above have led to the CRH-hypothesis of depression,i.e., hyperactivity of CRH neurons, and thus of the HPA-axis,induce the symptoms of depression.

Although some negative neuroendocrine findings seem tosuggest that CRH might not be involved in the pathogenesis

Fig. 6 – Oxytocin mRNA in the paraventricular nucleus (PVN).*Statistically significant difference (p bbbb 0.05). Contr, controls;non-mel, non-melancholic type depressed patients; mel,melancholic type depressed patients. Bars show means. Errorbars indicate the S.E.M. A.u.=arbitrary units. (From Meynenet al., 2007a, Fig. 1, with permission).


of depression, we should realize that the endocrine measure-ments leading to these findings relate to the CRH neuronsthat project to the periphery. Actually, the CRH-hypothesis ofdepression may still hold for these cases, since this hypoth-esis includes the idea that a subgroup of CRH neurons thatproject to brain areas other than the median eminence areactivated in depression and induce the symptoms. Thesesubgroup CRH neurons are not monitored endocrinologicallyin the periphery.

2.1.2. AVP hypothesis of depressionOtherneuropeptides involved in the symptomsofdepressionareAVP andOXT. In the PVNof patientswithmajor depression, AVPand OXT neurons are activated as well (Purba et al., 1996), whichmay have functional consequences for HPA-axis reactivity(Table 1). There is also an enhanced pituitary AVP responsivityin depression (Dinan et al., 1999). It is important to note that,whereas inacute stressCRH is themaincauseof increasedACTHrelease, animal experiments show that in chronic stress there isa switch fromCRH toAVP stimulation ofACTH release (Scott andDinan, 1998). Since depression is, by definition, a state that lastsfor weeks at a minimum, these observations could indicate thatHPA-axis hyperactivity in depression may be AVP-driven ratherthan CRH-driven.

Interestingly, the SON also shows enhanced AVP mRNAproduction in depression (Meynen et al., 2006) (Fig. 5). This maybe related to the increased plasma levels of AVP (van Londenet al., 1997, 1998, 2001) and to an enhanced suicide risk (Inderet al., 1997). Considering the possibility that AVP produced in theSONmay not only be the source of increased AVP plasma levels,but may also be responsible for the HPA-axis hyperdrive in de-pression, two points are of relevance. First, animal studies showthat the release of magnocellular AVP, originating in the PVN orSON, might also take place in the median eminence and thus in

Fig. 5 – Amount of vasopressin (AVP) mRNA signal in thesupraoptic nucleus (SON) and paraventricular nucleus (PVN) indepressed subjects (n = 9). *Statistically significant difference atp bbbb 0.05. Bars show means, error bars indicate the S.E.M.; a.u.,arbitrary units. (From Meynen et al., 2006, Fig. 1, withpermission.)

the portal system, where it might potentiate ACTH release(Antoni, 1993; Wotjak et al., 1996). Second, it is possible that anincreasedAVP release fromtheSON into the systemic circulationcontributes to the increased ACTH release from the pituitary. Aclear indication that AVP in the systemic circulationmight play arole in HPA-axis regulation is provided by the finding of (Gispen-de Wied et al., 1992), that intravenous administration of AVPresults in increased levels of ACTH and cortisol in both controlsand depressed subjects. Another indication is the finding thatplasmaAVP levels are positively correlatedwith cortisol levels indepression as observed in different studies (Brunner et al., 2002;deWinter et al., 2003; Inder et al., 1997). Furthermore, theremightbe a feedback mechanism between the HPA-axis and the SONand PVN: GRs are present in both the PVN and SON in rats(Morimoto et al., 1996), as well as in rhesus monkeys (Sanchezet al., 2000). In humans we have found that AVP is not onlyreduced in the PVN but also in the SON in response to increasedglucocorticoidplasma levels (Erkut et al., 1998). A recent study onAVP-deficient Brattleboro rats has shown that AVP is involved inthe development of depression-like behavior, in particular of thecoping styleandanhedonia.Moreover, behavioral andendocrineresponseswere found to be dissociated. It is suggested that brainvasopressinergic circuits other than from those regulating theHPA-axis are involved in generating depression-like behavior(Mlynarik et al., 2006), a finding which deserves further study inhuman.Amajor SNPhaplotype of theAVPV1b receptorhas beenfound to protect against recurrent major depression (van Westet al., 2004), supporting the possibility of a direct involvement ofAVP in depression.

The parallel activation of OXT neurons has been connectedwith decreased appetite and weight loss in depression due to thecentral effects of this neuropeptide as a satiety hormone (GimplandFahrenholz, 2001; Purbaetal., 1996;Meynenetal., 2007a). Lossof weight is one of the features of melancholic type depression.Interestingly, it was found recently that OXT mRNA is increasedin melancholic type depressed patients compared to non-


melancholic type depressed patients. In addition, in the groupstudied, the highest amount of OXT mRNA was found in amelancholic type depressed subject who had lost 16 kg during adepressiveepisode in the last yearofher life (Meynenet al., 2007a)(Fig. 6).

