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Early-life stress and inflammation: A systematic review of a key experimental approach in rodents:

Early-life stress and inflammation: A systematic review of a key experimental approach in rodents: Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and physical consequences. In this systematic review, we identified 46 studies that conducted repeated maternal separation or single- episode maternal separation and reported measurements of interleukin-1b, interleukin-6, interleukin-10, tumour necrosis factor-alpha, or microglia activation and density. We report that in the short-term and in the context of later-life stress, repeated maternal separation has pro-inflammatory immune consequences in diverse tissues. Repeated maternal separation animals exhibit greater microglial activation and elevated pro-inflammatory cytokine signalling in key brain regions implicated in human psychiatric disorders. Notably, repeated maternal separation generally has no long-term effect on cytokine expression in any tissue in the absence of later-life stress. These observations suggest that the elevated inflammatory signalling that has been reported in humans with a history of early-life stress may be the joint consequence of ongoing stressor exposure together with potentiated neural and/or immune responsiveness to stressors. Finally, our findings provide detailed guidance for future studies interrogating the causal roles of early-life stress and inflammation in disorders such as major depression. Keywords Maternal separation, early-life adversity, depression, chronic stress, cytokines, immune system, neuroimmune responsiveness Received: 7 August 2020; accepted: 11 November 2020 concluded that among patients who suffer from depressive disor- Introduction ders, a history of ELS is associated with an increased number of Early-life stress (ELS), synonymous in the human literature with depressive episodes, increased duration of the current depressive childhood maltreatment (Danese et al., 2007; Hodel et al., 2015), episode, and decreased responsiveness to treatment (Nanni et al., is associated with many adverse neuropsychiatric and physical 2012). Similarly, a recent meta-analysis of bipolar disorder health outcomes later in life. ELS has repeatedly been associated patients concluded that a history of childhood maltreatment is with increased risk for later-life diagnosis of depressive disorders associated with earlier disorder onset, increased severity and including major depressive disorder and dysthymia, anxiety dis- number of depressive and manic episodes, and increased risk of orders including post-traumatic stress disorder (PTSD), social suicide attempts, anxiety disorders including PTSD, substance phobia, generalised anxiety disorder, and panic disorder, and sub- stance use disorders such as alcohol use disorder (Edwards et al., 2003; Gibb et al., 2007; Spinhoven et al., 2010; Teicher and Department of Psychology, University of Cambridge, Cambridge, UK Samson, 2013; Wright et al., 2009). At least two meta-analyses Department of Psychiatry, University of Cambridge, Cambridge, UK have demonstrated strong associations between child abuse and Molecular Immunity Unit, MRC Laboratory of Molecular Biology, adverse physical health outcomes in adulthood, with child abuse Cambridge, UK being associated especially with increased risk of neurological, GlaxoSmithKline Research & Development, Stevenage, UK musculoskeletal, respiratory, cardiovascular, and gastrointestinal symptoms and conditions (Irish et al., 2010; Wegman and Stetler, Corresponding author: 2009). In addition to likely increasing the risk of developing Jeffrey W. Dalley, Department of Psychology, University of Cambridge, these disorders, ELS also appears to predispose to a more severe Downing Street, Cambridge CB2 3EB, UK. clinical course of at least some of them. A large meta-analysis Email: jwd20@cam.ac.uk Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Brain and Neuroscience Advances Figure 1. The maternal separation (MS) procedure. A single episode of maternal separation (SEMS) involves separating rat or mouse pups from their dam, most commonly for 3 h. During this period, the physical and emotional needs of pups go unmet by their mother, resembling neglect. In repeated maternal separation (RMS), this procedure is repeated daily, most commonly commencing on post-natal day (PND) 1 or 2 and concluding on either PND 14 or 21. Other aspects of the protocol are less consistent across studies, such as whether pups are also separated from one another, whether pups are warmed or not warmed during separation, whether separation occurs during the light or dark cycle, and whether control animals are handled or not handled during early life. use disorders, and rapid cycling between mania and depression The most widely used animal model for investigating the rela- (Agnew-Blais and Danese, 2016). tionships between ELS and its psychiatric and physical conse- Many studies have also demonstrated that people with a his- quences is repeated maternal separation (RMS) (Andersen, 2015; tory of ELS have higher inflammatory responses to acute stress Schmidt et al., 2011). This procedure involves repeatedly sepa- and higher peripheral pro-inflammatory signalling in general. rating rat or mouse pups from their mother, most commonly for For example, a history of ELS has been associated with a larger 3–6 h each day, beginning on either post-natal day (PND) 1 or 2, increase in circulating interleukin (IL)-6 when people are asked and continuing through either PND 14 or 21. During these sepa- to deliver a speech about their job qualifications and perform ration periods, around 35%–40% of studies also separate pups mental arithmetic in front of expressionless judges of their per- from one another; this combined separation is sometimes referred formance (Carpenter et al., 2010; Janusek et al., 2017; Pace to as early deprivation (Pryce and Feldon, 2003). More informa- et al., 2006). In addition, a recent meta-analysis showed that tion on RMS can be found in Figure 1. people with a history of childhood trauma have significantly While many studies have examined the effects of RMS on the elevated circulating IL-6, tumour necrosis factor-alpha (TNF- immune system, the results are somewhat inconsistent. For exam- α), and C-reactive protein (CRP), in the absence of any specific ple, within the same tissues, there are many reports of increased, laboratory stressor, although not necessarily in the absence of decreased, or unaltered expression of specific cytokines the stresses of everyday adult life (Baumeister et al., 2016). (Kruschinski et al., 2008; Roque et al., 2016; Wang et al., 2017). What is not clear, however, is whether this propensity to higher Furthermore, there are many reports suggesting that RMS causes inflammation in later life plays a causal role in the neuropsychi- long-lasting effects on a diverse array of not just immunological atric or physical health consequences of ELS. Such questions of outcomes but also depressive-like behaviour, anxiety-like behav- causality are well-suited for investigation using animal models iour, and gastrointestinal tract function, among others (Dallé because elements of the immune system may be selectively tar- et al., 2017; Mizoguchi et al., 2019; Oines et al., 2012). Equally, geted using pharmacological, genetic, or cellular interventions however, for some of these outcomes, there are many reports that during ELS, adult stress, or both. Research in experimental ani- find no long-lasting effect (Bassey and Gondré-Lewis, 2019; mals holds the additional advantage compared to work in Harrison et al., 2014; Stuart et al., 2019). humans of allowing access to brain tissue at any point during In this systematic review, we sought to establish a clearer and after ELS, enabling precise characterization of its molecular picture of the effects of RMS on the immune system. We and cellular consequences in the