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Brain, Behavior, and Immunity 26 (2012) 251–266

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Brain, Behavior, and Immunity

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y b r b i

Review

Neuroimmunological effects of physical exercise in depression

Harris Eyre a, Bernhard T. Baune b,⇑ a Psychiatry and Psychiatric Neuroscience Research Group, School of Medicine and Dentistry, James Cook University, 101 Angus Smith Drive, Townsville, Queensland 4811, Australia b Discipline of Psychiatry, School of Medicine, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia

a r t i c l e i n f o

Article history: Received 15 June 2011 Received in revised form 25 September 2011 Accepted 26 September 2011 Available online 2 October 2011

Keywords: Neuroimmunology Neurobiology Human Rodent Depression Exercise Physical activity Immunology Stress

0889-1591/$ - see front matter � 2011 Elsevier Inc. A doi:10.1016/j.bbi.2011.09.015

⇑ Corresponding author. Address: Discipline of Psy University of Adelaide, North Terrace, Eleanor Harrald Australia. Fax: +61 8 8222 2865.

E-mail address: Bernhard.Baune@Adelaide.edu.au

a b s t r a c t

The search for an extended understanding of the causes of depression, and for the development of addi- tional effective treatments is highly significant. Clinical and pre-clinical studies suggest stress is a key mediator in the pathophysiology of depression. Exercise is a readily available therapeutic option, effective as a first-line treatment in mild to moderate depression. In pre-clinical models exercise attenuates stress- related depression-like behaviours. Cellular and humoral neuroimmune mechanisms beyond inflamma- tion and oxidative stress are highly significant in understanding depression pathogenesis. The effects of exercise on such mechanisms are unclear. When clinical and pre-clinical data is taken together, exercise may reduce inflammation and oxidation stress via a multitude of cellular and humoral neuroimmune changes. Astrocytes, microglia and T cells have an antiinflammatory and neuroprotective functions via a variety of mechanisms. It is unknown whether exercise has effects on specific neuroimmune markers implicated in the pathogenesis of depression such as markers of immunosenescence, B or T cell reactivity, astrocyte populations, self-specific CD4+ T cells, T helper 17 cells or T regulatory cells.

� 2011 Elsevier Inc. All rights reserved.

1. Introduction

The increasing prevalence of unipolar major depressive disorder makes the search for an extended understanding of the causes of depression, and for the development of additional effective treat- ments highly significant (WHO, 2008). Depression is caused by a complex interaction of multiple factors which can be most reason- ably understood by applying a bio-psycho-social framework. These bio-psycho-social factors are interrelated, with chronic stress being a major influencer (Moller-Leimkuhler, 2010). Chronic psychologi- cal stress precedes the majority (some 80%) of episodes of clinical depression (Kessler, 1997; Mazure, 1998; Caspi et al., 2003; McEwen, 2003; Bartolomucci and Leopardi, 2009; Risch et al., 2009). Similarly in animal models chronic stress is a precipitant of depression-like behaviour (Willner, 2005; Kubera et al., 2011). The pathophysiology of stress-associated depression is hypothesised to be associated with various neurobiological changes which are thought to be essential to molecular mechanisms of memory, learn- ing, and symptoms of depression (Baune, 2009; Miller et al., 2009). These neurobiological changes in depression occur in the mono- amine system, hypothalamo–pituitary–adrenal (HPA) axis, neuro-

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chiatry, School of Medicine, Building, Adelaide, SA 5005,

(B.T. Baune).

genesis system and the neuroimmune system. A special emphasis has been given to neuroimmune processes since they may directly and indirectly affect the pathophysiology of depression by effecting other important neurobiological processes of depression (Garcia- Bueno et al., 2008; Maes et al., 2009; Kubera et al., 2011).

Production of neuroinflammatory factors, i.e. tumour necrosis factor alpha – TNF-a, interleukin-6 – IL-6, C-reactive protein – CRP, interleukin-1beta – IL-1b affect the main neuroimmune mechanisms potentially leading to symptoms of depression-like behaviour (Garcia-Bueno et al., 2008; Anisman, 2009; Maes et al., 2009; Kubera et al., 2011; Wager-Smith and Markou, 2011). These findings have lead to the formulation of the cytokine model of depression due to the capacity of pro-inflammatory cytokines to induce ‘sickness behaviour’, which closely resembles depression- like behaviour in humans (Dantzer et al., 2008; Capuron and Miller, 2011). Neuroinflammatory mechanisms in depression are thought to negatively interact with various pathways and can lead to monoamine dysfunction (e.g. low serotonin levels, creation of neu- rotoxic tryptophan-like by-products (3-hydroxykynurenine (3-HK) and quinolinic acid (QA)), HPA axis dysfunction (e.g. hypercortiso- laemia and reduced glucocorticoid receptor density), neurogenesis dysfunction (e.g. apoptosis and reduced neurotrophin creation) and neuroimmune dysfunction (e.g. decreased T cell proliferation, increased apoptotic rate and impaired T cell function) (Caruso et al., 1993; Maes et al., 1995; Mellor et al., 2003; Clark et al., 2005; Miller et al., 2009; Kubera et al., 2011). Pro-inflammatory

252 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

cytokines can arise from central and systemic cellular neuroim- mune changes. Cells which are implicated in their creation include astrocytes, microglia, macrophages and T cells (Garcia-Bueno et al., 2008).

Few studies in depression research have directly examined the relative expression and function of relevant T cell subsets, and other relevant immune cells, beyond the characterisation of CD4+, CD8+ T cells and T cell mitogen responses in depression (Capuron and Miller, 2011). Other cellular neuroimmune mecha- nisms have also been implicated in the pathophysiology of depres- sion. These neuroimmune mechanisms include dysfunction of CD4+CD25+ T regulatory (Treg) cells, T helper (TH17) cells, self- specific CD4+ T cells, monocyte-derived macrophages, macro- phages, astrocytes and microglia (Schwartz and Shechter, 2010a,b; Capuron and Miller, 2011). These cells are suggested to have various roles involving regulation of inflammatory mediators, regulating neurogenesis, regulating reactive oxygen species (ROS) formation and also cell-to-cell interactions which may mediate neuroimmune mechanisms of the pathogenesis of depression. In this review we will provide a comprehensive and up-to-date re- view of the humoral and cell-mediated neuroimmunological mechanisms associated with depression by reviewing the most re- cent literature. We will evaluate these mechanisms for their poten- tial to act as novel targets for therapeutic interventions.

In recent years it has been suggested that interventions such as antidepressants, and alternative approaches such as exercise may exert therapeutic neuroimmune-modulating effects. In relation to antidepressants, a recent review article by Kubera et al. (2011) sug- gests that antidepressants may positively influence inflammatory, oxidative, apoptotic and antineurogenic mechanisms relevant to stress-associated depression-like behaviour. A review article by this group (Janssen et al., 2010) presents a detailed assessment of the cytokine response to antidepressants, and how treatment re- sponse might be affected by genetic variants relating to cytokines. Anti-psychotic medication and electroconvulsive therapy (ECT) are other psychiatric interventions showing neuroimmune-modulat- ing effects (Hestad et al., 2003; Pae et al., 2010). The efficacy of alternative therapies in clinical depression (i.e. polyunsaturated fatty acids (e.g. Omega-3), anti-inflammatories (Acetlysalicylic acid and Celecoxib), exercise (resistance, aerobic and flexibility) and mindfulness-based therapies (i.e. mindfulness-based cognitive therapy, mindfulness meditation and mindfulness-based stress reduction therapy)) may also be correlated with neuroimmune- modulating abilities (Maes et al., 2000; Carlson et al., 2007; Dinan et al., 2009; Guo et al., 2009; Song and Wang, 2011). One study has shown that tricyclic antidepressants (TCA) cause an increase in inflammation, as measured by CRP, however, other authors have debated these findings (Hamer et al., 2011; Pizzi et al., 2011).

Exercise is a readily available therapeutic option, effective as a first-line treatment in mild to moderate depression (Carek et al., 2011). Additionally, exercise has a utility in preventing depression and has beneficial effects on other common co-morbidities (i.e. cardiovascular disease risk factors and glycemic control). A pro- spective, randomised controlled trial found that exercise was as effective as Sertraline (selective serotonin reuptake inhibitor) for the treatment of depression – the effect size of exercise was 2.0 (Blumenthal et al., 2007). Several reviews show exercise compares favourably to antidepressants and cognitive behavioural therapy (CBT) as a first-line treatment for mild to moderate depression (Mead et al., 2009; Carek et al., 2011).