2.1.3. Glucocorticoids in depressionThere are also observations that point to a causal role forglucocorticoids in depression. Using awhole gene-based associationanalysis of SNPs, genetic variations in the GR gene (NuclearReceptor Subfamily 3, Group C, Member 1; NR3C1) have beenexamined and the data suggest that polymorphisms in the 5'region of the NR3C1 gene may play a role in the geneticvulnerability for major depression (van West et al., 2006). A fewstudies have reported that glucocorticoid (receptor) antagonistsmay be effective in the treatment of major depression (Murphy,1997; Wolkowitz et al., 1999), supporting the idea of an in-volvement of glucocorticoids in depression. Inhibitors of cortisolproduction such as metyrapone, aminoglutethamide or ketoco-nazole, may result in clinical success in major depressedpatients, which is not to be expected if an increase in CRH itselfwould be the cause of all the symptoms (Reus et al., 1997;Murphy, 1997). The GR antagonist mifepristone (RU486) iseffective in treating psychotic depression, producing clinicallyrelevant responses at high dosages in considerable numbers ofpatientswithina fewdaysof treatment (Goldet al., 2002; Belanoffet al., 2002). This is in clear contrast with most classic anti-depressants that generally need at least weeks to take effect.Unfortunately, these compounds inducemanyunspecific effects(Holsboer and Barden, 1996).

It is proposed that the severe, ‘melancholic type of depres-sion’, characterized by symptoms such as loss of pleasure in all(or almost all) activities, lack of mood reactivity to usuallypleasurable stimuli, worse mood in the morning, early morningawakening and significant anorexia orweight loss, would be dueto a hyperactivity of CRH neurons (Gold and Chrousos, 2002). Incontrast, ‘atypical depression’, a state of hyperphagia, hyper-somnia, enhanced affected responsiveness to external stimuli,lethargy and fatigue would be based upon increased levels ofcorticosteroids and decreased levels of CRH (Gold et al., 1995;Gold and Chrousos, 2002). Indeed, CRH receptor antagonists,cortisol synthesis inhibitors, and corticosteroid receptor antago-nists have all been reported effective in some depressed patients(Holsboer, 2000; Gold et al., 2002). In addition, a well-known sideeffect of glucocorticoid treatment is depression, while one-thirdof the patients who are receiving glucocorticoids experiencesignificant mood disturbances (Mitchell and O'Keane, 1998).Moreover, atypical depression is found in a large proportion ofCushing's syndrome patients, especially those with longer du-ration (Gold et al., 1995; Dorn et al., 1995),which indicates that anelevated level of cortisol, rather than of CRH, causes this type ofdepression. This conclusion is supported by a small study thatshowed that depression can be treated with ketoconazole, anantiglucocorticoid (Wolkowitz et al., 1999), and by the observa-tion that metyrapone successfully treats depression in Cushingpatients (Checkley, 1996) (Table 1). However, it should be notedthat after correction of the hypercortisolism in Cushing'ssyndrome, atypical depression frequently continues to bepresent and suicidal ideation and panic may even increase(Dorn et al., 1997).

2.2. Causes of HPA-axis hyperactivity

The increase inHPA-axis activity inmany depressed cases raisesthequestionof thepossible underlyingpathogenicmechanisms.So far, an imbalance in the ratio between MR and GR has beenshown indepressedpatients (Young et al., 2003) but it is not clearwhether this should be considered cause or effect. Impairednegative feedback control of the HPA-axis and adrenal hyper-trophy are commonly found in a subgroup of depressed patients(Checkley, 1996; Modell et al., 1997). They coincide with episodesof depression and reverse, at least partially, after recovery. Someobservations suggest that the impaired negative corticosteroidfeedbackon theHPA-axis inanumberofhealthyprobandsat riskfor affective disorder is caused by a disturbed corticosteroidreceptor function, indicating a genetically transmitted risk factor(Holsboer et al., 1995; Holsboer, 2000). Genetic variations (poly-morphisms) of the GR may explain why only some 50% of thedepressed patients show hypercortisolaemia and why consider-able variation in their symptoms occurs (Checkley, 1996;Holsboer, 2000).

An alternative possibility involves changes during earlydevelopment that can induce altered feedback control of theHPA-axis that may persist into adulthood, and could lead toacquired GR resistance in some specific feedback areas (Bronne-gard et al., 1996; De Bellis et al., 1999; De Kloet et al., 1997) and GRhypersensitivity in other brain regions (Nemeroff, 1996). Depres-sionandanxietyhavebeen foundtobemore frequent in thesonsand daughters of womenwho had been treatedwith DES duringpregnancy (Vessey et al., 1983; Brown et al., 1995) and in childrenofmothers whowere pregnant during the ‘hunger winter’ in theNetherlands during the SecondWorldWar (Susser and Lin, 1992;Susser et al., 1996). However, so far, the HPA-axis has not beeninvestigated in these patients.

2.3. Sex differences and reproductive stages

Unipolar depression and dysthymia are twice as common inwomen as they are in men (Seeman, 1997; Piccinelli andWilkinson, 2000). During the reproductive years, a woman isexposed to monthly fluctuations of circulating estradiol andprogesterone that accompany the menstrual cycles, whichare expected to influence the secretion of hypothalamic CRHand catecholamines until menopause. Premenstrual syn-drome or premenstrual dysphoric disorder is characterizedby feelings of depression, anxiety and mood swings duringthe last week of the luteal phase, with decreased secretion ofCRH and an increased incidence of suicides and enhancedvulnerability to autoimmune and allergic inflammatoryphenomena (Rabin et al., 1990; Fourestie et al., 1986; Skobeloffet al., 1996; Hayward et al., 1997). It has been found that thetime of the maximum emotional disturbance coincideswith the decrease of plasma estradiol levels during the latterpart of the luteal phase of the cycle when plasma progester-one levels are still elevated (Hayward et al., 1997). Otherstudies have suggested that the period of peak estradiolsecretion in the state immediately before ovulation isassociated with elevations in mood, a phenomenon thatmight contribute to fecundity (Blum et al., 2004; Davydovet al., 2004; Endicott, 1993; Henderson and Whissell, 1997).Premenstrual dysphoric syndrome is characterized by


disturbances in circadian rhythms and the response tocritically timed light administration. Interventions withbright light improve mood in these patients (Parry andNewton, 2001). Although at present there is no conclusiveevidence that premenstrual dysphoric disorder is indeedassociated with abnormalities in the levels of sex hormones,both suppression of ovarian function by an LHRH agonistsand ovariectomy are effective treatments for this type ofmood disorder (Steiner, 1996; Rubinow et al., 1998a). The fluidretention in the premenstrual syndrome has been proposedto be related with the increased AVP levels (Reid and Yen,1981; Ishunina and Swaab, 1999; Ishunina et al., 1999), whichindeed show fluctuation during the menstrual cycle, al-though the relationship between these fluctuations andpsychological symptoms of the premenstrual syndromeremains unclear at present.