central nervous system (CNS). hypothesised that much of the variability in the literature could Dutcher et al. 3 Figure 2. Effects of repeated maternal separation (RMS) on cytokine expression. The most commonly reported outcomes (increase, decrease, or no change) are summarised for each cytokine for each stress condition, in both blood and non-blood tissue. Dark blue shading indicates a high level of confidence (three or more studies supporting each outcome), whereas light blue shading indicates low confidence. Measurements were considered short-term if tissue samples were collected within 3 weeks after the conclusion of RMS, and long-term otherwise. be explained by two variables: (1) whether assessments were Results made shortly after the conclusion of RMS or instead closer to Overview or during adulthood and (2) whether the animals experienced any further stress following RMS. While a wide variety of The most frequently reported effects of RMS on cytokine expres- immunological parameters have been measured in RMS ani- sion were determined and are displayed in Figure 2. In the short- mals, we focused our review on a manageable subset of these term, RMS generally increases TNF-α, IL-6, and IL-10 in intended to provide a representative picture of clinically sig- non-blood tissue while leaving these unaffected in blood (plasma, nificant pro-inflammatory innate immune system changes in serum, or the supernatant of cultured whole blood). Without fur- the periphery and CNS. Specifically, we included measure- ther stress, RMS has no long-term effect on cytokine expression ments in any tissue of the four cytokines most commonly in both non-blood tissues and blood. However, if further stress is assayed in RMS studies (IL-1β, IL-6, IL-10, and TNF-α), as applied, RMS animals exhibit increased IL-1β, TNF-α, IL-6, and well as interpretable measures of effects on microglia, the resi- IL-10 in non-blood tissue, although studies also regularly dent immune cells of the CNS (Graeber, 2010), including the reported no change in TNF-α or IL-6, and a decrease in IL-10. In density of microglia in brain tissue and their degree of activa- both contexts involving recent stress, increases in cytokine tion. Included cytokines are all pro-inflammatory except IL-10, expression were much more commonly observed in non-blood which has predominantly anti-inflammatory actions (Pestka tissue than in blood. The effects of RMS on microglia are et al., 2004; Sabat et al., 2010). described in the subsequent sections and summarised in Supplemental Figure S3. Methods Short-term effects of maternal separation The full methods can be found in the Supplemental material. In brief, a search was conducted, results were screened against eli- IL-1β. Several studies have examined the short-term effects of gibility criteria, and then included findings were presented maternal separation (MS) on hippocampal IL-1β. In animals sac- descriptively and summarised in the form of most frequent out- rificed immediately after the final MS episode, RMS increased comes. Measurements were considered to assess long-term hippocampal IL-1β mRNA levels by roughly 20 times compared effects of RMS if they were collected more than 3 weeks after its to never-stressed animals (Roque et al., 2016). When sacrificed conclusion, and short-term effects otherwise. Reported measure- 24 h after the final episode, IL-1β expression was still signifi- ments of cytokine expression in blood always refer to protein cantly elevated, but reduced to 2–2.5 times the level of unstressed level. For non-blood tissues, because protein and mRNA results animals (Roque et al., 2016). In animals given intraperitoneal were generally concordant (Supplemental Figure S1, and see (IP) saline injections immediately after their final RMS episode Avitsur et al., 2006; Ganguly et al., 2019), the assay substrate and sacrificed 90 min later, hippocampal IL-1β protein showed a may not be specified in the main text but can be found in trend increase in RMS animals (Saavedra et al., 2017); here, Supplemental Figure S2, along with the species and gender of the because both RMS and control animals received IP injections, animals in each included study. both groups experienced a brief stressor which may have reduced 4 Brain and Neuroscience Advances the statistical power to detect an RMS-induced effect on cytokine that had never been stressed, although the magnitude of this dif- expression. A further study using a shorter RMS protocol reported ference was small. Corroborating this finding, increased hippo- no effect of RMS on hippocampal IL-1β protein in animals sacri- campal TNF-α was reported in rats sacrificed on the final day of ficed on the final day of RMS (Giridharan et al., 2019). Animals RMS (Giridharan et al., 2019). Altogether, these results suggest sacrificed immediately after single-episode maternal separation that RMS likely increases hippocampal TNF-α, but that this (SEMS) were not found to have increased hippocampal IL-1β effect may be modest compared to the increase in IL-1β. Further- expression relative to unstressed animals (Roque et al., 2016). more, the peak daily hippocampal TNF-α level may decrease However, among animals sacrificed immediately at the conclu- rather than increase with repeated exposure. sion of an episode of MS, those who had undergone RMS had In other brain regions, one study reported increased TNF-α roughly five times the hippocampal IL-1β level that SEMS ani- expression in the PFC in animals sacrificed on the day of their mals had (Roque et al., 2016). Altogether these findings suggest final RMS episode (Giridharan et al., 2019), and another found that RMS may cause hippocampal IL-1β to undergo daily cycling that RMS animals sacrificed immediately after their final episode with peaks shortly after each MS episode, with a rapid return had higher hypothalamic TNF-α than SEMS animals sacrificed towards normal until the stress is applied again. The daily peak at the same time (Roque et al., 2016). However, this latter appears to rise with each additional repetition such that eventu- increase in RMS animals was not significant when compared ally the daily elevation does not normalise even by the start of the either to animals that were never stressed or to animals that were next day’s episode. sacrificed at 24 h following their final RMS episode. In addition, Findings in other regions of the brain suggest that the effects there was no suggestion of a difference in hypothalamic TNF-α of RMS on brain IL-1β are probably region-specific, while between RMS animals sacrificed 24 h after their final episode SEMS likely has no effect on brain IL-1β in any region. Two and never-stressed animals. These findings suggest that RMS studies reported no effect of RMS, in the hypothalamus, in the may cause modest increases in TNF-α expression in the hypo- same study that demonstrated a profound increase in hippocam- thalamus and PFC, but, contrary to the findings in the hippocam- pal IL-1β immediately after the final episode (Roque et al., pus, that these increases may be greater at the conclusion of RMS 2016), and in the prefrontal cortex (PFC), in animals sacrificed rather than 24 h later, and that peak expression may increase with on the day of the final RMS episode (Giridharan et al., 2019). chronicity. Two studies reported no effect of SEMS on hypothalamic IL-1β Most studies to date report no short-term effect of MS on (Roque et al., 2016; Zajdel et al., 2019), mirroring the lack of TNF-α expression in non-brain tissues. Studies have found no effect in the hippocampus. Two final studies reported a decrease effect of RMS or SEMS on plasma TNF-α (Barouei et al., 2015; in IL-1β expression in RMS animals, specifically in the prelim- Roque et al., 2016; Saavedra et al., 2017) or of SEMS on liver bic PFC at almost 3 weeks following the final RMS episode TNF-α (Zajdel et al., 2019). In colon tissue, RMS during PND (Majcher-Maślanka et al., 2019), and in a whole-brain homogen- 5-9 increased TNF-α