The efficacy of exercise in depression is classically attributed to its impact on changing certain neurobiological mechanisms includ- ing monoamine metabolism (e.g. increasing serotonin levels in the CNS), HPA axis function (e.g. decreasing long-term basal levels of cortisol), neurotrophic factors (e.g. increasing brain derived neuro- trophic factor (BDNF) and neurogenesis) and neuroinflammation

(e.g. decreasing pro-inflammatory mediators) (Chaouloff et al., 1985; Droste et al., 2003; Garcia et al., 2003; Greenwood et al., 2005; Kohut et al., 2006; Nabkasorn et al., 2006; Tang et al., 2008; Bednarczyk et al., 2009; Clark et al., 2009; Van der Borght et al., 2009; Christiansen et al., 2010; Donges et al., 2010; Mata et al., 2010; Rethorst et al., 2010; Sousae Silva et al., 2010). The ef- fects of exercise on neuroimmune mechanisms other than neuroin- flammation (e.g. cell-mediated factors such as Tregs, Th17 cells, CNS macrophages, microglia etc.) are unclear (Beavers et al., 2010a; Archer et al., 2011). Moreover, how these cellular changes relate to positive effects on the monoamine system, HPA axis and neurotrophic system also remains poorly understood (Beavers et al., 2010a; Archer et al., 2011). Surprisingly, a comprehensive analysis of the effects of exercise on neuroimmune mechanisms and stress-associated depression, including both clinical and pre- clinical research, is lacking in the literature.

In this review we provide a theoretical model whereby we show that the beneficial effects of exercise in depression are potentially mediated through various pathways of the neuroimmune system (see Figs. 2 and 3). Our proposed model on the effects of exercise will be based on evidence and empirical relationships from previ- ously published literature. The model on various aspects of the neuroimmune system may also be relevant for its therapeutic ef- fects in other neuropsychiatric disorders including anxiety disor- der, schizophrenia, Alzheimer’s disease, Parkinson’s disease and mild cognitive impairment (Conn, 2010a,b; Lautenschlager et al., 2010; Petzinger et al., 2010; Tajiri et al., 2010; Carek et al., 2011; Nation et al., 2011; Wolf et al., 2011).

The aims of this review article are to present evidence for the involvement of the neuroimmune system in the pathogenesis of stress-associated depression, and also to provide evidence for the immunomodulatory effects of exercise in depression. It is proposed that exercise will exert its action on symptoms of depression via a variety of neuroimmunological mechanisms (Figs. 2 and 3).

2. Methods

An electronic search of reputable databases such as PubMed, PsychoInfo, OvidSP and ScienceDirect were utilised in the creation of this literature review. Initial searching (revealing 1500 ab- stracts) was conducted using various combinations of the follow- ing keywords: neurotrophin, neuroinflammation, neuroimmune, intervention, monoamine, depression, exercise, physical activity, cytokine, hypothesis, stress, chronic, psychological, stress-induced depression, model, mouse, rat and human. Abstracts were selected based on the year of publication (between 1990 and 2011), publi- cation in the English language and of peer-reviewed type. They were excluded if they included anecdotal evidence. In this process 1000 abstracts were excluded and the remaining 500 full text arti- cles were sought. The resulting 500 full text articles were read thoroughly and their utilisation in this review was based on their journal type (i.e. peer reviewed) and salience to the aims set forth in this review. Finally 214 articles were utilised in the making of this literature review (Fig. 1 depicts this strategy).

3. Stress-associated depression: clinical and pre-clinical evidence

The concept of stress-associated depression-like behaviour has been known for many years with evidence derived from both clin- ical and pre-clinical models. The following section will briefly out- line most recent evidence for stress-associated depression, before moving onto its neuroimmune correlates.

Psychological stress is a known precipitant of depressive symptoms in the clinical setting; moreover depression is known

Fig. 1. Study inclusion flowchart.

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to further exacerbate the stress response leading to a vicious cycle which intensifies subsequent stressors (Kessler, 1997; Mazure, 1998; Caspi et al., 2003; McEwen, 2003; Bartolomucci and Leop- ardi, 2009; Risch et al., 2009). Chronic stress is also associated with precipitation and exacerbation of anxiety disorder and cognitive impairment (e.g. mild cognitive impairment and Alzheimer’s dis- ease) via similar neurobiological mechanisms which are reviewed in: (Brady and Sinha, 2005; Miller et al., 2007; Conrad, 2010; de Rooij et al., 2010; Nation et al., 2011).

When considering translational research between clinical and pre-clinical models it is important to describe the ‘stressors’ which are associated with the onset of depression (Anisman et al., 2002). Anisman et al. (2002) suggests that the ‘stress’ involved in the stress-depression continuum needs to be considered based on severity, chronicity and predictability. Numerous investigators in this field have found protracted, unpredictable and relatively mild psychological stress is highly relevant to depressive symptoms in humans (Tennant, 2002; Bartolomucci and Leopardi, 2009; Baune, 2009). Similar observations are noted in rodent studies, particu- larly from the use of the unpredictable chronic mild stress para- digm (Willner, 2005). Many other investigators have established the link between unpredictable, chronic, mild stress and depres- sion in human and rodent studies (Dura et al., 1990; Caspi et al., 2003; McEwen, 2003; Risch et al., 2009; Frodl et al., 2010; Kubera et al., 2011; Karg et al., 2011; Wager-Smith and Markou, 2011).

There is a large body of evidence in pre-clinical rodent models supporting the concept of stress-associated depression-like behav- iour. Researching depression-like behaviour in rodents includes two main components, modelling and testing. Modelling whereby certain variables (e.g. environment) are manipulated in order to in- duce the required phenotype, and testing where the outcome of the modelling is evaluated (Pollak et al., 2010).

Many models investigating rodent ‘depression’ include chronic stress paradigms (e.g. chronic mild stress or chronic foot shock

stress), adverse life events (e.g. prenatal stress) and genetic modifi- cation (e.g. regarding depression-related genes). For the purpose of this review, the unpredictable chronic mild stress (uCMS) paradigm is selected as it shows strength in all descriptive validation criteria (Willner, 1997). Additionally, the uCMS protocol is known to elicit anxiety-like symptoms, schizophrenia-like behaviour and impair- ments in cognition-like behaviour (Mineur et al., 2006; Conrad, 2010; Salomons et al., 2010; Wolf et al., 2011). The stressors of uCMS are congruous in duration, intensity and predictability to the stressors known to be associated with human depression (Ten- nant, 2002). The uCMS paradigm consists of unpredictable and chronic exposure to environmental changes (e.g. cage dampening, cage tilting and food/water deprivation). The unpredictability of the uCMS paradigm is important for the development of depres- sion-like behaviour as predictable chronic mild stress is shown to improve depression-like behaviour, hippocampal neurogenesis and memory (Parihar et al., 2011). The chronicity of unpredictabil- ity in environment is important in the development of depression in clinical and pre-clinical models. Indeed, in clinical models, there is a large body of literature outlining the role of uncertainty in med- ical illnesses (i.e. exacerbations of illness in multiple sclerosis, asth- ma, atrial fibrillation and other chronic illnesses), certain psychological processes and traits (i.e. pessimism, hopelessness, depressive predictive certainty, intolerance of uncertainty, neurot- icism) and environment unpredictability in the development of depression (Mullins et al., 2000; Kroencke et al., 2001; Lynch et al., 2001; Miranda et al., 2008; McEvoy and Mahoney, 2011).

The specific tests examining the outcome of this model utilised in this review will be the forced swim test (FST), tail suspension test (TST), sucrose consumption and sucrose preference tests. These tests show good rationale and consistently high validity. TST and FST are based on the principle that immobility is sugges- tive of ‘apathy’, ‘disengagement’, ‘despair’ or ‘entrapment’; all of which are well known symptoms/signs of depression (Deussing,

254 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

2006). Sucrose testing assesses ‘anhedonia’ or loss of capacity to experience pleasure: this is inferred by the measured consumption or preference for a ‘pleasureable’ sucrose fluid. Lower levels of con- sumption suggest anhedonia. Together these three tests measure depression-like behaviour.

Various molecular biological correlates are suggested to be associated with the model of stress-associated depression-like behaviour. These findings can be separated into four mechanisms including (1) monoamine dysfunction, (2) HPA axis dysfunction, (3) neurogenesis dysfunction and (4) neuroimmune system dys- function (Fig. 2) as shown in various studies in humans with depression and in animals investigating depression-like behaviour (Eaton et al., 1996; Lanfumey et al., 2000; Wust et al., 2000; Pruess- ner et al., 2003; Gronli et al., 2006; Banasr et al., 2007; Goshen et al., 2008; Li et al., 2008; Luo et al., 2008; Pace and Miller, 2009; Elizalde et al., 2010; Frodl et al., 2010; Larsen et al., 2010; Karg et al., 2011).

3.1. Stress-associated neuroimmunological changes in depression

For the purpose of this review, we focus on the neuroimmune dysfunction related to the development of depression-like behav- iour in clinical and pre-clinical studies.

