Accepted Manuscript And the BBI 2014 award for lead actor in “neuroinflammation and depression” goes to… Valeria Mondelli PII: DOI: Reference:

S0889-1591(14)00401-2 http://dx.doi.org/10.1016/j.bbi.2014.07.009 YBRBI 2413

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Brain, Behavior, and Immunity

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15 July 2014 15 July 2014

Please cite this article as: Mondelli, V., And the BBI 2014 award for lead actor in “neuroinflammation and depression” goes to…, Brain, Behavior, and Immunity (2014), doi: http://dx.doi.org/10.1016/j.bbi.2014.07.009

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And the BBI 2014 award for lead actor in “neuroinflammation and depression” goes to…

Valeria Mondelli Institute of Psychiatry, King’s College London, Department of Psychological Medicine, London, UK

Corresponding Author: Dr Valeria Mondelli, MD, PhD, Sections of Perinatal Psychiatry & Stress, Psychiatry and Immunology (SPI-Lab), Centre for the Cellular Basis of Behaviour, The James Black Centre, Institute of Psychiatry, Kings College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom Tel: (+ 44) 0 20 7848 0352, Fax: (+ 44) 0 20 7848 0986 Email: [email protected]

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If I were to judge the best actor in a leading role for a movie on “neuroinflammation and depression” this year, the Oscar would undoubtedly go to microglia. The fascinating story of neuroinflammation and depression has been “on the screens” for several years now, with the first ideas behind the script coming from the observation of the striking similarities between the symptoms of cytokine-induced sickness behaviour and depression (Dantzer et al., 2008). Over the past couple of decades, the consistent findings of elevated peripheral inflammatory markers in depression have further supported a role of neuroinflammation in the pathogenesis of this disorder (Baumeister et al., 2014).

However, while peripheral inflammation in depression has been the main presence on stage in the last few years, only very few studies have investigated inflammation in the brain or the association between peripheral and central inflammation in depressed patients, leaving central inflammation, in some way, behind the scenes. At a cellular level, central immune responses are mainly regulated by two leading actors, microglia and astrocytes, which generally play inflammatory and anti-inflammatory roles, respectively. Microglia are the resident immune cells in the brain and their number and function appear to be tightly controlled by the local microenvironment. Given their role, it is not surprising that the spotlight of the research on neuroinflammation in depression is now on microglia. Similar to the best actors on stage, microglia change their appearance and shape according to its performance/function. Although under quiescent condition microglia may be involved in facilitation of neurogenesis, activation of microglia has been implicated by some authors in neurogenesis suppression (Yirmiya and Goshen, 2011).

The most recent exciting data investigating the role of microglia in depression still come from animal studies. These data have established a direct causal role to show that deviation 2

of microglia from their homeostatic state has an etiological role in chronic stress-induced depression (Kreisel et al., 2014). Of course, animal studies conducted in vivo allow brains from animals to be dissected and analysed following specific treatments. In humans in vivo experiments, a variety of neuroimaging techniques must be used, and the ligands used to identify microglia are not particularly sensitive. To date, only one PET study, using a TSPO ligand, has investigated microglia activation in vivo in a small sample of depressed individuals. However, the authors did not find a significant difference in microglia activation between patients and controls (Hannestad et al., 2013). Of note, this study focussed only on individuals with mild-to-moderate depression and with low levels of C reactive protein, which might therefore not reflect what is happening in severely depressed patients or depressed patients in whom peripheral inflammation has been reported. Similarly, very few post-mortem studies have focussed on microglia in patients with major depression; these studies actually included patients with different psychiatric diagnosis and could not find a particular effect of diagnosis on density of microglia, but rather an association between suicide and higher microglia density in several brain regions (Steiner et al., 2008).

In this issue of BBI, microglia take centre stage again thanks to an elegant study by TorresPlatas and colleagues. The results support the presence of microglial activation in depressed patients (Torres-Platas et al., 2014). In particular, the authors provide the first evidence of increased microglia priming in post-mortem brain samples from middle-aged depressed suicides. The authors focussed on the dorsal anterior cingulate cortex, a region that has previously been found to be activated in response to peripheral inflammation (Miller et al., 2013). Further supporting the presence of a neuroinflammatory process in the same subjects is the high density of perivascular macrophages when compared with matched

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controls. The use of neuropathology techniques in the paper is excellent and their findings represent a valuable contribution to our understanding of neuroinflammatory processes associated with depression.