mRNA at sacrifice immediately after the ate at 48 h after the final episode (Dimatelis et al., 2012). Only final episode, although RMS but not control animals received one included study looked at the short-term effects of MS on daily IP saline injections (Li et al., 2017). IL-1β in a non-blood tissue other than the brain, finding no effect of SEMS on liver IL-1β (Zajdel et al., 2019). IL-6. Included studies generally suggest that while RMS can The effects of RMS on plasma IL-1β appear short-lived. Two increase IL-6 expression in blood, this increase is likely short- studies found no effect of RMS on plasma IL-1β, at 5 and 15 days lived. Roque et al. (2016) demonstrated that both RMS and following the final RMS episode (Grassi-Oliveira et al., 2016), SEMS cause similar increases in plasma IL-6 at the immediate and in animals given an IP saline injection shortly after the final conclusion of an MS episode. This study also demonstrated that episode and sacrificed 90 min later (Saavedra et al., 2017). by 24 h following the conclusion of an RMS episode, plasma However, another study reported that RMS decreased plasma IL-6 had decreased to below the level of unstressed animals. If IL-1β both immediately after the final RMS episode and 24 h IL-6 does indeed rapidly change from elevated to decreased later, to roughly 65%–70% and 80%–85% of the level of within a 24-h period following MS, these changes may be diffi- unstressed animals, respectively (Roque et al., 2016). In contrast cult to detect. Indeed, three studies found no effect of RMS on to RMS, SEMS did not elicit this decrease in animals sacrificed plasma IL-6, in animals sacrificed on the final day of RMS immediately after the episode, but rather appeared to increase (Moya-Pérez et al., 2017; Saavedra et al., 2017) or 10 days later IL-1β plasma levels compared with unstressed animals (Roque (Barouei et al., 2015). et al., 2016). Findings regarding the effect of MS on IL-6 in tissues other than blood generally seem to suggest that RMS but not SEMS TNF-α. Two included studies examined the short-term effects of increases IL-6 expression in a variety of tissues, at least for a MS in the hippocampus. Roque et al. (2016) found in animals short period of time. In the hypothalamus, among animals sacri- sacrificed immediately after MS that while SEMS caused a mod- ficed immediately following an episode of MS, one study dem- est increase in hippocampal TNF-α expression, the mean hippo- onstrated that RMS animals had elevated hypothalamic IL-6 campal TNF-α level in RMS animals sacrificed at the same time mRNA compared to unstressed animals, while SEMS animals was indistinguishable from that of never-stressed animals. This did not (Roque et al., 2016). Again, hypothalamic IL-6 returned suggests that with repeated episodes of MS, the ability of each to baseline within 24 h following RMS (Roque et al., 2016). daily episode to raise TNF-α expression may decrease, which is Another study confirmed the lack of an effect of SEMS on not the opposite of the finding regarding hippocampal IL-1β expres- only hypothalamic IL-6 but also liver IL-6, even in animals sac- sion. A significant increase in hippocampal TNF-α was found in rificed immediately following the episode (Zajdel et al., 2019). RMS animals 24 h following separation compared with animals RMS has also been reported to increase IL-6 in the PFC on the Dutcher et al. 5 final day of RMS (Giridharan et al., 2019) and in colon tissue this discrepancy are unclear but may include use of pair housing within 3 days after RMS (Li et al., 2017; O’Malley et al., 2011). and sacrifice closer to the conclusion of RMS than most other The only non-blood tissue in which IL-6 has been reported to be included studies of long-term effects. The reduced opportunity unaffected by RMS is the hippocampus, even in animals sacri- for social play may have slowed the normalisation of the stress ficed immediately following the final episode (Giridharan et al., response and consequent immune effects in these animals, such 2019; Roque et al., 2016). that it did not occur by the relatively early time of sacrifice (Brenes Sáenz et al., 2006; Hui et al., 2011; Odeon and Acosta, 2019; Veena et al., 2009). IL-10. Studies investigating the short-term effects of MS on In general, RMS has no lasting impact on IL-6 in a variety of IL-10 expression have generally found either an increase or no brain regions and tissues, including the hippocampus (Zhu et al., change in RMS animals. In animals sacrificed on the final day of 2017), dorsal striatum (Banqueri et al., 2019), PFC (Banqueri RMS, increases in IL-10 expression were found in PFC and small et al., 2019), plasma (Barouei et al., 2015), spinal cord (Genty intestine but not in hippocampus or serum (Giridharan et al., et al., 2018), colon (Fuentes et al., 2016; Pierce et al., 2014), 2019; Moya-Pérez et al., 2017). A different study collected genitourinary tract (Pierce et al., 2014), and lung (Avitsur et al., plasma from both males and females at 5, 15, and 35 days follow- 2006). Nevertheless, increased IL-6 mRNA has been reported in ing RMS, and in almost all cases no effect on IL-10 was reported, the hippocampus (Banqueri et al., 2019) and colon (Lennon with the exception of an isolated finding in males at 15 days fol- et al., 2013). lowing RMS of increased IL-10 (Grassi-Oliveira et al., 2016). In a similar vein, RMS alone appears to have no lasting effects Finally, one study found a decrease in IL-10 in RMS animals in on IL-10 expression in plasma (Grassi-Oliveira et al., 2016), whole-brain homogenates (Dimatelis et al., 2012). splenocyte culture with lipopolysaccharide (LPS) (Kiank et al., 2009), colon, and genitourinary tract (Pierce et al., 2014, 2016). Microglial activation and density. Included studies consis- As with IL-1β, Barreau et al. (2004) alone reported increased tently report that RMS leads to microglial activation. Three stud- IL-10, in the colon, liver, and spleen. ies measured microglial activation within 3 days after the To date, only one study has looked at microglial activation in conclusion of RMS, and all three demonstrated increased microg- adult animals not subjected to further stress (Ganguly et al., lial activation on morphological analysis, regardless of whether 2018). Here, no effects were found in relation to microglial soma they used a binary classification system (Roque et al., 2016; Saa- area, summed microglial process length, or microglial process vedra et al., 2017) or directly assessed soma area and arborization end-point count in the prelimbic PFC (Ganguly et al., 2018). In area (Baldy et al., 2018). This finding was consistent across both terms of microglial density, while one study reported an increase CNS regions examined: in the hippocampus, specifically the in CA3, dorsal striatum, and nucleus accumbens (Banqueri et al., hilus (Roque et al., 2016; Saavedra et al., 2017) and CA3 (Saave- 2019), another study found no effect in the prelimbic PFC dra et al., 2017), and in the medulla (Baldy et al., 2018). With (Ganguly et al., 2018). respect to microglia density, there is no consensus regarding the short-term effects of RMS. Some studies report decreased microglia density, including in CA3 and the hippocampal hilus Long-term effects of RMS in the presence of (Saavedra et al., 2017) and the prelimbic PFC (Majcher-Maślanka later-life stress et al., 2019), while others reported no effect in the hippocampal hilus (Roque et al., 2016) and increased microglia density in the Studies measuring the effects of RMS on IL-1β expression in medulla (Baldy et al., 2018). animals subjected to further stress commonly report increased IL-1β expression in RMS animals, including in the hippocampus (Amini-Khoei et al., 2017, 2019; Wang et al., 2017; Zhu et al., Long-term effects of RMS in the absence of 2017), PFC (Wang et al., 2017), paraventricular nucleus (PVN) later-life stress (Tang et al., 2017), striatum (Dallé et al., 2017), cerebrospinal The majority of studies have found no