Antepartum depression is found in some 5% of pregnantwomen (Campagne, 2004). This conditionmay be a risk factor forthe development of preeclampsia (Kurki et al., 2000) and is thestrongest predictor of postpartum depression (Graff et al., 1991).Maternal depressive symptoms during pregnancy may lead tobehavioral changes in the child (Oren et al., 2002). Pharmacolog-ical treatment of depression of pregnant women is complicatedbecause of the possible behavioral–teratological effects (Swaaband Boer, 2001). It is therefore of great practical interest that anopen trial has shown that morning light therapy may be effec-tive as an antidepressant during pregnancy (Oren et al., 2002). Arandomized controlled trial should confirm these promisingdata. The latter half of human pregnancy is associated withhypercortisolism. Indeed, the levels of free plasma cortisol and24-h urinary free cortisol excretion in pregnancy overlap withlevels in patients with mild Cushing syndrome (Nolten et al.,1980). Placental CRH is the cause of this hypercortisolism(Chrousos et al., 1998).

The postpartum period is characterized by an increasedincidence of psychiatric disturbances. The ‘postpartum blues’,transient depressed feelings, occur in 60% to 70% of women,while apostpartumdepressionaffects about 10%andvery severepostpartum psychosis affects about 1 in 1000 (Affonso andDomino, 1984). The postpartum estrogen withdrawal state hasoften been held responsible for this disorder. However, availablestudies show a lack of evidence that serum sex hormones ac-count for mood disturbances in these women. Yet there isevidence that estradiol might be effective in its treatment(Gregoire et al., 1996; Sichel et al., 1995). Clinical implications ofplacental CRH extend beyond pregnancy, labor, and delivery(McLean et al., 1995; Magiakou et al., 1996b). There is evidenceshowing that the postpartum period might be associated withlow hypothalamic CRH secretion, which would predisposepatients to atypical depression (Magiakou et al., 1996a). It issupposed that in the postpartum state the placenta, the majorsource of CRH and estrogen during pregnancy, is no longerpresent, whereas the hypothalamic CRH neuron is probablysuppressed as a result of previous exposure to high levels ofcortisol and concurrent after-birth estrogen deficiency. High-dose estrogen has a marked antidepressant effect during thisperiod, possibly because it reestablishes normal stress systemsecretion of CRH and norepinephrine (Gregoire et al., 1996).Postpartum women are also at risk for hypothalamic–pituitary–thyroid (HPT) axis dysfunction, which may increase their

vulnerability to affective disorders (Sichel et al., 1995; Wisnerand Stowe, 1997).

Depressive symptoms are also common during the transi-tion to menopause, and there are suggestive data that estrogendeficiency may increase the susceptibility for depression(Birkhauser, 2002). However, although perimenopause may bea period of risk formood disturbances, it generally does not leadto major depression. According to some studies (Banger, 2002)depressive disorders do not occur more frequently during peri-menopause, although perimenopausal womenwith both estro-gen and hence CRH withdrawal states indeed show moodimprovements with estrogen therapy (Soares et al., 2001).Estrogen replacement therapy also improvesmood in postmen-opausal women and estrogens may improve the effect of someantidepressants in postmenopausal women (Birkhauser, 2002).

2.4. Sex hormone level fluctuations

It was found in males that testosterone levels were lower inseverely depressed patients (Heuser, 2002) and oldermenwithlower bioavailable testosterone levels were more frequentlydepressed (Barrett-Connor et al., 1999). Low testosterone levelswere also found in men with dysthymic disorder (Seidmanet al., 2002). Both the testosterone level and AR polymorphismare related to the risk for middle-aged men to becomedepressed. Men who have low total testosterone levels and ashorter CAG codon repeat length in the AR have a greaterlikelihood of becoming depressed (Seidman, 2001). It is ofinterest that the testosterone levels of bodybuilders who takesupraphysiological doses of testosteronehad a strong negativecorrelation with depression scores (Dickerman and McCon-athy, 1997). Studies in anabolic androgenic steroid users showthat some of them develop manic or aggressive reactions tothese drugs. Supraphysiological doses of testosterone indeedincreased ratings ofmanic symptoms innormalmen (Popeet al.,2000).

Based upon the observations mentioned above, that 1) menshow higher HPA-axis activity than women (Uhart et al., 2006;Vierhapper et al., 1998; Shamim et al., 2000; Traustadottir et al.,2003; Kudielka et al., 1998; Roca et al., 2005; Bao and Swaab, 2007),while 2) the lifetime prevalence of major depression is twice ashighinwomenas inmen(LehtinenandJoukamaa,1994;Pearlsteinet al., 1997); and 3) the prevalence of mood disorders increasesduring the reproductiveyears, especially during timesof change ingonadal hormone levels, e.g., the premenstrual and postpartumperiods and the transition tomenopause (Lehtinenand Joukamaa,1994; Pearlstein et al., 1997; Young and Korszun, 2002), it could bespeculated that thechangesof sexhormone levelsmayplayamoreimportant role in the vulnerability to mood disorders than thebasal absolute levels. In this respect it is of interest to see thatdepressed female patients had significantly higher amplitudes ofdiurnalestradiol rhythmsthancontrols (Baoetal., 2004).Moreover,it is unknown whether a different local production e.g., ofestrogens, involving aromatase and adrenal or brain-derivedandrogens due to the changes of circulating sex steroids, may actas a ligand and regulate sex hormone receptors in the brain(Kroboth et al., 1999), or whether the regulation of sex hormonereceptors ismodulatedbyneurotransmitters, suchasnorepineph-rine, dopamine or serotonin (Asberg et al., 1976; Blaustein et al.,1986), and this deserves further study in relation to depression.