3.1.1. Clinical studies Clinical evidence suggests chronic stress induces depressive

symptoms and various neuroimmune changes. Systemic IL-6, CRP and NF-jB are consistently elevated in association with chronic stress-related depressive symptoms (see Table 1). Chronic stress induces increased Natural Killer (NK) cell function, increased Immunosenescence (i.e. lower CD4:CD8 ratio, higher proportion of CD8+ T lymphocytes (CTL) with an effector-memory phenotype or late differentiated (CD27�CD28�) and lower proportions of CTLs in early differentiation phase (CD27+CD28+)), lower CD4+ helper T cells, higher CD8+ suppressor T cells, higher CD8+/ CD57+ activated T lymphocytes and a higher CD4+/CD8+ ratio (Pace et al., 2006; Caserta et al., 2008; Bosch et al., 2009; Beavers et al., 2010a). TNF-a has also demonstrated to be induced by chronic stress (Amati et al., 2010).

Subjects with the short–short allele of the serotonin transporter (5-HTTLPR) polymorphism (which is correlated to lower serotonin availability and susceptibility to stress and depression) showed a pro-inflammatory state (increased IL-6/IL-10 ratio) when compared to long-long counterparts. This finding may be interpreted as a pos- sible biomarker suggesting stress susceptibility (Fredericks et al., 2010). In depressed patients, systemic inflammatory response is found to be exaggerated by acute stressors. Pace et al. (2006) found patients with Major Depressive Disorder having higher levels of NF- jB (inflammation-related nuclear transcription factor) when ex- posed to acute stress, as opposed to controls. A pre-clinical study

Fig. 2. Neuroimmunological effects of exercise in depression. Exercise impacts positively on neuroimmune mechanisms which in turn affect attenuation of depression and chronic stress (dotted line). Chronic stress impacts negatively on neuroimmune mechanisms which in turn affect initiation and perpetuation of depression (bolded line).

by Anisman et al. reflects a similar augmentation in inflamma- tion-related mediators after acute stress in mice with depression- like behaviour; a significant elevation in circulating cytokine levels (i.e. IL-6, TNF-a, IL-10 but not IL-1b, IFN-c) was found after social isolation stress in addition to chronic cytokine-induced (IFN-a) depression (Anisman et al., 2007). Acute stress results in a hyper- reactivity of the pro-inflammatory response versus non-stressed control (Maes et al., 1998; Steptoe et al., 2001; Bierhaus et al., 2003; Brydon et al., 2004, 2008; Kop et al., 2008). Chronic stress in the studies mentioned above was quite widely varied, such var- iability needs to be considered when comparing neuroimmune markers. It included parenting a child with cancer, care giving for a family member with dementia, early life stress, maltreatment and social isolation. There was also a wide variety of stress scales and depressive symptom scales utilised in these articles which diminishes the comparability of the different studies.

3.1.2. Pre-clinical studies There is a robust literature surrounding the neuroimmune

changes associated with uCMS-related depression-like behaviour in rodent studies (see Table 2). uCMS is associated with molecular neuroimmune changes in the CNS including increased proinflamma- tory cytokines (TNF-a, IL-1b, IL-6) (Sudom et al., 2004), increased complement activity (Ayensu et al., 1995), increased TLR-4, in- creased NK-kB, increased ROS (Lucca et al., 2009), increased COX-2 and PGE-2 (Guo et al., 2009). Increases in proinflammatory cytokines and oxidative stress markers are seen in plasma and in the CNS in various brain regions including then hypothalamus, pituitary, hip- pocampus, prefrontal cortex and cortex. There are no studies assess- ing stress-associated changes in inflammatory cytokines or oxidative stress markers in the amygdala. uCMS is also associated with increased systemic B cell reactivity, decreased systemic T cell reactivity, increased systemic T cell dependent/independent humor- al immunity markers and increased splenic mononuclear prolifera- tion (Azpiroz et al., 1999; Edgar et al., 2002, 2003; Silberman et al., 2004; aan het Rot et al., 2009). uCMS was also found to be associated with a decrease in hippocampal astrocyte density (Ritchie et al., 2004). Several studies support the evidence cited above (Kubera et al., 1998; Silberman et al., 2002, 2005; Munhoz et al., 2006; Pal- umbo et al., 2010; Rubinstein et al., 2010).

Stress-induced changes to neurobiological systems which were previously thought to be unrelated to the immune system have been discovered to influence the neuroimmune environment and induce depression-like behaviour. These include the cannabinoid system, IGF-1 and COX system (Duman et al., 2009; Guo et al., 2009; Beyer et al., 2010; Park et al., 2011). The interaction of these systems with the neuroimmune environment needs further exploration.

There are a number of putative psychoneuroimmunological fac- tors associated with the pathogenesis of depression (Kubera et al., 2011; Schwartz and Shechter, 2010a,b) (see Tables 1 and 2). The most well acknowledged understanding for the development of depression suggests that risk factors (mainly exposure to stress, but also genetic polymorphisms) combine to trigger a cascade of neuro-injury. Neuro-injury is thought to be mediated via activation of pathogen associated molecular patterns (PAMPS) and danger associated molecular pattern detectors (DAMPs) within the innate immune system (Kubera et al., 2011; Loftis et al., 2010; Maes et al., 2011). In addition there is modification of immune cell receptors (e.g. toll-like receptors) resulting in the overproduction of pro-inflammatory mediators like TNF-a, IL-1b, IL-6 and Prostaglan- din-E2 (PGE-2) in various brain regions (i.e. hippocampus, prefron- tal cortex and nucleus tractus solitaries) (Chang et al., 2008; Gibb et al., 2008; Maccioni et al., 2009; Kubera et al., 2011). Pro-inflam- matory cytokines can be released centrally (via microglia and astrocytes) or peripherally (via monocytes, macrophages, Th17 cells and other T cells) and certain cytokine signals are able to

Table 1 Neuroimmunological changes in stress-associated depression: clinical studies.

Study Study population (source and number)

Age, mean (range)

Study design

Stressor type Psychological measures

Biological measure Findings

Miller et al. (2002)

Oncology clinic, N = 50 37 Cross- sectional

Parents of children with cancer

CES-D POMS PSS

Expose blood to cort ? measure IL-1b, IL-6, TNF-a (i.e. measure anti-inflamm effect of cort)

" stress = " depressive sx’s " stress = " IL-6

Kiecolt- Glaser et al. (2003)

Nursing home, N = 225 (55– 89)

Prospective 8 years

Dementia caregiver

PSS BDI NLS

Plasma IL-6 Caregiving = " stress Caregiving = " IL-6 Caregiving = " depressive symptoms (Depressive symptoms were not correlated with IL-6 levels)

Pace et al. (2006)

Health volunteers, N = 28 (MDD in 14 subjects (DSM-4))

29.9 Prospective TSST Speech task Examination

SCID HDS ZDS CTQ (Early life stress)

Plasma IL-6 Lymphocyte subsets NF-jB activation within PBMCs

MDD = " CTQ score MDD + " CTQ = " IL-6 TSST = " IL-6 MDD > non-MDD TSST = " NF-jB MDD > non-MDD TSST = " NK cells MDD = non-MDD CTQ ns D with IL-6 or NF-jB D NK = ns D NF-jB and D IL-6

Danese et al. (2009)

New Zealand population sample, N = 862

32 Cross- sectional

NZSEI (SES) Childhood maltreatment measure RCS (childhood social isolation)

Psychiatric interview for MDD (DSM-4)

Plasma CRP MDD / definite maltreatment RR1.69 MDD / social isolation RR1.76 " CRP / definite maltreatment RR1.56 " CRP / social isolation RR1.60

Fredericks et al. (2010)

Healthy SS or LL 5- HTTLPR polymorphism specific patients, N = 30

21.7 Prospective TSST Speech task Examination

SCID LESS CTQ SSGS RAG SUDS BDI

Serum – IL6 and IL10 Genotyping

TSST = " in SSGS shame and pride subscales, SUDS and RAG TSST = " IL6, " IL10 IL-6/IL-10 ratio " in SS vs. LL at baseline and after TSST NS difference in IL6 or IL10 between LL and SS genotypes either before or after TSST At baseline, NS difference btw SS and LL for CTQ, BDI, RAG or LESS

Bob et al. (2010)

Unipolar MDD – inpatient, N = 40

42.3 (30– 58)