long-term effect of RMS fluid (Réus et al., 2013), colon (Amini-Khoei et al., 2019), kid- on IL-1β expression, in plasma (Kruschinski et al., 2008), lung ney (De Miguel et al., 2018), lung (Avitsur et al., 2006), and (Avitsur et al., 2006; Kruschinski et al., 2008), colon (Lennon serum (Réus et al., 2013; Wang et al., 2017). However, several et al., 2013), spinal cord (Genty et al., 2018), or hippocampus studies report no change or even decreased IL-1β expression in (Zhu et al., 2017). Only Barreau et al. (2004) reported increased RMS animals, although often in the context of a direct inflamma- IL-1β in adult RMS animals not subjected to further stress, in the tory insult, possibly suggesting a degree of psychosocial stress- colon, liver, and spleen. evoked immune cell habituation or exhaustion. While no effect of In the absence of later-life stress, RMS does not have signifi- RMS was found in serum (Avitsur et al., 2013; Breivik et al., cant effects on TNF-α expression in a range of regions and tis- 2015) or spleen (De Miguel et al., 2018), among animals sub- sues, including hippocampus (Banqueri et al., 2019; Zhu et al., jected first to mild psychosocial stress and then shortly after to 2017), dorsal striatum (Banqueri et al., 2019), PFC (Banqueri high-dose LPS, those who had undergone RMS had decreased et al., 2019), lung (Avitsur et al., 2006), colon (Lennon et al., serum IL-1β (Avitsur et al., 2013). In another case involving both 2013; Pierce et al., 2014), genitourinary tract (Pierce et al., psychological distress and a severe physical inflammatory insult, 2014), splenocytes (Kiank et al., 2009), or plasma (Barouei nerve compression trauma increased spinal cord IL-1β mRNA in et al., 2015; Grassi-Oliveira et al., 2016). However, Riba et al. control but not RMS animals (Genty et al., 2018). The experi- (2017, 2018) reported elevated levels of TNF-α in the small mental methodologies of the later-life stressors are summarised intestine of RMS animals sacrificed at PND 50. The reasons for in Supplemental Figure S2. 6 Brain and Neuroscience Advances Most studies in which animals underwent a second stress hippocampus, together with higher IL-1β (Wang et al., 2017), have reported an increase in TNF-α in RMS animals, although splenocytes cultured with LPS, along with non-significantly ele- generally in non-blood tissues rather than blood. Regarding just vated TNF-α (Kiank et al., 2009), the serum, together with the brain, an increase in TNF-α expression in RMS animals was increased IL-1β and TNF-α (Réus et al., 2013), and colon tissue, reported in the hippocampus (Amini-Khoei et al., 2017; Han alongside increased interferon gamma (Shao et al., 2019). et al., 2019; Pinheiro et al., 2015; Zhu et al., 2017), although in However, most studies have reported no effect of RMS on IL-10 Han et al. (2019), this difference was not tested statistically; the expression, including in whole blood cultured with or without PFC (Ganguly et al., 2019; Pinheiro et al., 2015), although only LPS or concanavalin A (Desbonnet et al., 2010; O’Mahony et al., in males but not females in Ganguly et al. (2019); the PVN (Tang 2009), serum (Breivik et al., 2015; Carboni et al., 2010; Wang et al., 2017); the striatum (Dallé et al., 2017); and the nucleus et al., 2017), plasma (Kruschinski et al., 2008), PFC (Pinheiro accumbens in males but not females (Ganguly et al., 2019). et al., 2015; Wang et al., 2017), colon (Pierce et al., 2014, 2016), Several studies, however, did not find any effect of RMS in the bladder (Pierce et al., 2016), and lung (Kruschinski et al., 2008), hippocampus (Viola et al., 2019; Wang et al., 2017) and PFC and an increase in IL-10 has been reported by three studies, in the (Amini-Khoei et al., 2019; Viola et al., 2019). Reports measuring genitourinary tract (Pierce et al., 2014), hippocampus (Pinheiro TNF-α expression in other non-blood tissues generally find et al., 2015), and bladder (Pierce et al., 2016). either increased expression or no change in RMS animals. While Only two included studies measured microglia activation or increases have been reported in large intestine tissue (Amini- density in RMS animals in the context of later-life stress. In ani- Khoei et al., 2019), the reproductive tract (Pierce et al., 2014), mals that received daily IP saline injections from PND 28 to 42, and lung (Avitsur et al., 2006), a lack of effect has been reported at 2 weeks after the conclusion of injections, RMS animals had in the bladder or colon (Pierce et al., 2014), lung (Kruschinski slightly but significantly reduced hippocampal microglial pro- et al., 2008), spleen (De Miguel et al., 2018), and splenocyte cul- cess length and count, consistent with a more activated pheno- ture with LPS (Kiank et al., 2009). In most studies that have type on average (Han et al., 2019). Among animals subjected to looked at TNF-α in blood in animals exposed to later-life stress, an additional 2 weeks of daily 2-h restraint stress from PND 42 to no effect of RMS has been shown, including in the serum (Avitsur 56, the same effects of MS on process length and number et al., 2013; Carboni et al., 2010; Wang et al., 2017), plasma described above were observed, but here the effects were robust (Barouei et al., 2015), and whole blood, with or without ex vivo enough to also be detected using a morphological classification- stimulation with LPS (Desbonnet et al., 2010; O’Mahony et al., based approach. Regarding microglia density, one study found 2009) or concanavalin A (Desbonnet et al., 2010). However, a that MS confers a vulnerability lasting at least into young adult- few studies have found a long-term effect of RMS on blood TNF- hood to a greater increase in spinal cord microglia in response to α, with two studies finding an increase (Do Prado et al., 2016; compression trauma of a nearby nerve (Mizoguchi et al., 2019). Réus et al., 2013), and one finding a decrease in females but not males, and only after low-dose but not high-dose LPS or saline Discussion administration (Avitsur et al., 2013). In animals subjected to later-life stress, in contrast to the rela- In this systematic review, we sought to establish a clearer picture tively consistent findings of increased IL-1β and TNF-α in RMS of the effects of ELS on the innate immune system by surveying animals, especially in non-blood tissue, the findings regarding cytokine and microglia findings in the most widely used animal IL-6 are mixed. Many studies have found no effect of RMS on model of ELS. RMS is considered to have etiological validity as IL-6, including in lung tissue or bronchoalveolar lavage fluid an analogue of human ELS because it occurs in a period of early (Kruschinski et al., 2008; Vig et al., 2010), the reproductive tract life analogous to early childhood in humans, and its effects are (Pierce et al., 2014), the bladder (Pierce et al., 2016), the colon mediated by reduced parental attendance to emotional and physi- (Fuentes et al., 2016; Pierce et al., 2014), the kidney and spleen cal needs, just as they are in caregiver neglect, the most prevalent (De Miguel et al., 2018), the hypothalamic PVN (Tang et al., form of human childhood maltreatment (Schmidt et al., 2011; 2017), the medial PFC (Viola et al., 2019), the spinal cord (Genty Semple et al., 2013). et al., 2018), plasma (Barouei et al., 2015; Kruschinski et al., Overall, RMS did not appear to cause a persistent production 2008), serum (Avitsur et al., 2013; Carboni et al., 2010), and of a pro-inflammatory state by immune cells, given that among whole blood cultured ex vivo with LPS (Desbonnet et al., 2010; included studies, where animals experienced no later-life stress, O’Mahony et al., 2009). However, there are a number of studies generally no long-term effect of RMS on cytokine expression that have reported an increase in IL-6 in RMS animals, specifi- was found. However, in the context of later-life stress, RMS ani- cally in the colon and bladder (Pierce et al., 2016), lung (Avitsur mals very commonly exhibited