Not only sexual function but also mood improved in hy-pogonadal men who received testosterone replacement (Finket al., 1999; Seidman and Walsh, 1999; Wang et al., 1996; Fink etal., 1998; Wong et al., 2000). Although this is a promisingobservation, there are not enough controlled studies at presentthat prove that testosterone administration is indeed effective inmooddisorders (Sternbach, 1998). Estrogen replacement therapy(ERT) may make women with Alzheimer's disease (AD) lessvulnerable to depression (Carlson et al., 2000) andmay augmentthe fluoxetine response in elderly depressed patients (Schneideret al., 1997). On the other hand, it should be noted that estrogensubstitution in postmenopausal women with depressive symp-toms was effective in some studies but not in others (Rubinowet al., 1998b; Rasgon et al., 2001). Progestins during sequentialhormonal replacement therapy cause negative mood and phys-ical symptoms that are accentuated by increasing the estrogendose (Bjorn et al., 2003).

2.5. The circadian system

The SCN that induces circadian and circannual variations inneuronal activity (Hofman and Swaab, 1992, 1993) is supposedalso to be related to circadian and circannual fluctuations inmood and to sleeping disturbances in depression (van Londenetal., 2001).Apolymorphismin theclockgeneNPAS2appeared tobe associated with seasonal affective disorder (Johansson et al.,2003), indicating that the SCNmay also play a causal role in thistype of depression. A disorder of SCN function, characterized byan increased number of AVP-expressing neurons, a decreasedamount of AVPmRNA in this nucleus, and diminished circadianfluctuation of AVP mRNA has been found in depressed patients(Zhou et al., 2001) (Fig. 7). Decreased activity of the SCN in de-pression is presumed to be at least partly due to the increased

Fig. 7 – The number of arginine vasopressin-immunoreactive (AVPmRNA (B) in the suprachiasmaticnucleus (SCN) in control subjects (nS.D. Note the change in the balance between the presence of moredisorder of the transport ofAVP that leads to accumulationof thepep2001, Fig. 2, with permission.)

circulating plasma cortisol levels that are known to inhibit SCNfunction (Liu et al., 2006a). Light therapy is found to be effective,not only for the seasonal subtype but also for major depression,while morning light, as an adjuvant to conventional antidepres-sants in unipolar patients, or lithium in bipolar patients, hastensand potentiates the antidepressant response (Wirz-Justice et al.,2005). Animal data have shown that AVP neurons of the SCNexert an inhibitory influence on CRH neurons in the PVN(Kalsbeek et al., 1992). It is thus logical to propose that in de-pressedpatients, stress results inadisproportionallyhighactivityof theHPA-axis because of a deficient cortisol feedback effect dueto the presence of glucocorticoid resistance. Meanwhile AVPneurons in the SCN react to the increased cortisol levels andsubsequently fail to inhibit sufficiently the CRH neurons in thePVN of depressed patients. Such an impaired negative feedbackmechanism may lead to a further increase in the activity of theHPA-axis in depression. Both high CRH and cortisol levelscontribute to the symptoms of depression (see above) (Swaabet al., 2005), while light therapy may activate the SCN, directlyinducing an increased synthesis and release of AVP that willinhibit the CRH neurons (Fig. 8). However, it should be noted thathuman beings are diurnal creatures that might hold a differentmode of interaction between SCN–AVP neurons and the PVN–CRH neurons, as is the case in the nocturnal rat. It can also behypothesized that the diminished AVP activity in the SCN indepression isdue to inhibitionbyhyperactiveCRHneurons in thePVN that project to the SCN. This possibility deserves furtherstudy.

2.6. Influence of the cortex

Depression is also commonly observed after stroke. The severityof themooddisorder in this condition is increasedparticularly in

-IR) neurons (A) and the mask area of silver grains of the AVP=11) anddepressed subjects (n = 11). The error bars indicate theAVP and less AVP mRNA in depression. There is probably atide, in spite of thedecreasedproduction rate. (FromZhouet al.,


patients with left prefrontal cortex lesions or with rightposterior–dorsal lesions (Robinson et al., 1984; Iacoboni et al.,1995). Postmortem studies have further provided morphologicalevidence for the involvement of the prefrontal cortex indepression; cell loss takes place in the prefrontal cortex, whilecell atrophy occurs in the dorsolateral and orbitofrontal cortex(Rajkowska, 2000). PET and SPECT studies have further shownthat bilateral hypometabolism occurs in the orbital–inferiorprefrontal lobe of most types of depression (George et al., 1993;Mayberg, 1994; Morris et al., 1996; Galynker et al., 1998). Whetherthese metabolic changes in the cortex of depressed patients arecause or effect of the disorder remains a matter of debate.Increased glucocorticoid levels are known to inhibit prefrontalcortex metabolism (Brunetti et al., 1998; Fulham et al., 1995). Inaddition, glucocorticoid receptor dysregulation is found in theneocortex and hippocampus of patients with depression (Web-ster et al., 2002; Pariante and Miller, 2001). Furthermore, theprefrontal cortex inhibits the HPA-axis, as is clear from lesionstudies, particularly of the left prefrontal cortex; a lesion in thatarea appears to go together with symptoms of depression andhypercortisolism. On the other hand, the hypercortisolism thatoccurs in depression will inhibit prefrontal cortex activity.Together, these two effects might even reinforce each other(Swaab et al., 2000). In depression pathogenesis, a changed inter-action between the prefrontal cortex and the HPA-axis maytherefore be crucial.