Cross- sectional

None BDI-2 TSC-40 DES SDQ-20

Serum IL-6 IL-6 / BDI-2, TSC-40, SDQ-20 IL-6 not / DES

NB: Level of significance set at p < 0.05. Legend: N = number, PSS = Perceived Stress Scale, STAI = State-Trait Anxiety Inventory, POMS – Profile of Mood States, cort = cortisol, CES-D = Centre for Epidemiological Studies Depression, sx = symptom, BDI = Beck Depression Inventory, NLS = NYU Loneliness Scale, PSSS = Perceived Social Support Scale, ROS = Role Overload Scale, BSI = Brief Symptom Inventory, TSST – Trier social stress test, PBMC = Peripheral Blood Mononuclear Cells, NF-jB = Nuclear Factor Kappa B, EMSA = Electrophoretic Mobility-Shift Assay, AD = Adrenaline, NA = Noradrenaline, MDD = Major Depressive Disorder, HDS = Hamilton Depression Scale, ZDS = Zung Depression Scale, CTQ = Childhood Trauma Ques- tionnaire, NK = natural killer cells, CRP = C-Reactive Protein, DSM – Diagnostic and Statistical Manual, SES = Socio-Economic Status, RCS = Rutter Child Scale, NZSEI = New Zealand Socioeconomic Index, vs. = versus CAD = Coronary Artery Disease, PCI = Percutaneous Coronary Intervention, sICAM1 = soluble Intra-cellular Adhesion Molecule-1, D = change in, / = correlation, HJSS = Healthcare Job Satisfaction Scale, GHQ = General Health Questionnaire, MSPSS = Multidimensional Scale and Perceived Social Support, SCID = Structured Clinical Interview for DSM-4, LESS = Life Events Scale for Students, SGSS = State Shame and Guilt Scale, RAG = Russell Affect Grid, SUDS = Subjective Units of

H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266 255

reach the brain parenchyma through humoral, neural and cellular pathways (Ziv et al., 2006; Quan and Banks, 2007; Maes et al., 2011; Capuron and Miller, 2011). More specifically, these path- ways include: cytokine passage through leaky regions of the BBB (IL-6, IL-1b, TNF-a), active transport via saturable cytokine-specific transport molecules (IL-1, TNF), activation of brain endothelial cells which release secondary messengers within the brain (PGE2, nitric oxide (NO)), cytokine signal transmission via afferent nerve fibres (IL-1) and entry into the brain of peripherally activated monocytes via microglia production of monocyte chemoattractant protein-1 (MCP-1) (Watkins et al., 1995; Plotkin et al., 1996; Goehler et al., 1999; Quan and Banks, 2007; D’Mello et al., 2009; Capuron and Miller, 2011).

Proinflammatory cytokines are thought to have an active role in molecular mechanisms that influence monoamine metabolism,

neuronal genesis/survival, HPA axis sensitivity to cortisol and certain cellular neuroimmune functions (Barrientos et al., 2003; Miller et al., 2009; Kubera et al., 2011). The cytokines can induce enzymatic activity increasing indoleamine-pyrrole 2,3-dioxygen- ase and tryptophan 2,3-dioxygenase (TDO) whilst at the same time decreasing blood tryptophan and hence serotonin levels (Goshen et al., 2008). Reduced serotonin in turn creates more vulnerability to stress and sets up a positive feedback loop for continued neuro- biological damage. A byproduct of IDO/TDO is kyrunenine, a metabolite of tryptophan, which is further metabolised by im- mune-related cells in the brain (i.e. macrophages, microglia and astrocytes) leading to the formation of potentially neurotoxic com- pounds such as 3-HK and QA (Capuron and Miller, 2011). Neuronal toxicity may cause apoptosis with lowered levels of Bcl-2 and BAG- 1 (Bcl-2 associated athanogene 1) and increased levels of caspase-3

Table 2 Neuroimmunological effects of depression-like behaviour: pre-clinical studies.

Study Animal/strain uCMS duration (weeks)

Test Other Biological measure Findings

Koo et al. (2010)

Rat/Sprague–Dawley (WT and NF-jB/LacZ transgenic reporter mice)

4 weeks (atypical) Or acute stress exposure

Sucrose consumption

CNS infusion of NF-jB inhibitor or IL-1b

BrdU injection (neurogenesis marker) – SGZ, DG In vitro AHPs (nestin + brdU measured with immunofluorescence and TUNEL assay)

CMS = ; sucrose consumption CMS + NF-jB inhibitor – ; sucrose consumption Acute or Chronic stress = ; neurogenesis Acute or Chronic stress + NF-jB inhibitor – ; neurogenesis IL-1b = ; AHP IL-1b + NF-jB inhibitor – ; AHP

Silberman et al. (2004)

Mice/BALB/c 6 Sucrose consumption

Serum cort Splenic NE T-cell dependent (SRBC and allogeneic cells) and independent (DxB512 and LPS) humoral response determined. Cells exposed to NE, E and cort Splenic lymphoid cell suspensions were obtained Mitogen assay – PHA (lymphoid proliferation)

CMS = ; sucrose pref from 4 to 6 wks CMS = " cort and NE from 0 to 3 wks (ns 4–6 wks) CMS = ; T cell dependent humoral immunity markers CMS – D T cell independent humoral immunity markers CMS = ; T cell response to PHA (wk 6)

Grippo et al. (2005)

Rat/Sprague–Dawley 4 Sucrose pref Hypothalamus, Ant Pit, Post Pit: cytokines Plasma: cytokines

uCMS induced anhedonia / " pro-inflamm cytokines (TNF-a, IL-1b, IL-6) in the brain and in plasma uCMS = " TNF-a Hypothal, Pit uCMS = " IL-1b Hypothal

Tannenbaum et al. (2002)

Mice/CD-1 54 days FST IL-1b injection IP

PVN, ME: 5-HT Plasma: CORT, GH

IL-1b + uCMS = FST immobility IL-1b = " cort IL-1b + CMS = " 5-HT

Goshen et al. (2008)

Mice/IL-1r KO vs. WT (C57BL/6x129/Sv)

5 Sucrose pref Hippocampal: IL-1b, IL-6

uCMS = " IL-1b uCMS = NS DIL-6

Litteljohn et al. (2010)

Mice/IFN-c KO vs. WT (C57BL/6 J)

42 days, atypical

FST Choc milk pref

PVN, CeA, PFC – monoamine levels (NE, CA, 5- HT) and their metabolites Plasma cort Serum cytokines – TNF- a, IL2, IL10, IL-4, IL-1b

CMS = " cort in WT (not IFN-c KO) CMS = " TNF-a in WT (not IFN-c KO) CMS = " IL-2 in WT (not IFN-c KO) CMS ns D IL10, IL-4, IL-1b CMS = " DA in PFC, PVN in WT and KO (ns in CeA) CMS = no change in NE or 5-HT in PFC or PVN or CeA CMS = " FST immobility (WT and KO) CMS = ; choc milk pref (WT and KO)

Gu et al. (2009)

Mice/apoE �/� 4 or 12 Sucrose consumption

Serum cort IHC of aortic root – TLR-4 Western blotting of aortic root – TLR-4, NK-kB ELISA of serum MCP-1, IL-1b, TNF-a RT-PCR of aortic root – genes for TLR-4, NK-kB, IL-1b etc.

CMS = ; sucrose consumption CMS = " cort CMS = " TLR-4, " NK- kB (both Western blotting, RT-PCR) TLR- 4 IHC also CMS = " IL-1 b

NB: Level of significance set at p < 0.05. Legend: wks = weeks, NE = norepinephrine, DA = dopamine, 5-HT = serotonin, E = Epinephrine, PVN = Paraventricular Nucleus, PFC = Prefrontal Cortex, ME = Median Emi- nence, IP = intraperitoneally, cort = corticosterone, immob = immobility, PGE2 = Prostaglandin E2, COX = Cyclo-Oxygenase enzyme, CeA = Central Amygdaloid Nucleus, LN = lymph node, ROS = Reactive Oxygen Species, TBARS = Thiobarbituric acid reactive species, T4 = Thyroxin, T3 = Triiodothyronin, D = change in, MR = Muscarinic cholin- ergic receptor, LPS = lipopolysaccharide, SRBC = sheep red blood cells, DxB512 = Dextran B512, PHA = Phytohemagglutinin, PKC = protein kinase C, NKCA = Natural Killer Cell activity, IL-1r = IL-1receptor, Hypothal = Hypothalamus, Pit = Pituitary, IHC = Immunohisto chemistry, EMSA = Electrophoretic mobility shift assay, SGZ = Subgranular zone, DG = Dentate Gyrus, AHP = Adult Hippocampal Progenitor. NB: Increased immobility in the FST suggests depression-like behaviour. Specifically, immobility suggests apathy, disengagement and/or despair.

256 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

(Kubera et al., 2011). It is important to note that a recent study in IFN-a-treated patients showed that CSF tryptophan levels re- mained stable despite decreased blood levels of tryptophan (Raison et al., 2010). This highlights the importance of conducting measurements in both the periphery and CSF (Dantzer et al., 2011).

Cytokines increase the activity and surface density of 5-HT, DA and NA transporters at the neuronal poles (Moron et al., 2003; Zheng et al., 2006). This increases monoamine uptake and turnover and decreasing concentrations in the synaptic cleft which subse- quently impairs neuronal functioning. The hypothesised reduction in 5-HT activity may exert downstream effects on BDNF transcrip-

tion via 5-HT receptor coupling to the cyclic adenosine monophos- phate (cAMP) response element-binding (CREB) (Mattson et al., 2004).