a more pro-inflammatory et al., 2006), whole blood cultured with concanavalin A but not cytokine expression profile than controls. The contrast between saline (Desbonnet et al., 2010), striatum (Dallé et al., 2017), and these two sets of findings suggests that RMS causes a long-last- hippocampus (Han et al., 2019; Zhu et al., 2017), albeit not tested ing sensitization of the mechanism by which an active psychoso- statistically in Han et al. (2019). Finally, one study reported cial stressor results in pro-inflammatory signalling in tissues decreased IL-6 expression in RMS animals, specifically in the (summarised in Figure 3). In this mechanism as presently under- medial PFC (Viola et al., 2019). stood, (1) the CNS makes an assessment of stressor intensity and As with IL-6, findings regarding IL-10 expression in animals generates a proportional systemic production of neurotransmit- exposed to a second stress are mixed. Consistent with a pro- ters and hormones such as noradrenaline, adrenaline, and corti- inflammatory state, five studies have reported decreased IL-10 sol, which then act directly and indirectly on (2) innate immune expression in RMS animals, in the striatum, concurrently with cells, which respond by altering their production of pro-inflam- increased IL-1β, IL-6, and TNF-α (Dallé et al., 2017), the ventral matory cytokines (Fleshner and Crane, 2017; Miller and Raison, Dutcher et al. 7 Figure 3. Hypothesised effects of early-life stress (ELS). The findings of this review suggest that ELS exerts a long-lasting augmentation to individuals’ physiological responsiveness to stressors. When exposed to stressors later in life, individuals with a history of ELS may exhibit elevated autonomic nervous or endocrine signalling, and/or elevated immune cell responses to that signalling, and in turn elevated pro-inflammatory cytokine expression. possible that individuals with a history of ELS exhibit a more 2016; Ulrich-Lai and Herman, 2009; Weber et al., 2017). It is intense stress–immune response to sample collection itself, in possible that the sensitising effects of RMS are mediated through which case findings suggesting elevated inflammation should be modification of either or both components of this mechanism. To interpreted not necessarily as reflecting a stable elevated baseline, our knowledge, only one study has been conducted to date that but instead as suggesting increased variability and peak daily pro- directly assessed these two possibilities. Kiank et al. (2009) har- inflammatory signalling or increased average inflammation over vested splenocytes, a rich collection of innate and adaptive time. These findings point towards opportunities for therapeutic immune cells, from RMS and control rats and performed an ex intervention in patients with a history of ELS, aimed at preventing vivo assessment of their cytokine production in response to LPS, or treating disorders thought to be caused or exacerbated by avoiding the confounding of the stress caused by in vivo LPS inflammation, such as major depression and cardiovascular dis- administration. They found differences in cytokine production by ease (Batten et al., 2004; Nanni et al., 2012; Steptoe and Kivimäki, immune cells between RMS and control animals only when both 2012). Identification and reduction of ongoing stressors, as well groups experienced later-life stress; in the absence of later-life as certain psychotherapeutic, meditation, and relaxation regimens, stress, LPS-stimulated cytokine production by immune cells was represent readily available non-pharmacological interventions completely unaffected by RMS. This suggests that rather than that, given our findings, may be particularly beneficial for patients priming innate immune cells to effect a greater pro-inflammatory with a history of ELS (Antoni et al., 2012; Creswell et al., 2012; response to activating signals, RMS may instead result in greater Morgan et al., 2014; Pace et al., 2009). nervous and/or neuroendocrine production of activating signals While we did not collect data directly examining the causal in response to later-life stress. Indeed, many studies in both role of ELS-associated inflammation with respect to any particu- humans and animals have reported long-lasting effects of ELS on lar disorders, our findings have some generalizable implications the brain which could result in increased autonomic and endo- regarding causality. Where long-term non-immunological effects crine responsiveness to stress. For example, RMS has been of RMS have been identified in animals not subjected to any fur- reported to increase neuron density in the amygdala (Bassey and ther stress, such as neurobiological effects (Matthews et al., 2001), Gondré-Lewis, 2019; Gondré-Lewis et al., 2016) and decrease our results suggest that ongoing pro-inflammatory signalling may parvalbumin-positive interneuron density in the medial prefron- be unlikely to play a causal role in those effects. However, the tal cortex (mPFC) (Do Prado et al., 2016; Grassi-Oliveira et al., immune system may still be causally involved in that the early-life 2016; Wieck et al., 2013), while human ELS has been shown to inflammation may have long-lasting effects on other systems or decrease dorsal mPFC volume in adulthood (Van Harmelen et al., processes, for example, neurodevelopment, which persist beyond 2010). However, in rodent models of adulthood stress, stress- the resolution of the early-life inflammation (Estes and McAllister, induced priming of immune cells has been demonstrated both to 2016; Knuesel et al., 2014). Intervention studies targeting the subsequent stressors (Audet et al., 2011) and inflammatory stim- immune system, particularly in early life, are necessary to eluci- uli (Frank et al., 2014; Wohleb et al., 2012), indicating that fur- date the precise consequences of RMS-associated inflammation, ther work is required to understand the role of immunological and this review provides clear guidance for such studies. In RMS priming in the elevated neuroimmune responsiveness that fol- animals, it should be expected that pro-inflammatory signalling lows ELS. will peak during or immediately after early-life or later-life stress Another implication of our findings is that the elevated inflam- exposure and rapidly decline in the absence of stress. Normalisation mation that has been identified in humans with a history of ELS of inflammatory signalling should be expected within several may be a direct result of (1) ongoing adulthood stress, on a back- weeks if not within 1 day (Roque et al., 2016), although recovery ground of (2) increased responsiveness to stress. Ongoing adult- may be slowed if animals are deprived of standard stress-relieving hood stress may, for example, result from everyday occupational, cage elements such as tunnels, nesting, and littermates (Do Prado financial, or relationship stressors, or from the consequences of et al., 2016). Therefore, both inflammation and its hypothesised one or more of the psychiatric disorders that individuals with a consequences should be measured during or immediately after history of ELS are at increased risk of developing. It is also 8 Brain and Neuroscience Advances stress, and interventions targeting the immune system will likely References be most effective if administered during early-life or later-life Agnew-Blais J and Danese A (2016) Childhood maltreatment and stress, or both. In addition, measurement of inflammatory signal- unfavourable clinical outcomes in bipolar disorder: A system- ling in non-blood tissues relevant to disorders of interest is encour- atic review and meta-analysis. The Lancet Psychiatry 3(4): aged, as this appears to be more sensitive than measurement in 342–349. blood. For three out of four cytokines, the most common short- Amini-Khoei H, Haghani-Samani E, Beigi M, et al. (2019) On the role of corticosterone in behavioral disorders, microbiota composition term effect in non-blood tissues was an increase, whereas in the alteration and neuroimmune response in adult male mice subjected blood, no change was most common. In addition, while most to maternal separation stress. 