3. Alzheimer's disease (AD)

3.1. The stress system in AD

AD is a multifactorial disease and ‘aging’ is its major risk factor.The presence of apolipoprotein E (ApoE) e4 alleles is responsiblefor some 17% of the cases. Mutations in the amyloid precursorprotein presenilin 1 and 2 genes contribute less than 1% to theprevalence of AD (Tol et al., 1999). Additional possible risk factorsfor AD are being female, lack of sex hormones, smoking, lowdegree of education and cardiovascular disorders (Swaab, 2004).

The HPA-axis shows extensive changes in AD.We observed ahyperactivation of CRH neurons with age, which is significantlypresent in men (Raadsheer et al., 1993, 1994b; Bao and Swaab,2007) (Fig. 1). This finding is in full agreement with hormoneassays that indicate a general activation of various HPA-axisparameters during the course of human aging. Cortisol plasmalevels are increased in AD (Umegaki et al., 2000; Murialdo et al.,2000a; de Bruin et al., 2002; Rasmuson et al., 2002) andmay occurin an early stage, relating to cognitive decline (Umegaki et al.,2000). The salivary cortisol levels are found to be correlated withseverity of disease, as measured by the mini-mental state ex-aminationand theglobal deterioration scale (Giubilei et al., 2001).Hypercortisolemia in AD appears to be related to the clinicalprogression but not to aging or length of survival (Weiner et al.,

Fig. 8 – Depression; schematic illustration of an impairedinteraction between the decreased activity of vasopressinneurons (AVP) in the suprachiasmatic nucleus (SCN) and theincreased activity of corticotropin-releasing hormone (CRH)neurons in the paraventricular nucleus (PVN). Thehypothalamo–pituitary–adrenal (HPA) system is activated indepression and affects mood, via CRH and cortisol.We found adecreased amount of vasopressin (AVP) mRNA of the SCN indepression.ThedecreasedactivityofAVPneurons in theSCNodepressed patients is the basis of the impaired circadianregulation of the HPA system in depression. Moreover, animaldata have shown that AVP neurons of the SCN exert aninhibitory influence on CRH neurons in the PVN. Increasedlevels of circulating glucocorticoids decrease AVPmRNA in theSCN,whichwill result in smaller inhibition of the CRHneuronsIn the light of our data we propose the following hypothesis forthe pathogenesis of depression. In depressed patients, stressacting on the HPA system results in a disproportionally highactivity of the HPA system because of a deficient cortisolfeedback effect due to the presence of glucocorticoid resistanceThe glucocorticoid resistance may either be caused by apolymorphism of corticosteroid receptor or by a developmentadisorder. Also AVP neurons in the SCN react to the increasedcortisol levels and subsequently fail to inhibit sufficiently theCRH neurons in the PVN of depressed patients. Such animpaired negative feedback mechanismmay lead to a furtherincrease in the activity of the HPA system in depression. Bothhigh CRH and cortisol levels contribute to the symptoms ofdepression. Light therapy activates the SCN, directly inducingan increased synthesis and release of AVP that will inhibit theCRHneurons. Antidepressantmedication generally inhibits theactivity of CRH neurons in the PVN. ACTH, corticotropin.

f

.

.

l


1997). There is a linear relationship between plasma and CSFcortisol levels (Erkut et al., 2002a) and indeed we have found CSFcortisol levels also to be increased inAD (Swaab et al., 1994; Erkutet al., 2004; Hoogendijk et al., 2006). Moreover, the presence of 1or 2 alleles of ApoE-e4 is accompanied by higher cortisol CSFlevels in both ADpatients and controls (Peskind et al., 2001). CRHmRNA was found to be increased in the hypothalamic PVN,causing hyperactivity of the HPA-axis in Alzheimer patients(Raadsheer et al., 1995) (Fig. 4). There is a very high prevalence ofdepression in AD, affecting up to 50% of the patients (Zubenkoet al., 2003; Lyketsos and Lee, 2004). Recently,we found a positivecorrelation between the Cornell scale for Depression in Demen-tia and the number of CRH neurons in the PVN, suggesting thatdepressive disorder and depression in AD share, at least partly,their pathogenesis (Meynen et al., 2007b). In demented patientswith delirium, HPA-axis feedback was found to be disturbed(Robertsson et al., 2001).

The AVP-producing neurons in the SON and PVN generallyremain intact in AD (Van der Woude et al., 1995) and the AVPneurons even appear to be activated in the course of aging (seeabove). Yet some studies report changes in circulating AVP andOXT levels in AD, although these data are somewhat equivocal.TheAVPCSF levels donot change indementiaaccording to someauthors (Jolkkonen et al., 1989; Gottfries et al., 1995) whereasothers say they are increased (Tsuji et al., 1981) or reduced(Mazurek et al., 1986; Gottfries et al., 1995). The fact that the typeof dementia is often not specified in these papers may be part ofthe reason for the discrepancies.