Treatment with lipopolysaccharide (LPS), a potent inflamma- tory cytokine stimulator, has been shown to reduce expression of the BDNF receptor tyrosine kinase-B (TrkB) (Wu et al., 2007). Cyto- kine activation of inflammatory signalling molecules include nu- clear factor kappaB (NF-jB), p38, mitrogen-activated protein kinase (MAPK) and STAT5 (Miller et al., 2009). Some of these have been shown to inhibit glucocorticoid receptor (GR) functioning through GR translocation as well as GR-DNA binding (Miller

H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266 257

et al., 2009). This presents a potential explanation for why stress related hypercortisolaemia may occur. Stat5, a transcription factor, has been found to negatively regulate IL-17 production and sup- press proinflammatory cytokine signalling (IL-17A, IL-17F, IL-21, IL22, IL-26, TNF-a) by impairing Th17 cell generation (Laurence et al., 2007; Fouser et al., 2008; Ouyang et al., 2008). Other inflam- matory mediators such as Cyclooxygenase-2 and PGE-2 are also found to be increased in depression however their role in patho- physiology is largely unknown (Guo et al., 2009). Cell-mediated immune activation also takes place in the early stages of depres- sion, this is indicated via increased production of interferon-gam- ma (IFN-c), neopterin and IL-12 (Maes et al., 2011). Pro-inflammatory cytokines also have a role in impairing T cell function, promoting apoptosis and impeding proliferation (Caruso et al., 1993; Maes et al., 1995; Mellor et al., 2003; Clark et al., 2005). It is also important to recognise that some opposing evidence has been reported. Type 1 interferons a and b have been shown to pre- vent activated T cell death after antigen exposure suggesting that they act as survival factors for these cells (Marrack et al., 1999). Osteopontin, or early T cell activation gene-1, costimulates T cell proliferation and enhances IFN-c and IL-12 production whilst diminishing IL-10 (Ashkar et al., 2000; O’Regan et al., 2000; Chabas et al., 2001).

Evidence suggests a role for Treg cells in the pathogenesis of depression. These cells have been shown to have a neuroprotective function and also have a counter-regulatory effect on pro-inflam- matory mediators (Cohen et al., 2006; Ishibashi et al., 2009; Liu et al., 2009; Capuron and Miller, 2011). There numbers are de- creased in the disease state, and interestingly the cell population has been demonstrated to increase following successful antide- pressant therapy (Himmerich et al., 2010).

It has recently been suggested that an impaired physiological surveillance of neuroimmunological processes at the blood–brain barrier may result in failure of ‘protective autoimmunity’ in the central nervous system (CNS) mediated by a malfunction of phys- iologically circulating self-specific CD4+ T cells (Moalem et al., 1999; Schwartz and Kipnis, 2002; Schwartz and Shechter, 2010a,b). Chronic stress could be a potential mediator of this mal- function. Normally CNS surveying T cells, central to ‘immunosur- veillance’, contribute to the healthy brain’s plasticity (i.e. supporting hippocampal neurogenesis, hippocampal-dependent cognitive abilities and mental behaviour). The physiological sur- veying CD4+ T cells are skewed towards a Th-2 phenotype and re- lease intra-CNS regulatory cytokines (e.g. IL-4) and growth/survival factors (e.g. IGF-1) (Beers et al., 2008; Chiu et al., 2008). These CNS surveying cells ensure controlled trophic support, effective buffer- ing against cytotoxicity, antioxidative effects and general meta- bolic stability. This model suggests that in depression, impaired physiological surveillance may occur due to suppressed peripheral immunity. Such a suppressed peripheral immune system deprives the brain of these cells which are needed to restore homeostasis – damage ensues. Indeed, mice lacking CD4+ T cells show reduced neuroprotective and anti-inflammatory factors as well as increased TNF- a and superoxide (Beers et al., 2008). A depletion in CD4+ T cells also leads to reduced hippocampal neurogenesis, impaired cognition-like behaviour and decreased BDNF (Wolf et al., 2009). How the typical depression-related increased proinflammatory and oxidative state is linked to aberrant immunosurveillance is still under investigation (Schwartz and Shechter, 2010a,b).

Monocyte-derived macrophages have a role in the CNS for reg- ulating microglial functions by secreting growth factors (e.g. IGF-1) and anti-inflammatory cytokines (e.g. IL-10). These macrophages may attenuate the neurotoxic mediators (i.e. pro-inflammatory cytokine production and ROS production) released from microglia in depression (Schwartz and Shechter, 2010a,b; Derecki et al., 2011). It is suggested that astrocytes and microglia have a gluta-

mate mediatory role in depression pathogenesis. In a pro-inflam- matory state in the CNS, they have a role in glutamate mediated neuronal excitotoxicity (via modulation of NMDA receptors), reduced BDNF and ROS release (Bezzi et al., 2001; Capuron and Miller, 2011). Conversely astrocytes may also have a role in sup- pressing neurotoxic microglial responses which may be relevant to depression. The mechanism of this suppression is linked to the CD200 glycoprotein and the CX3CR1 receptor which both deliver an inhibitory signal to the microglia (Hoek et al., 2000; Cardona et al., 2006). However, the process of glutamatergic interplay, be- tween neurons and glia, in a pro-inflammatory CNS state, is com- plex and largely unknown (Hoek et al., 2000; Cardona et al., 2006; Vesce et al., 2007; Cali and Bezzi, 2010).

Depletion of circulating immune cells such as CD4+ and CD 8+ T cells and T regs exacerbates the disease process in several neurode- generative conditions including amyotrophic lateral sclerosis and other autoimmune diseases (Kipnis et al., 2002; Beers et al., 2008; Chiu et al., 2008). Cognitive impairment associated with bone marrow depletion of mice is reversed by transplantation (Brynskikh et al., 2008; Derecki et al., 2010).

There is a large amount of primary literature and reviews illus- trating similar neuroimmunological processes associated with other stress-related neuropsychiatric pathologies including Alzhei- mer’s disease, mild cognitive impairment, anxiety disorder and schizophrenia. Reviews which summarise the clinical and pre- clinical neuroimmunological evidence can be found in the follow- ing articles: (McAfoose and Baune, 2009; Banks, 2010; Perl, 2010; Haroon et al., 2011; Kelley and Dantzer, 2011; Muller and Dursun, 2011; Northrop and Yamamoto, 2011).

3.2. Exercise in depression

Exercise has efficacy in the treatment of mild to moderate depression (Carek et al., 2011). Similar behavioural results are found in pre-clinical rodent models. In this review we propose that the therapeutic effect of exercise is largely attributed to its activity on the neuroimmune system (see Fig. 2).

Several recent review papers which assessed the utility of exer- cise in clinical depression suggest that exercise is a useful thera- peutic option (Mead et al., 2009; Strohle, 2009; Conn, 2010a,b; Carek et al., 2011). These papers have assessed prospective-longi- tudinal studies in clinically depressed populations. Exercise can be either a stand alone or adjunctive therapy, and has preventative properties (Baldwin, 2010; Rees and Sabia, 2010; Rothon et al., 2010).

The most recent meta-analyses from 2010 by Conn (2010a,b) included 70 studies with 2679 clinically depressed subjects and suggested that there was a moderate and statistically significant effect size for exercise in treating depression (supervised exer- cise effect size is 0.372 and un-supervised exercise effect size is 0.522). A recent review conducted for the Cochrane review database, with 27 articles in total and 907 participants, showed evidence suggesting exercise was effective in the treatment of depression (standardised mean difference was �0.82, equalling a large clinical effect) (Mead et al., 2009). After stringent exclu- sion criteria only three trials with adequate methodology were included and the overall effect was moderate and not significant. Important to note are methodological inconsistencies in this field, as discussed in 2009 by a Cochrane database review by Mead et al. (2009). Of consideration is inadequate allocation con- cealment, lack of intention to treat analysis and lack of blinded outcome assessment. Further, there is heterogeneity when assessing duration of exercise therapy, type of exercise therapy and intensity of therapy.

Exercise is hypothesised to impact mental health via a number of psychological mechanisms including: distraction to negative

258 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

affect and hence rumination, enhanced self-efficacy, self-esteem, behavioural activation, sense of achievement/mastery and self- determination (Salmon, 2001). Depression may cause a reduction in physical activity via anhedonia and vegetative symptoms including psychomotor retardation and lethargy. Exercise has a propensity in reducing psychological stress, which recently has been correlated with the promotion of stress resilience (via posi- tive self-esteem) in adolescents and adults (Baldwin, 2010; Rees and Sabia, 2010; Rothon et al., 2010).

The evidence for the preventative properties of depression is mainly derived from cross-sectional evidence with a limited number of longitudinal studies. Epidemiological evidence sug- gests a cross-sectional association between sedentary lifestyles and depression, mainly in women and adults above the age of 40 with similar trends in adolescents (Martinsen, 2008; Carek et al., 2011). More longitudinal studies are required to further understand the role of physical activity in the prevention of depressive disorders.