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The author(s) declared the following potential conflicts of interest with Baldy C, Fournier S, Boisjoly-Villeneuve S, et al. (2018) The influence respect to the research, authorship, and/or publication of this article: of sex and neonatal stress on medullary microglia in rat pups. Experi- T.W.R. is a consultant and receives royalties from Cambridge Cognition; mental Physiology 103(9): 1192–1199. received research grants from GlaxoSmithKline and Shionogi; and is a Banqueri M, Méndez M, Gómez-Lázaro E, et al. (2019) Early life stress consultant for Greenfield Bioventures, Cassava, Heptares, and Arcadia. by repeated maternal separation induces long-term neuroinflamma- J.W.D. has received research grants from Boehringer Ingelheim Pharma tory response in glial cells of male rats. Stress (Amsterdam, Nether- GmbH and GlaxoSmithKline. S.K. is employed by GlaxoSmithKline. lands) 22(5): 563–570. E.T.B. is a consultant for Sosei Heptares. The remaining authors declare Barouei J, Moussavi M and Hodgson DM (2015) Perinatal maternal pro- no conflicts of interest. biotic intervention impacts immune responses and ileal mucin gene expression in a rat model of irritable bowel syndrome. Beneficial Microbes 6(1): 83–95. Funding Barreau F, Ferrier L, Fioramonti J, et al. (2004) Neonatal maternal depri- The author(s) disclosed receipt of the following financial support for the vation triggers long term alterations in colonic epithelial barrier and research, authorship, and/or publication of this article: The authors of this arti- mucosal immunity in rats. Gut 53(4): 501–506. cle are funded in part by a GlaxoSmithKline Varsity Award with core funding Bassey RB and Gondré-Lewis MC (2019) Combined early life stress- from the Medical Research Council (G1000183) and Wellcome Trust ors: Prenatal nicotine and maternal deprivation interact to influence (093875/Z/10/Z) in support of the Behavioural and Clinical Neuroscience affective and drug seeking behavioral phenotypes in rats. Behav- Institute at Cambridge University. E.G.D. acknowledges funding from the ioural Brain Research 359: 814–822. Gates Cambridge Trust. M.L. was supported by a fellowship from the Medical Batten SV, Aslan M, Maciejewski PK, et al. (2004) Childhood maltreat- Research Council (MR/S006257/1). M.R.C. received support from the ment as a risk factor for adult cardiovascular disease and depression. National Institute for Health Research (NIHR), Cambridge Biomedical The Journal of Clinical Psychiatry 65(2): 249–254. 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Early-life stress and inflammation: A systematic review of a key experimental approach in rodents:

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Abstract

Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and physical consequences. In this systematic review, we identified 46 studies that conducted repeated maternal separation or single- episode maternal separation and reported measurements of interleukin-1b, interleukin-6, interleukin-10, tumour necrosis factor-alpha, or microglia activation and density. We report that in the short-term and in the context of later-life stress, repeated maternal separation has pro-inflammatory immune consequences in diverse tissues. Repeated maternal separation animals exhibit greater microglial activation and elevated pro-inflammatory cytokine signalling in key brain regions implicated in human psychiatric disorders. Notably, repeated maternal separation generally has no long-term effect on cytokine expression in any tissue in the absence of later-life stress. These observations suggest that the elevated inflammatory signalling that has been reported in humans with a history of early-life stress may be the joint consequence of ongoing stressor exposure together with potentiated neural and/or immune responsiveness to stressors. Finally, our findings provide detailed guidance for future studies interrogating the causal roles of early-life stress and inflammation in disorders such as major depression. Keywords Maternal separation, early-life adversity, depression, chronic stress, cytokines, immune system, neuroimmune responsiveness Received: 7 August 2020; accepted: 11 November 2020 concluded that among patients who suffer from depressive disor- Introduction ders, a history of ELS is associated with an increased number of Early-life stress (ELS), synonymous in the human literature with depressive episodes, increased duration of the current depressive childhood maltreatment (Danese et al., 2007; Hodel et al., 2015), episode, and decreased responsiveness to treatment (Nanni et al., is associated with many adverse neuropsychiatric and physical 2012). Similarly, a recent meta-analysis of bipolar disorder health outcomes later in life. ELS has repeatedly been associated patients concluded that a history of childhood maltreatment is with increased risk for later-life diagnosis of depressive disorders associated with earlier disorder onset, increased severity and including major depressive disorder and dysthymia, anxiety dis- number of depressive and manic episodes, and increased risk of orders including post-traumatic stress disorder (PTSD), social suicide attempts, anxiety disorders including PTSD, substance phobia, generalised anxiety disorder, and panic disorder, and sub- stance use disorders such as alcohol use disorder (Edwards et al., 2003; Gibb et al., 2007; Spinhoven et al., 2010; Teicher and Department of Psychology, University of Cambridge, Cambridge, UK Samson, 2013; Wright et al., 2009). At least two meta-analyses Department of Psychiatry, University of Cambridge, Cambridge, UK have demonstrated strong associations between child abuse and Molecular Immunity Unit, MRC Laboratory of Molecular Biology, adverse physical health outcomes in adulthood, with child abuse Cambridge, UK being associated especially with increased risk of neurological, GlaxoSmithKline Research & Development, Stevenage, UK musculoskeletal, respiratory, cardiovascular, and gastrointestinal symptoms and conditions (Irish et al., 2010; Wegman and Stetler, Corresponding author: 2009). In addition to likely increasing the risk of developing Jeffrey W. Dalley, Department of Psychology, University of Cambridge, these disorders, ELS also appears to predispose to a more severe Downing Street, Cambridge CB2 3EB, UK. clinical course of at least some of them. A large meta-analysis Email: jwd20@cam.ac.uk Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Brain and Neuroscience Advances Figure 1. The maternal separation (MS) procedure. A single episode of maternal separation (SEMS) involves separating rat or mouse pups from their dam, most commonly for 3 h. During this period, the physical and emotional needs of pups go unmet by their mother, resembling neglect. In repeated maternal separation (RMS), this procedure is repeated daily, most commonly commencing on post-natal day (PND) 1 or 2 and concluding on either PND 14 or 21. Other aspects of the protocol are less consistent across studies, such as whether pups are also separated from one another, whether pups are warmed or not warmed during separation, whether separation occurs during the light or dark cycle, and whether control animals are handled or not handled during early life. use disorders, and rapid cycling between mania and depression The most widely used animal model for investigating the rela- (Agnew-Blais and Danese, 2016). tionships between ELS and its psychiatric and physical conse- Many studies have also demonstrated that people with a his- quences is repeated maternal separation (RMS) (Andersen, 2015; tory of ELS have higher inflammatory responses to acute stress Schmidt et al., 2011). This procedure involves repeatedly sepa- and higher peripheral pro-inflammatory signalling in general. rating rat or mouse pups from their mother, most