A decreased number of neurons expressing AVP, neuroten-sin and vasoactive intestinal peptide (VIP) in the SCN has beenfound in AD patients (Swaab et al., 1985; Zhou et al., 2001, 1995;Stopa et al., 1999). In addition, it is clear from the neurofibrillarychanges, from the increasednumber of GFAP-positive astrocytes(Swaab et al., 1992; Stopa et al., 1999; van de Nes et al., 1998) andfrom the 3 times lower amount of AVP mRNA in the SCN ofAlzheimerpatients (Liu et al., 2000) that theSCN is affected inAD.The SCN is strongly affected from the earliest AD stages onwards(Wuetal., inpress).Alterationsobserved in theSCNareaccompa-nied by a disruption of circadian rhythms, nightly restlessness,and a phase delay in body temperature rhythm (Harper et al.,2001). Indeed, stimulation of the SCN by light improves circadianrhythmicity, decreases behavioral disturbances such as nightlyrestlessness (Van Someren et al., 1999) and can even improvecognitive performance (Yamadera et al., 2000; Graf et al., 2001).

3.2. AD and sex hormones

Diminishment of sex hormones, i.e. of estrogens in menopauseand of testosterone in agingmen, is considered to be a risk factorfor AD (Atwood et al., 2005). According to some studies, theprevalence of AD is higher in women than in men (Bachmanet al., 1992; Brayne et al., 1995; Fratiglioni et al., 1997; Launer et al.,1999; Letenneur et al., 2000), although other researchers did notfind an association between AD and gender (Hebert et al., 2001;Lindsay et al., 2002; Gatz et al., 2003) andsuggested that the largernumber of women with AD is only due to the longer lifeexpectancy of women rather than to sex-specific risk factorsfor the disease (Hebert et al., 2001). Our observation of anincreased number of nucleus basalis of Meynert neuronscontaining AD-pathology, i.e. hyperphosphorylated tau, in

women as compared to age-matched men (Salehi et al., 2000),and the association found between AD and a locus on the X-chromosome (Zubenko et al., 1998), support, however, thepresence of sex differences in AD. In addition, ERα polymorph-isms PvuII and XbaI are associated with the risk of developingcognitive impairment (Yaffe et al., 2002) and CAG-repeat poly-morphism of AR is also associated with AD in men (Lehmannet al., 2003). Moreover, an interaction between ERα and ERβpolymorphisms and the risk of developing AD has also beenrecognized (Lambert et al., 2001).

Various studies suggest a relationship between sex hormonelevels and cognitive performance and AD. Lower endogenousestradiol levelsarecorrelatedwithpoor cognitive, behavioral andfunctional status in older but undemented individuals (Farraget al., 2002; Senanarong et al., 2002). In women, higher estradiollevels as well as higher testosterone levels are associated withbetter verbal memory. Moreover, estradiol is associated with adiminished susceptibility to interference (Wolf and Kirschbaum,2002). In elderly, non-demented men, higher free testosteronelevels are associated with better scores on visual and verbalmemory, visuospatial functioning, and visuomotor scanning,andwith a reduced rate of longitudinal decline in visualmemory(Wolf and Kirschbaum, 2002; Moffat et al., 2002). Several studieshave reinforced the idea that the postmenopausal decrease inestrogen levels may be an important factor in triggering thepathogenesis of AD, since women with high serum concentra-tions of bioavailable estradiol are less likely to develop cognitiveimpairment than women with low concentrations (Inestrosaet al., 1998; Manly et al., 2000; Yaffe et al., 2000). In old men,endogenous testosterone levels are not associated with risk forcognitive decline and AD, whereas higher estrogen levelsincrease this risk (Geerlings et al., 2006). An interesting relation-ship has been observed between CSF levels of estradiol and AD-pathology β-amyloid. Estradiol CSF levels are lower in ADpatients than in controls, and within the Alzheimer group theestradiol levels are inversely correlated with Aβ-42 concentra-tions. This observation has been interpreted as corresponding tothe beneficial effects of estrogen replacement therapy on AD(Schonknecht et al., 2001).

ERT as a preventive measure for AD is becomingincreasingly controversial. Epidemiological evidence, ran-domized controlled trials, and cross-sectional and longitudi-nal studies have indeed indicated that ERT in postmeno-pausal women is effective in protecting against a decline inverbal memory in healthy postmenopausal women and inpreventing and delaying the onset of AD (Henderson et al.,1996; Stephenson, 1996; Sherwin, 2002; van Duijn, 1999).However, other studies reported no effect on cognition wasobserved after 4 years of hormone therapy (Grady et al.,2002). It has also been found that estrogen plus progestin didnot improve cognitive function when compared with place-bo; what is more, there was even a small increased risk ofclinically meaningful cognitive decline that occurred in theestrogen plus progestin group (Rapp et al., 2003). At least partof the controversial literature on the possible positive effectsof sex hormones in AD may be based upon the differenteffects that different sex hormones may have on differentbrain areas, depending on, e.g. age and ApoE genotype. Thereis a need for more long-term, randomized controlled trialswith estrogens, starting immediately in the postmenopausal

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period in mentally unaffected women, in order to get moreinformation on the possible prevention of AD.