As there is an increase in obesity, aka obesity epidemic, and an increase in the elderly population of ‘developed’ countries, and these two populations exhibit increased prevalence of depression, it is important to describe the relationship between exercise and depression in these populations (Lloyd-Sherlock, 2000; Laks and Engelhardt, 2010; Luppino et al., 2010; Finucane et al., 2011). Depression rates are lower in physically active overweight/obese adults. Physical activity reduces depressive symptoms in obese, depressed patients and physical activity pre- vents the onset of depression in obese patients (de Wit et al., 2010; Vallance et al., 2011). Higher levels of habitual physical activity are protective against the subsequent risk of develop- ment of, and relapse of, depressive disorders among older pa- tients (Strawbridge et al., 2002; Teychenne et al., 2008; Carroll et al., 2010; Pasco et al., 2011). Exercise is also found to be ben- eficial in the treatment and prevention of cognitive disorders (Alzheimer’s disease and mild cognitive impairment), Parkinson’s disease, bipolar disorder, schizophrenia and anxiety disorder (Ng et al., 2007; Baker et al., 2010; Gorczynski and Faulkner, 2010; Radak et al., 2010; Gleeson et al., 2011; Graff-Radford, 2011; Lautenschlager et al., 2011). A recent review provides evidence to suggest exercise may lower disease risk and/or have therapeu- tic value in treating coronary heart disease, stroke, cancer and type 2 diabetes mellitus via its anti-inflammatory effect (Gleeson et al., 2011).

Rodent studies suggest exercise decreases stress-associated depression-like behaviours (see Table 4). Authors such as Zheng et al. and Solberg et al. found exercise reversed uCMS induced anhedonia-like behaviour in sucrose testing after 4 and 6 weeks, respectively (Solberg et al., 1999; Zheng et al., 2006). Furthermore it was found exercise reversed uCMS induced depression-like symptoms on the FST (i.e. less immobility time) after 4 weeks (Solberg et al., 1999). Rodents models show physical activity can reduce stress-associated anxiety-like behaviours, schizophrenia- like behaviour and enhance cognition-like behaviour (Clark et al., 2008; Parachikova et al., 2008; Trejo et al., 2008; Nakajima et al., 2010; Wolf et al., 2011).

Unlike studies assessing the acute immunological effects of exercise, this review focuses on chronic exposure to physical activ- ity. This is important to mention given the numerous studies in both clinical and pre-clinical models showing an upregulation of IL-6 and IL-8 during and immediately after exercise (Fischer, 2006; Pedersen, 2009). The acute, transient upregulation of IL-6 appears to cause a rise in anti-inflammatory cytokines IL-10 and IL-1Ra (Steensberg et al., 2003). Interestingly, a recent pre-clinical study by Funk et al. (2011) suggests that the acute upregulation of IL-6 with exercise may be neuroprotective given it negates the neurotoxic changes of TNF-a.

3.3. Neuroimmunological effects of exercise

While the evidence been presented in this review suggests sig- nificant effects of stress on neuroimmunological changes related to depression as well as good efficacy of exercise in treating depres- sion, the potential neuroimmunological effects of exercise in depression still need to be explored from both a clinical and pre- clinical perspective. It is proposed the neuroimmune effects in the brain are ascribed to exercise’s therapeutic effect. The authors will conclude this section by proposing a theoretical or conceptual model for the neuroimmunological effects of exercise in depression.

3.3.1. Immunological effects of exercise: clinical studies Clinical evidence suggests exercise reverses neuroimmune pro-

cesses relevant to stress-associated depression-like behaviour (see Table 3). The studies in this field show exercise can decrease stress- related depression correlated with decreased IL-6, IL-18, CRP and TNF-alpha. There is evidence to suggest that biological changes in the brain relevant to depression may differ between aerobic and flexibility exercise, further there may also be an effect for the intensity of exercise on various biomarkers (Kohut et al., 2006; Hamer et al., 2009).

There are numerous studies which suggest exercise has effects on reversing chronic stress related neuroimmune changes. In these studies exercise is associated with a reduction in C-reactive protein, Toll-Like Receptor-4, IL-6, IL-8, TNF-alpha and IL-1beta; an increase in anti-inflammatory mediators such as IL-10 is also noted (Tisi et al., 1997; Geffken et al., 2001; Church et al., 2002; Ford, 2002; Wannamethee et al., 2002; Stewart et al., 2005; Kadog- lou et al., 2007; Sloan et al., 2007; Nicklas et al., 2008; Campbell et al., 2009; Beavers et al., 2010b; Donges et al., 2010; Martins et al., 2010). These humoral neuroimmune factors are measured either in plasma or are derived from induced immune cells (i.e. Lipopolysaccharide (LPS) used with Peripheral Blood Mononuclear Cells (PBMCs)). Beavers et al. (2010a,b) has carried out a thorough review investigating the impact of exercise on chronic inflamma- tion. Cellular neuroimmune factors modified by exercise include increased CD11b and CD66b PBMCs, enhanced gene expression from PBMCs (i.e. IL-5, IL-8, IL-2), increased Treg cells and increased CD14+CD16+ monocytes (Nawaz et al., 2001; Yeh et al., 2006; Timmerman et al., 2008; Coen et al., 2010; Thompson et al., 2010; Wang et al., 2011).

On the contrary, there are additional studies showing no ef- fect for exercise on inflammatory or oxidative markers (Hammett et al., 2004; Nicklas et al., 2004; Fairey et al., 2005; Marcell et al., 2005; Campbell et al., 2008, 2009, 2010; Christian- sen et al., 2010). These inconclusive studies are in a minority and, in some cases, may be attributed to a lower intensity or intermittent type of exercise. There are is also a wide variety of immune measures utilised throughout these studies. It is important to note that studies within this field may have limita- tions given they use in vitro measures to model complex biolog- ical processes in vivo. Further details about limitations with respect to immune measures were recently reviewed (Gleeson et al., 2011).

3.3.2. Immunological effects of exercise: preclinical studies There is strong evidence that exercise reverses stress-associ-

ated depression-like behaviour in rodent models (see Table 4) with the implication of a wide range of neuroimmune mecha- nisms. When investigating the effect of exercise on neuroim- mune changes in uCMS exposed rodents, exercise decreased IL- 1b, IL-6, IL-1ra, TNF-alpha and oxidative stress markers (Chenna- oui et al., 2008; Nichol et al., 2008; Parachikova et al., 2008; Gimenez-Llort et al., 2010). These changes are noted to occur

Table 3 Neuroimmunological effects of exercise: clinical studies.

Study Study population (source, number)

Age, mean (range)

Study design Exercise type, duration

Psychological measures

Biological measure

Findings

Kohut et al. (2006)

Community, N = 105 >64 years RCT Aerobic or flexibility exc, 10 months

GDS PSS CS SPS LOT

Plasma – CRP, IL- 6, TNF-a, IL-18

EXC = ; depression EXC = " optimism Aerobic EXC = ; IL-6, IL-18, CRP, TNF-a Flexibility EXC = ; TNF-a ; CRP = ; depression Flex EXC = ns change in IL-6, IL-18, CRP

Hamer et al. (2009)

Healthy community dwellers, N = 4323

63.4 Longitudinal, 4 years

Self-reported physical activity

CES-D – (baseline and 4 years)

Venous blood CRP and fibrinogen

Moderate EXC = ; CES-D vs. light EXC group Vigorous EXC = ; CES-D vs. light and moderate EXC groups Moderate EXC = ; CRP vs. light EXC group Vigorous EXC = ; CRP vs. light and moderate EXC groups Vigorous EXC = ; fibrinogen vs. light and moderate EXC groups

NB: Level of significance set at p < 0.05. Legend: N = number, MADRS = Montgomery Asberg Depression Rating Scale, GDS = Geriatric Depression Scale, PSS = Perceived Stress Scale, CS = Coherence Scale, SPS = Social Provisions Scale, LOT = Life Orientation Test, SAA = Serum amyloid A protein, – = not equal to, D = change in, ns = non-significant, T2DM = Type-2 Diabetes Mellitus, hs CRP = high sensitivity C-Reactive Protein, MetS = Metabolic syndrome, TLF = toll-like receptor, PGN = peptidoglycan, NOS = not otherwise specified, PBMC = peripheral blood mononuclear cell, NHANES = National health and Nutrition Examination Survey, CES-D = Centre for Epidemiologic Studies Depression Scale.

Table 4 Neuroimmunological effects of exercise: pre-clinical studies.