commonly for For example, a history of ELS has been associated with a larger 3–6 h each day, beginning on either post-natal day (PND) 1 or 2, increase in circulating interleukin (IL)-6 when people are asked and continuing through either PND 14 or 21. During these sepa- to deliver a speech about their job qualifications and perform ration periods, around 35%–40% of studies also separate pups mental arithmetic in front of expressionless judges of their per- from one another; this combined separation is sometimes referred formance (Carpenter et al., 2010; Janusek et al., 2017; Pace to as early deprivation (Pryce and Feldon, 2003). More informa- et al., 2006). In addition, a recent meta-analysis showed that tion on RMS can be found in Figure 1. people with a history of childhood trauma have significantly While many studies have examined the effects of RMS on the elevated circulating IL-6, tumour necrosis factor-alpha (TNF- immune system, the results are somewhat inconsistent. For exam- α), and C-reactive protein (CRP), in the absence of any specific ple, within the same tissues, there are many reports of increased, laboratory stressor, although not necessarily in the absence of decreased, or unaltered expression of specific cytokines the stresses of everyday adult life (Baumeister et al., 2016). (Kruschinski et al., 2008; Roque et al., 2016; Wang et al., 2017). What is not clear, however, is whether this propensity to higher Furthermore, there are many reports suggesting that RMS causes inflammation in later life plays a causal role in the neuropsychi- long-lasting effects on a diverse array of not just immunological atric or physical health consequences of ELS. Such questions of outcomes but also depressive-like behaviour, anxiety-like behav- causality are well-suited for investigation using animal models iour, and gastrointestinal tract function, among others (Dallé because elements of the immune system may be selectively tar- et al., 2017; Mizoguchi et al., 2019; Oines et al., 2012). Equally, geted using pharmacological, genetic, or cellular interventions however, for some of these outcomes, there are many reports that during ELS, adult stress, or both. Research in experimental ani- find no long-lasting effect (Bassey and Gondré-Lewis, 2019; mals holds the additional advantage compared to work in Harrison et al., 2014; Stuart et al., 2019). humans of allowing access to brain tissue at any point during In this systematic review, we sought to establish a clearer and after ELS, enabling precise characterization of its molecular picture of the effects of RMS on the immune system. We and cellular consequences in the central nervous system (CNS). hypothesised that much of the variability in the literature could Dutcher et al. 3 Figure 2. Effects of repeated maternal separation (RMS) on cytokine expression. The most commonly reported outcomes (increase, decrease, or no change) are summarised for each cytokine for each stress condition, in both blood and non-blood tissue. Dark blue shading indicates a high level of confidence (three or more studies supporting each outcome), whereas light blue shading indicates low confidence. Measurements were considered short-term if tissue samples were collected within 3 weeks after the conclusion of RMS, and long-term otherwise. be explained by two variables: (1) whether assessments were Results made shortly after the conclusion of RMS or instead closer to Overview or during adulthood and (2) whether the animals experienced any further stress following RMS. While a wide variety of The most frequently reported effects of RMS on cytokine expres- immunological parameters have been measured in RMS ani- sion were determined and are displayed in Figure 2. In the short- mals, we focused our review on a manageable subset of these term, RMS generally increases TNF-α, IL-6, and IL-10 in intended to provide a representative picture of clinically sig- non-blood tissue while leaving these unaffected in blood (plasma, nificant pro-inflammatory innate immune system changes in serum, or the supernatant of cultured whole blood). Without fur- the periphery and CNS. Specifically, we included measure- ther stress, RMS has no long-term effect on cytokine expression ments in any tissue of the four cytokines most commonly in both non-blood tissues and blood. However, if further stress is assayed in RMS studies (IL-1β, IL-6, IL-10, and TNF-α), as applied, RMS animals exhibit increased IL-1β, TNF-α, IL-6, and well as interpretable measures of effects on microglia, the resi- IL-10 in non-blood tissue, although studies also regularly dent immune cells of the CNS (Graeber, 2010), including the reported no change in TNF-α or IL-6, and a decrease in IL-10. In density of microglia in brain tissue and their degree of activa- both contexts involving recent stress, increases in cytokine tion. Included cytokines are all pro-inflammatory except IL-10, expression were much more commonly observed in non-blood which has predominantly anti-inflammatory actions (Pestka tissue than in blood. The effects of RMS on microglia are et al., 2004; Sabat et al., 2010). described in the subsequent sections and summarised in Supplemental Figure S3. Methods Short-term effects of maternal separation The full methods can be found in the Supplemental material. In brief, a search was conducted, results were screened against eli- IL-1β. Several studies have examined the short-term effects of gibility criteria, and then included findings were presented maternal separation (MS) on hippocampal IL-1β. In animals sac- descriptively and summarised in the form of most frequent out- rificed immediately after the final MS episode, RMS increased comes. Measurements were considered to assess long-term hippocampal IL-1β mRNA levels by roughly 20 times compared effects of RMS if they were collected more than 3 weeks after its to never-stressed animals (Roque et al., 2016). When sacrificed conclusion, and short-term effects otherwise. Reported measure- 24 h after the final episode, IL-1β expression was still signifi- ments of cytokine expression in blood always refer to protein cantly elevated, but reduced to 2–2.5 times the level of unstressed level. For non-blood tissues, because protein and mRNA results animals (Roque et al., 2016). In animals given intraperitoneal were generally concordant (Supplemental Figure S1, and see (IP) saline injections immediately after their final RMS episode Avitsur et al., 2006; Ganguly et al., 2019), the assay substrate and sacrificed 90 min later, hippocampal IL-1β protein showed a may not be specified in the main text but can be found in trend increase in RMS animals (Saavedra et al., 2017); here, Supplemental Figure S2, along with the species and gender of the because both RMS and control animals received IP injections, animals in each included study. both groups experienced a brief stressor which may have reduced 4 Brain and Neuroscience Advances the statistical power to detect an RMS-induced effect on cytokine that had never been stressed, although the magnitude of this dif- expression. A further study using a shorter RMS protocol reported ference was small. Corroborating this finding, increased hippo- no effect of RMS on hippocampal IL-1β protein in animals sacri- campal TNF-α was reported in rats sacrificed on the final day of ficed on the final day of RMS (Giridharan et al., 2019). Animals RMS (Giridharan et al., 2019). Altogether, these results suggest sacrificed immediately after single-episode maternal separation that RMS likely increases hippocampal TNF-α, but that this (SEMS) were not found to have increased hippocampal IL-1β effect may be modest compared to the increase in IL-1β. Further- expression relative to unstressed animals (Roque et al., 2016). more, the peak daily hippocampal TNF-α level may decrease However, among animals sacrificed immediately at the conclu- rather than increase with repeated exposure. sion of an episode of MS, those who had undergone RMS had In other brain regions, one