3.3. Hippocampal damage in AD and depression: is theglucocorticoid cascade hypothesis valid

The hippocampus is strongly affected in AD. Also the sensitivityfor estrogens in the hippocampus is changed in AD, possiblybecause of the changes in the ratio of the various splice variantsand isoforms of the ERα (Ishunina et al., in press). Neuronal losswas reported in the hippocampus of stressed or corticosteroid-treated rodents and primates. On the basis of earlier animalexperiments, overexposure of the brain to glucocorticoids duringprolonged periods of stress was expected to be damaging to thebrain, especially in aged animals, and particularly affecting thehippocampus (Sapolsky, 1985, 1996; Landfield et al., 1978). Since,under normal conditions, the hippocampus inhibits the HPA-axis activity, the damage to the hippocampus was proposed tocause a disinhibition of the HPA-axis, which would lead to itsfurther activation, and to subsequent rises in glucocorticoidlevels and thus to accumulating damage to the hippocampus.This hypothesized feed-forward cascade became known as the‘glucocorticoid cascade hypothesis’ and was proposed to be amajor pathogenetic mechanism also in human neurodegenera-tive diseases associated with HPA-axis alterations such asdepression and AD (Sapolsky et al., 1986). The excessive, repet-itive hypersecretion of cortisol, and possibly even the increasedbasal levels of the hormone, were supposed to accelerate thecourse of hippocampal damage in Alzheimer patients (Sapolskyet al., 1986). Increased cortisol levels would not only causehippocampal neuronal damage but was also proposed topotentiate amyloid toxicity, while DHEA andDHEAS are believedto exert a neuroprotective action (Murialdo et al., 2000b).

It has been hypothesized that in various cases the ‘glucocor-ticoid cascade’ might be involved in the pathogenesis of thedisorder (Sapolsky et al., 1986). Glucocorticoid treatment causesmemory disturbances in the absence of concomitant stress ex-posure (LupienandMcEwen, 1997; Lupienet al., 1998;Wolf, 2003).Depressed patients who did not suppress cortisol when givendexamethasone made more mistakes in a verbal memory task(Wolkowitz et al., 1990). A considerable percentage of Alzheimerpatients indeed presents with a non-suppression of plasmacortisol following dexamethasone administration (O'Brien et al.,1996; Swaab et al., 1994), while the degree of HPA-axishyperactivity generally correlates with the severity of cognitiveimpairment and hippocampal atrophy (Gurevich et al., 1990; deLeon et al., 1988; Weiner et al., 1993; Lupien et al., 1998). Severalstudies have found a reduced hippocampal volume in patientswith unipolar depression, although there are discrepancies.Meta-analyses of hippocampal volumetric studies in patientswith mood disorders revealed that although such studies werehighly heterogeneous regarding age and gender distribution,age at onset of the disorder, average number of episodes, andresponsiveness to treatment, the hippocampal volume wasreduced in patients with unipolar depression, possibly as aconsequence of repeated periods of major depressive disorder(Videbech and Ravnkilde, 2004), especially when the hippocam-puswasmeasured as a discrete structure (Campbell et al., 2004).However, it should be noted that a reduced hippocampalvolume does not prove cell loss (see below); the hypercortiso-

laemic state in depressed patients might cause a change inwater content, as indicatedby the shortenedT1 relaxation timesin the hippocampus of depressed patients, especially in theelderly (Krishnan et al., 1991a). In addition, it should be studiedwhether a small hippocampal volume may predispose fordepression.

There are, however, also quite a number of observationsthat do not support the possible importance of the ‘glucocor-ticoid cascade hypothesis’ in the pathogenesis of AD. Incontrast to the often claimed association between elevatedcortisol levels and impaired declarativememory performance,subjects with a remarkably high cortisol increase in responseto psychological stress appeared to show improved memoryperformance (Domes et al., 2002). The activation of the HPA-axis and the impaired cognition in AD may both be explainedby the ongoing Alzheimer process in the hippocampus,without cortisol playing a crucial causal role. Although somepapers reported baseline levels of cortisol to be elevated inplasma and urine of Alzheimer patients (Davis et al., 1986;Maeda et al., 1991; Umegaki et al., 2000) others failed to do so(Ferrier et al., 1988). One study indicated that, as a group,Alzheimer patients have a mildly increased HPA-axis activity,but the increased baseline cortisol levels were not stablelongitudinally and did not increase with follow-up, which isnot consistent with the ‘glucocorticoid cascade hypothesis’(Swanwick et al., 1998). In presenile patients the postmortemCSF levels were found to be 5 times higher than in controls.However, due to the increasing cortisol levels in the course ofnormal aging, significant differences in postmortem CSFcortisol levels were no longer found between senile Alzheimerpatients and controls. Increased basal plasma and CSF cortisollevels thus do not seem to be necessary for the development ofAD pathogenesis (Swaab et al., 1994). In addition, the lumbarpuncture CSF levels of cortisol were found to be increased inAD in an ApoE genotype-dependent way. ApoE-e4 wenttogether with higher cortisol levels (Peskind et al., 2001).However, this observation may be explained by the strongerAlzheimer changes in the hippocampus of ApoE-e4-positivesubjects, which would cause a stronger disinhibition of theHPA-axis. One of the strongest arguments, so far, against thecausal involvement of the ‘glucocorticoid cascade hypothesis’in AD is that no Alzheimer or other neuropathological changesare present in the hippocampus of depressed patients, nor inpatients with Cushing's disease (Trethowan and Cobb, 1952),multi-infarct dementia (Maeda et al., 1991), multiple sclerosis(Purba et al., 1995; Erkut et al., 1995) or in patients treated withglucocorticoids (Lucassen et al., 2001; Müller et al., 2001;O'Brien et al., 2001b), despite a much stronger activation ofthe CRH neurons in depression than in AD (Raadsheer et al.,1995).