Interestingly, while these data further justify the award to microglia as the lead actor, they create new important questions. Microglia can rapidly and reversibly shift from one phenotype to another, as well as remain in the same morphological phenotype for extended periods of time. At this stage, it is unclear if the morphological changes identified by TorresPlatas and colleagues reflect what was happening at the time of death or if this was a cumulative effect of chronic immune activation during the lifetime of these individuals. Furthermore, it is still unclear how much these findings can be considered specific for depression, since increased inflammation is also observed in other psychiatric disorders such as bipolar disorder and schizophrenia (Baumeister et al., 2014). Indeed, this could be extremely relevant for psychosis, where we have recently shown increased peripheral inflammatory markers and a positive association between peripheral inflammation and brain structure abnormalities (Mondelli et al., 2011). A few in vivo studies have also demonstrated the presence of increased microglial activation in patients with schizophrenia (Doorduin et al., 2009), further supporting the idea that microglia could be the lead actor for neuroinflammation in other psychiatric disorders.

Microglia are undoubtedly the star of the moment, but there is still much we need to learn and to evaluate about the performance of these cells. Keeping the spotlight on microglia and avoiding letting them slip again behind the scenes will help keep the field of neuroinflammation and depression moving forward. What would be microglia’s next movie? Stay tuned. 4

Conflict of interest

None

Acknowledgments

Dr Mondelli is partially funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

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References Baumeister, D., Russell, A., Pariante, C.M., Mondelli, V., 2014. Inflammatory biomarker profiles of mental disorders and their relation to clinical, social and lifestyle factors. Soc. Psychiatry Psychiatr. Epidemiol. 49, 841-849. Dantzer, R., O'Connor, J.C., Freund, G.G., Johnson, R.W., Kelley, K.W., 2008. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9, 46-56. Doorduin, J., de Vries, E.F., Willemsen, A.T., de Groot, J.C., Dierckx, R.A., Klein, H.C., 2009. Neuroinflammation in schizophrenia-related psychosis: a PET study. J. Nucl. Med. 50, 18011807. Hannestad, J., DellaGioia, N., Gallezot, J.D., Lim, K., Nabulsi, N., Esterlis, I., Pittman, B., Lee, J.Y., O'Connor, K.C., Pelletier, D., Carson, R.E., 2013. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [(1)(1)C]PBR28 PET study. Brain. Behav. Immun. 33, 131-138. Kreisel, T., Frank, M.G., Licht, T., Reshef, R., Ben-Menachem-Zidon, O., Baratta, M.V., Maier, S.F., Yirmiya, R., 2014. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol. Psychiatry 19, 699-709. Miller, A.H., Haroon, E., Raison, C.L., Felger, J.C., 2013. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress. Anxiety 30, 297-306. Mondelli, V., Cattaneo, A., Belvederi Murri, M., Di Forti, M., Handley, R., Hepgul, N., Miorelli, A., Navari, S., Papadopoulos, A.S., Aitchison, K.J., Morgan, C., Murray, R.M., Dazzan, P., Pariante, C.M., 2011. Stress and inflammation reduce brain-derived neurotrophic factor

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expression in first-episode psychosis: a pathway to smaller hippocampal volume. J. Clin. Psychiatry 72, 1677-1684. Steiner, J., Bielau, H., Brisch, R., Danos, P., Ullrich, O., Mawrin, C., Bernstein, H.G., Bogerts, B., 2008. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J. Psychiatr. Res. 42, 151-157. Torres-Platas, S.G., Cruceanu, C., Chen, G.G., Turecki, G., Mechawar, N., 2014. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain. Behav. Immun. Yirmiya, R., Goshen, I., 2011. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain. Behav. Immun. 25, 181-213.

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And the BBI 2014 award for lead actor in "neuroinflammation and depression" goes to….

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