Study Animal Environmental exposures (exercise type/ duration and CMS/duration)

Laboratory measures Findings

Solberg et al. (1999)

Mice/ C57BL6 J

Vol wheel running/6 wks, CMS/6 wks FST Sucrose pref

Sucrose test CMS + EXC = ; sucrose pref vs. CMS alone FST CMS + EXC = ; immob vs. CMS alone Distance run CMS = ; EXC vs. control

Zheng et al. (2006)

Rat/Sprague– Dawley

Vol wheel running/4 wks, CMS/4 wks Hippocampal: BDNF, GR Plasma: cort Sucrose consumption

Sucrose test CMS + EXC = ; sucrose vs. CMS alone Plasma cort EXC = ; cort in CMS group vs. control BDNF EXC = " BDNF in CMS vs. control

Duman et al. (2009)

Mice/C57BL6 Vol wheel running/4 wks, CMS/2 wks Prefrontal cortex IGF-1 (ELISA) Prefrontal cortex and hippocampal IGF-1 and BDNF mRNA (ISH) FST Sucrose consumption Other Mice treated with IGF-1 (peripherally) or anti-IGF-1 (centrally)

Sucrose test CMS = ; sucrose vs. Control CMS + IGF-1 (peripheral) = " sucrose vs. CMS + vehicle FST CMS + IGF-1 = ; immob vs. CMS + vehicle CMS + anti-IGF-1 = " immob vs. CMS + vehicle EXC = ; immob vs. sedentary mice ISH ns D IGF-1 or BDNF mRNA in any brain region

NB: Level of significance set at p < 0.05. Legend: exc = exercise, WT = wildtype, SED = sedentary, EXC = exercise, Tg = transgenic, ConA = concanavalin A, MCP-1 = monocyte chemoattractant protein-1, LPS = lipo- polysaccharide, MDA + 4-HAD = malondialdehyde plus 4-hydroxyalkenal, GSH = Glutathione, GSSG = Oxidized GSH, GPx = GSH Peroxidase, SOD-CuZn = Superoxide Dismu- tase, IGF-1 = Insulin-like Growth Factor-1, vol = voluntary, FST = forced swim test, EXC = exercise, CMS = chronic mild stress, GR = glucocorticoid receptor, cort = corticosterone, ISH = In situ hybridisation.

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in plasma and in various brain regions including the hippocam- pus, cerebellum, pituitary and cortex. There are no studies assessing these factors in the prefrontal cortex or amygdala. The changes are in direct contrast to the effects of chronic stress on the brain and suggest exercise has the ability of reversing stress associated inflammatory and oxidative mechanisms, this is in keeping with our model seen in Fig. 2. Exercise has also

shown to increase IL-10, hippocampal chemokine CXCL1 and CXCL12, and systemic macrophage released MAPK phosphatise- 1 (MKP-1) concentrations, although some studies are contradic- tory (Parachikova et al., 2008; Chen et al., 2010; Kawanishi et al., 2010; Sigwalt et al., 2011). The upregulation of these immune regulators is significant given their effect on glial cells and neuroprotective mechanisms. CXCL1 is known to have neu-

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roprotective properties in the CNS (Parachikova et al., 2008). CXCL12 regulates astrocyte mediated neuronal excitability and enhances signal propagation within glial networks (Innocenti et al., 2000; Bezzi et al., 2001). MKP-1 negatively regulates proinflammatory macrophages activation (Chen et al., 2010). Furthermore, exercise showed a decreasing effect on systemic CD3+CD8+ cytolytic T cells and macrophages, whereas no exer- cise-related changes in M1 or M2 macrophage markers were ob- served (Rogers et al., 2008; Kawanishi et al., 2010). Decreasing numbers of macrophages and T cells in the periphery may sug- gest there is migration to the CNS and hence these cells may be attenuating neurotoxic microglia and mediating other neuroregenerative processes (Schwartz and Shechter, 2010a,b; Capuron and Miller, 2011). T cells were increased in the hippocampus along with CCR2 (a microglial chemoattractant factor) through exposure with exercise (Parachikova et al., 2008).

Another immune effect of exercise is suggested by Duman et al. (2009) suggesting that the exercise induced elevations in IGF-1 (prefrontal cortex and hippocampus) had a role in attenuating uCMS-associated depression-like behaviour, which suggests a likely anti-inflammatory effect of IGF-1 (Park et al., 2011). Interest- ingly IGF-1 is implicated in regulating the neuroprotective pro- cesses of monocyte-derived macrophages and self-specific CD4+ effector T cells (Schwartz and Shechter, 2010a,b). Finally, Funk et al. (2011) suggests that IL-6 which is up regulated acutely in the brain following exercise may buffer TNF-a mediated neurotox- icity which may present a mechanism for exercise’s neuroprotec- tive effects.

Exercise has a neuroprotective and anti-inflammatory effect on the brain and stress-related neuropsychiatric pathologies which include Alzheimer’s disease, mild cognitive impairment, anxiety disorder and schizophrenia. The clinical and pre-clinical evidence for these effects can be read in the following review articles:

Fig. 3. Neuroimmunological effects of exercise in depression. CNS = central nervous syst glucocorticoid, GR = glucocorticoid receptor, BDNF = brain-derived neurotrophic factor, quinolinate, 3-HK = 3-hydroxykynurenine, QA = quinolinic acid, MKP-1 = MAPK phosph

(Beavers et al., 2010a; Gleeson et al., 2011; Wolf et al., 2011; Yau et al., 2011).

3.4. A model for the neuroimmunological effects of exercise in depression

As previously shown, exercise has various neuroimmune mod- ulating effects which are relevant to both the innate and adaptive immune systems. In addition, several humoral and cell-based neu- roimmune mechanisms have been suggested as a result of exercise. Humoral neuroimmune mechanisms relevant to stress-associated depression, which are positively affected by exercise, include reduction in pro-inflammatory mediators (e.g. TNF-a, IL-6, IL-1b, TLR-4 and CRP), reduction in ROS, elevated IL-10, and increased CXCL1, CXCL12 and MKP-1. Modulation of pro-inflammatory cyto- kines and oxidative stress occurred in plasma and various brain re- gions including the hippocampus, cerebellum, pituitary and cortex. Cellular neuroimmune mechanisms positively affected by exercise, which are relevant to stress-associated depression, include de- creased CD8+ T cells, decreased macrophages, increased hippocam- pal T cells, increased CCR2 (microglial chemoattractant factor), increased CD14+16+ monocytes and increased CD11b and CD66b PBMCs.

Exercise may reduce inflammation and oxidation stress via var- ious pathways including (1) increased attraction of macrophage numbers into the CNS and hence enhancing their regulatory effects on neurotoxic microglia, and (2) upregulation of MKP-1 which plays an essential role in negatively regulating the proinflamma- tory macrophage MAPK activation (Chen et al., 2010). Exercise associated immunological mechanisms also include the upregula- tion of CXCL1, which has neuroprotective properties (Parachikova et al., 2008) and the upregulation of CXCL12 which enhances (a) glutamate release from astrocytes hence regulating neuronal excit- ability, (b) signal propagation within glial networks and (c) synap-

em, Th17 = T helper 17, COX-2 = cyclooxygenase 2, PGE-2 = prostaglandin E2, GC = 5-HT = serotonin, NA = noradrenaline, IDO = indoleamine 2,3-dioxygenase, QUIN = atase 1, Treg = T regulatory, IGF-1 = Insulin-like growth factor-1.

H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266 261

tic transmission (Kang et al., 1998; Innocenti et al., 2000; Bezzi et al., 2001). Exercise also plays a role in modulation of hippocam- pal T cells which are responsible for neuroregeneration and for modulation of microglia.

On the contrary, it is unknown whether exercise has an effect on markers of immunosenescence, PGE-2, B or T cell reactivity, astrocyte populations, self-specific CD4+ T cells, Th17 cells or Treg cells. It is recommended to further investigate the potential effects of exercise on these markers to elicit the neuroimmune mecha- nisms responsible for the therapeutic effect of exercise on stress- associated depression.

Exercise leads to a reduction in visceral fat mass and is a com- mon lifestyle intervention used to treat and prevent obesity. The reduction in visceral fat mass is a possible mechanism by which exercise exerts its anti-inflammatory effects (Petersen and Pedersen, 2005; Mathur and Pedersen, 2008). It is known that an increase in adipose tissue increases production of adipokines including TNF, leptin, retinal-binding protein 4, lipocalin 2, IL-6, IL—18, CCL2 and CXCL 5, whereas anti-inflammatory adiponectin is reduced (Ouchi et al., 2011). Additionally, exercise may reduce systemic inflammation by inhibiting monocyte and macrophage infiltration into adipose tissues as well as stimulating phenotype switching within adipose tissue (Kawanishi et al., 2010).

The International Society of Exercise and Immunology (ISEI) has recently published two position statements which provide a con- sensus, from world-leading experts, on current knowledge in the field of exercise-related immunology, as well as information on continued controversies and future directions in the field (Walsh et al., 2011a,b).