Although cell death is often presumed to be the mechanismbehind cerebral atrophy following prednisone administration,such a phenomenon could not be observed by histological andneuropathological examination of the hippocampus of patientsexposed to synthetic corticosteroids or who had a long history ofdepression andwere therefore likely tohavehigher cortisol levels(Lucassenet al., 2001;Müller et al., 2001) (Figs. 9 and10).Moreover,hippocampal volume reductions in Cushing's disease wereshown to be reversible after a decrease or cessation of the steroidexposure, which is in accordance with the general clinical

http://dx.doi.org/doi:10.1016/j.neurobiolaging.2006.07.024

Fig. 9 – Representative photomicrographs (Nissl staining) from the hippocampus of a depressed patient (A, B), a steroid-treatedpatient (C, D) and a control subject (E, F). Figures B, D and F show the CA3 area of the same patients at higher magnification. Nomorphological evidence forneuronaldamageor cell loss isobserved ineither thedepressedor thesteroid-treatedpatient. Scale bars:710 μm (A, C, E) and 45 μm (B, D, F). (FromMüller et al., 2001, Fig. 1, with permission.)


experience with depressive or Cushing's patients that treatmentor operation can relieve the depressive symptoms, the HPA-axisalterations and even the hippocampal atrophy (Starkman et al.,1999; Müller et al., 2001; Lucassen et al., 2001). Changes in watercontent of the hippocampus have been proposed as an alterna-tive explanation for hippocampal atrophy in depression (Lucas-sen et al., 2001; Müller et al., 2001; Krishnan et al., 1991a), whilealterations in neuronal components or glial cells in the adulthippocampaldentategyrussubareasmaybealternativemechan-isms (Czeh and Lucassen, in press). A number of studies reportedatrophy of the hippocampus in Vietnam-combat-veterans withposttraumatic stress disorder as another example of the ‘gluco-corticoid cascadehypothesis’, but nohypercortisolism is found in

these patients. On the contrary, this disorder is associated withdecreased HPA-axis activity and steroid feedback supersensitiv-ity, often for decades after the initial trauma (Bremner et al., 1995;Yehuda et al., 1995). An increased sensitivity or upregulation ofGR in PTSD and a pre-existing smaller hippocampal volume thusseems, at present, the best explanation for these data (Bremner,1999; Rasmusson et al., 2001).

4. Conclusions

Stress plays amajor role in various (patho)physiological process-es associated with mood disorders and neurodegenerative

Fig. 10 – In situ end-labeling (ISEL) results. (A) Positive labeling in the CA-4 area of depressed patient 94-112, showing necroticmorphology (upper arrow) as indicated by the comparable size of an intact, neighboring neuron (arrowhead) without chromatinreorganizationor apoptotic bodies being visible. Also seen is a labeled apoptotic cell as evidenced by its pycnotic appearance, strongcondensation and brown DAB precipitate (horizontal arrow). (B) ISEL-positive neuron (arrow) just outside the CA1 cell layer ofdepressed patient 90-001 with clear apoptotic morphology, i.e. a reduced size as compared to unstained, healthy-looking neurons(triangle), and apoptotic bodies clearly visible. (C) ISEL-positive, apoptotic cell (arrow) with a pycnotic, condensed appearanceadjacent to a nonstained large cell (arrowhead). CA1 of depressed patient 94-094. (D) Apoptotic neuron (arrow) in the subiculum ofdepressed patient 94-032 with three clear apoptotic bodies visible. (E) Frequent, granular morphology (arrows) suggestive ofchromatolytic processes, adjacent to normal-looking neurons in CA3 of depressed patient 90-001. (F) Normal-appearing neurons inCA1 of control subject 94-123. Also, one granular, chromatolytic-like structure is visible (arrow). Scale bars: 34μm (A, B, E and F) and15μm(CandD). Pleasenote that in theabsenceofanymajorpyramidcell loss (Müller et al., 2001andFig. 9) and the rareoccurrenceofapoptosis that notably was absent from areas at risk for glucocorticoid damage such as CA3, apoptosis most probably onlycontributes to aminor extent to thehippocampal volumechanges indepression. (FromLucassenet al., 2001; Fig. 1withpermission.)


diseases. In principle, stress has the potency to exert either ame-liorating or detrimental effects. The specific outcomedepends onmultiple variables. A crucial factor seems to be time: effects thatare beneficial to an organism in the short term may havedetrimental effects in the long-term. HPA-axis hyperactivity ispresent in a possibly large subpopulation of depressed subjects.There are two main hypotheses concerning the HPA-axis-hyperdrive and depression, i.e. 1) the CRH-hypothesis, according

to which CRH not only causes the neuroendocrine-hyperdrive,but is also responsible for depressive signs and symptoms viaCRH innervation of brain areas; and 2) the glucocorticoidhypothesis, which states that increased cortisol plasma levelsare causal to the development for depressive symptoms. Morerecently, attentionhasbeendrawn to the role ofAVPonHPA-axisactivation indepression.Aclear sexdifferencehasbeen indicatedin the stress response and in the susceptibility, progress, and


actual outcome of depression. The hippocampus shows noAlzheimer neuropathological changes or massive cell loss indepressed patients despite a possibly reduced hippocampalvolume. The latter does, however, not imply cell loss and canalternatively be ascribed e.g. to changes in water content, inneuronal components or in gliall cells. On the other hand, thehippocampus in AD shows a very pronounced and early cell lossthat may account for severe clinical disabilities such as memoryloss. The HPA-axis is only moderately activated in AD, possiblyresulting from, rather than causing, the hippocampal neurode-generation in this disorder. There are no conclusive arguments toassume a causal role for cortisol in AD pathogenesis. However,CRHandcortisol seemtobecausally involved in thedevelopmentof depression. Although there is no evidence for any majordamage in the human hippocampus in depression or followingglucocorticoid treatment, subtle changes can, of course, atpresent not be excluded.

Acknowledgments

Theauthorswant to thankMrs.WilmaVerweij forher secretarialassistance. Bao A-M and Swaab DF were supported by KNAW05CDP027, Meynen G by Internationale Stichting AlzheimerOnderzoek, project 99512 and the Netherlands Organisation forScientific Research (NWO), project 940-37-021.

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