The interplay of several neuroimmune mechanisms relevant to stress, depression-like behaviour and exercise are displayed in Fig. 3. It can be seen that chronic stress has an effect on pathophys- iological processes in depression (seen on the left) involving spe- cific cellular and molecular neuroimmune changes. These neuroimmune changes then modulate more general changes such as HPA axis function, monoamine metabolism and neurogenesis (seen at the bottom of the figure) to bring about depressive behav- iours. On the other hand, exercise appears to negate these general effects via opposing cellular and molecular neuroimmune changes (seen on the right) to elicit an antidepressive outcome on behaviour.

4. Discussion

Over the years, many investigators have established that there are neuroinflammatory and oxidative mechanisms associated with the pathogenesis of depression and stress-related depression (Miller et al., 2009; Kubera et al., 2011; Maes et al., 2011). Assess- ment of cell-mediated neuroimmune mechanisms in this disease entity is relatively new, and in need of further investigation. It is thought that astrocytes, various subsets of T cells, macrophages and microglia may be central to the cell-mediated interactions be- tween the various neurobiological processes involved in depres- sion pathogenesis (i.e. monoamine dysfunction, HPA axis dysregulation, neurogenesis-related abnormalities, inflammation and oxidative stress).

In the field of prevention and management of depression, exer- cise has shown clinical effects in humans and positive behavioural effects in rodents (Solberg et al., 1999; Zheng et al., 2006; Duman et al., 2009; Mead et al., 2009; Conn, 2010a,b; Rees and Sabia, 2010; Rothon et al., 2010; Carek et al., 2011). The mechanisms associated with the effect of exercise on depression are classically attributed to an anti-inflammatory effect, however these anti- inflammatory effects require further research (Archer et al., 2011). There is also a paucity of data investigating the cell-medi-

ated neuroimmune effects of exercise, i.e. modulation of T cell, astrocyte, macrophage and microglial functioning.

This review is the first to systematically draw together the liter- ature supporting a role for neuroimmune modulation as a mecha- nism for the therapeutic efficacy of exercise in depression (see Figs. 2 and 3). When clinical and pre-clinical data is taken together, exercise may reduce inflammation and oxidation stress via (1) increasing macrophage numbers into the CNS and hence enhanc- ing their regulatory effects on neurotoxic microglia, and (2) up reg- ulating MKP-1 which plays an essential role in negatively regulating the proinflammatory macrophage MAPK activation (Chen et al., 2010). Neuroimmune mechanisms associated with exercise also include the upregulation of CXCL1 which is consid- ered being neuroprotective and the upregulation of CXCL12 which exerts several enhancing effects on: (1) glutamate release from astrocytes hence regulating neuronal excitability, (2) signal propa- gation within glial networks and (3) synaptic transmission (Kang et al., 1998; Innocenti et al., 2000; Bezzi et al., 2001; Parachikova et al., 2008). It has been suggested that exercise also has a role in modulation of hippocampal T cells which are responsible for neu- roregeneration and modulation of microglia.

Surprisingly, it is unknown whether exercise has effects on spe- cific neuroimmune markers implicated in the pathogenesis of depression such as markers of immunosenescence, PGE-2, B or T cell reactivity, astrocyte populations, self-specific CD4+ T cells, Th17 cells or Treg cells. To clarify their potential involvement in mediating positive effects of exercise on depression mediated by the immune system, further investigations are warranted.

When investigating the neuroimmune mechanisms implicated in stress-associated depression there is a high degree of similarity between human and rodent studies. Similarities are seen in hu- moral factors, i.e. increased IL-6 and TNF-alpha; and similarities are seen in cellular biomarkers, i.e. increases in T cell and B cell numbers and reactivity. There are a number of neuroimmune fac- tors which have been investigated either in human of rodent stud- ies, not both though. These biomarkers include COX-2, oxidative stress markers, TLR-4, immunosenescence markers, astrocytes, microglia and other specific T cell types. Clearly, these markers are relevant for future investigation.

There is a robust literature found when assessing the neuroim- mune effects of exercise in relation to stress-related depression- like behaviour in both human and rodent studies. Exercise is seen to produce a reduction in IL-1beta, TNF-alpha, IL-6, oxidative stress markers, levels of PBMCs, various chemokines, specific T cell pop- ulations and monocyte populations. However, the literature shows some disparities among the investigated immune markers being studied in either clinical or pre-clinical models, not both. In order to advance the understanding of the mechanistic immune effects of exercise, it required to study the same immune markers in hu- mans and animals as much as possible.

However, overall the large number of studies reviewed in this article are generally consistent with the proposal that exercise is a theoretical model for reversing or attenuating neuroimmune mechanisms related to stress-associated depression-like behaviour (see Figs. 2 and 3).

There are some methodological limitations which need to be considered when interpreting the results presented in this review. Research investigating stress-associated depression and its neuro- immune correlates (in humans) show a wide variety of stress types, durations and severities; there are also multiple stress and depressive symptom scales used. Rodent studies in this field have a degree of methodological variability including the uCMS protocol components used, uCMS protocol duration, presence or absence of depression-like symptom testing, species utilised (mouse vs. rat), strain utilised (i.e. variability can be seen in stress resilience/vul- nerability between strains (Palumbo et al., 2010)), ratio of species

262 H. Eyre, B.T. Baune / Brain, Behavior, and Immunity 26 (2012) 251–266

gender and brain areas investigated (i.e. hippocampus, hypothala- mus, prefrontal cortex and pituitary).

Rodent studies utilised to model and test depression are often criticised for their profile across certain validation criteria (face validity, predictive validity, aetiological validity, construct valid- ity and reproducibility) (Pollak et al., 2010). From the authors’ perspective uCMS, FST, TST and sucrose tests are deemed to rate relatively highly across these validation domains versus other models and tests for depression-like behaviour. Their validity is demonstrated in two ways – firstly, the congruency of behav- ioural and immune outcomes between translational results in humans, i.e. chronic stress correlates to depression-like behav- iours in both clinical and pre-clinical studies and likewise exer- cise results in a reduction in depression-like behaviour. Secondly, evidence produced by previously published authors suggests high levels of validity across the various validity domains (de- scribed above) (Willner, 2005; Kubera et al., 2011; Pollak et al., 2010).

Human and rodent studies assessing the positive effects of exer- cise on neuroimmune mechanisms, and depressive behaviours, are difficult to compare due to obvious methodological variability. This inherent variability is increased by the utilisation of different types, durations and intensities of the exercise investigated. This is important considering variations in these domains are related to differing immune outcomes. Additionally, variability is in- creased by inconsistencies in the immune markers investigated, i.e. certain immune cell types and humoral immune mediators are assessed in human or rodent studies, not both. Also ‘stress’ and ‘depression-like behaviour’ scales are inconsistently employed in this field, for example some studies will assess the immune ef- fects of exercise with a behavioural correlate, whereas other stud- ies won’t employ such correlates.

There are a number of recommendations for future research in order to further support the theoretical model of exercise as a neu- roimmune modulator in depression. In human studies the utilisa- tion of multimodal research techniques is useful as it provides a better insight into complex interactions. A study by Frodl et al. (2010) presents an example of such an approach where there was utilisation of genotyping, fMRI and psychological tests in MDD subjects. The research for neuroimmune-related endopheno- types in depression (i.e. single nucleotide polymorphisms for IL- 1beta, TNF-alpha and COX-2) an example, are a promising approach as recently shown by a study from this group (Baune et al., 2010). However, interventions such as exercise have not been part of these studies yet.

Moreover, it is recommended to reach a consensus regarding the psychological scales or diagnostic techniques used to mea- sure ‘chronic stress’ and ‘depressive symptoms’ which would in- crease generalizability and comparability across studies. It can be hypothesised that exercise or physical activity may potentially have a differential effect on symptom categories and subtypes of depression; however, very limited evidence has been pre- sented yet. The only example of a study in this field was com- pleted by Mata et al. (2011), and assessed the differential effect of exercise on positive and negative effect in depression. Clearly, further research in this area is needed. Looking at the effects of various types of exercise (flexibility, aerobic, resistance or combi- nation) with varying duration and intensity is another recom- mendation to enhance future research. For rodent studies, the use of transgenic or knock-in/knock-out species with genetic modification relating to the immune system (i.e. mice over- expressing pro-inflammatory cytokines) is a recommended strat- egy to enhance the mechanistic understanding. Further use of swimming exercise as opposed to classical wheel running should also be used (Sigwalt et al., 2011). Future studies in this area should focus on the effects of exercise on various subsets of T

cells, astrocytes and microglia as these mechanisms are relatively new to enquiry.

Finally, a systematic approach to investigating immune changes in depression-related brain regions, in relevant immune cell types (peripheral and central) and glial cell types will enhance this line of research.

5. Conclusion

Neuroimmunological mechanisms play an active role in the pathogenesis of depression and in the clinical efficacy of exercise in depression. It is recommended that further systematic research will help to elicit the neuroimmunological mechanisms and under- pinnings to improve the understanding of depression and to en- hance alternative treatment approaches to depression such as physical exercise.

Conflict of interest

All authors declare that there are no conflicts of interest.

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