study reported increased TNF-α roughly five times the hippocampal IL-1β level that SEMS ani- expression in the PFC in animals sacrificed on the day of their mals had (Roque et al., 2016). Altogether these findings suggest final RMS episode (Giridharan et al., 2019), and another found that RMS may cause hippocampal IL-1β to undergo daily cycling that RMS animals sacrificed immediately after their final episode with peaks shortly after each MS episode, with a rapid return had higher hypothalamic TNF-α than SEMS animals sacrificed towards normal until the stress is applied again. The daily peak at the same time (Roque et al., 2016). However, this latter appears to rise with each additional repetition such that eventu- increase in RMS animals was not significant when compared ally the daily elevation does not normalise even by the start of the either to animals that were never stressed or to animals that were next day’s episode. sacrificed at 24 h following their final RMS episode. In addition, Findings in other regions of the brain suggest that the effects there was no suggestion of a difference in hypothalamic TNF-α of RMS on brain IL-1β are probably region-specific, while between RMS animals sacrificed 24 h after their final episode SEMS likely has no effect on brain IL-1β in any region. Two and never-stressed animals. These findings suggest that RMS studies reported no effect of RMS, in the hypothalamus, in the may cause modest increases in TNF-α expression in the hypo- same study that demonstrated a profound increase in hippocam- thalamus and PFC, but, contrary to the findings in the hippocam- pal IL-1β immediately after the final episode (Roque et al., pus, that these increases may be greater at the conclusion of RMS 2016), and in the prefrontal cortex (PFC), in animals sacrificed rather than 24 h later, and that peak expression may increase with on the day of the final RMS episode (Giridharan et al., 2019). chronicity. Two studies reported no effect of SEMS on hypothalamic IL-1β Most studies to date report no short-term effect of MS on (Roque et al., 2016; Zajdel et al., 2019), mirroring the lack of TNF-α expression in non-brain tissues. Studies have found no effect in the hippocampus. Two final studies reported a decrease effect of RMS or SEMS on plasma TNF-α (Barouei et al., 2015; in IL-1β expression in RMS animals, specifically in the prelim- Roque et al., 2016; Saavedra et al., 2017) or of SEMS on liver bic PFC at almost 3 weeks following the final RMS episode TNF-α (Zajdel et al., 2019). In colon tissue, RMS during PND (Majcher-Maślanka et al., 2019), and in a whole-brain homogen- 5-9 increased TNF-α mRNA at sacrifice immediately after the ate at 48 h after the final episode (Dimatelis et al., 2012). Only final episode, although RMS but not control animals received one included study looked at the short-term effects of MS on daily IP saline injections (Li et al., 2017). IL-1β in a non-blood tissue other than the brain, finding no effect of SEMS on liver IL-1β (Zajdel et al., 2019). IL-6. Included studies generally suggest that while RMS can The effects of RMS on plasma IL-1β appear short-lived. Two increase IL-6 expression in blood, this increase is likely short- studies found no effect of RMS on plasma IL-1β, at 5 and 15 days lived. Roque et al. (2016) demonstrated that both RMS and following the final RMS episode (Grassi-Oliveira et al., 2016), SEMS cause similar increases in plasma IL-6 at the immediate and in animals given an IP saline injection shortly after the final conclusion of an MS episode. This study also demonstrated that episode and sacrificed 90 min later (Saavedra et al., 2017). by 24 h following the conclusion of an RMS episode, plasma However, another study reported that RMS decreased plasma IL-6 had decreased to below the level of unstressed animals. If IL-1β both immediately after the final RMS episode and 24 h IL-6 does indeed rapidly change from elevated to decreased later, to roughly 65%–70% and 80%–85% of the level of within a 24-h period following MS, these changes may be diffi- unstressed animals, respectively (Roque et al., 2016). In contrast cult to detect. Indeed, three studies found no effect of RMS on to RMS, SEMS did not elicit this decrease in animals sacrificed plasma IL-6, in animals sacrificed on the final day of RMS immediately after the episode, but rather appeared to increase (Moya-Pérez et al., 2017; Saavedra et al., 2017) or 10 days later IL-1β plasma levels compared with unstressed animals (Roque (Barouei et al., 2015). et al., 2016). Findings regarding the effect of MS on IL-6 in tissues other than blood generally seem to suggest that RMS but not SEMS TNF-α. Two included studies examined the short-term effects of increases IL-6 expression in a variety of tissues, at least for a MS in the hippocampus. Roque et al. (2016) found in animals short period of time. In the hypothalamus, among animals sacri- sacrificed immediately after MS that while SEMS caused a mod- ficed immediately following an episode of MS, one study dem- est increase in hippocampal TNF-α expression, the mean hippo- onstrated that RMS animals had elevated hypothalamic IL-6 campal TNF-α level in RMS animals sacrificed at the same time mRNA compared to unstressed animals, while SEMS animals was indistinguishable from that of never-stressed animals. This did not (Roque et al., 2016). Again, hypothalamic IL-6 returned suggests that with repeated episodes of MS, the ability of each to baseline within 24 h following RMS (Roque et al., 2016). daily episode to raise TNF-α expression may decrease, which is Another study confirmed the lack of an effect of SEMS on not the opposite of the finding regarding hippocampal IL-1β expres- only hypothalamic IL-6 but also liver IL-6, even in animals sac- sion. A significant increase in hippocampal TNF-α was found in rificed immediately following the episode (Zajdel et al., 2019). RMS animals 24 h following separation compared with animals RMS has also been reported to increase IL-6 in the PFC on the Dutcher et al. 5 final day of RMS (Giridharan et al., 2019) and in colon tissue this discrepancy are unclear but may include use of pair housing within 3 days after RMS (Li et al., 2017; O’Malley et al., 2011). and sacrifice closer to the conclusion of RMS than most other The only non-blood tissue in which IL-6 has been reported to be included studies of long-term effects. The reduced opportunity unaffected by RMS is the hippocampus, even in animals sacri- for social play may have slowed the normalisation of the stress ficed immediately following the final episode (Giridharan et al., response and consequent immune effects in these animals, such 2019; Roque et al., 2016). that it did not occur by the relatively early time of sacrifice (Brenes Sáenz et al., 2006; Hui et al., 2011; Odeon and Acosta, 2019; Veena et al., 2009). IL-10. Studies investigating the short-term effects of MS on In general, RMS has no lasting impact on IL-6 in a variety of IL-10 expression have generally found either an increase or no brain regions and tissues, including the hippocampus (Zhu et al., change in RMS animals. In animals sacrificed on the final day of 2017), dorsal striatum (Banqueri et al., 2019), PFC (Banqueri RMS, increases in IL-10 expression were found in PFC and small et al., 2019), plasma (Barouei et al., 2015), spinal cord (Genty intestine but not in hippocampus or serum (Giridharan et al., et al., 2018), colon (Fuentes et al., 2016; Pierce et al., 2014), 2019; Moya-Pérez et al., 2017). A different study collected genitourinary tract (Pierce et al., 2014), and lung (Avitsur et al., plasma from both males and females at 5, 15, and 35 days follow- 2006). Nevertheless, increased IL-6 mRNA has been reported in ing RMS, and in almost all cases no effect on IL-10 was reported, the hippocampus (Banqueri et al., 2019) and colon (Lennon with the exception of an isolated finding in males at 15 days fol- et al., 2013). lowing RMS of increased IL-10 (Grassi-Oliveira et al., 2016). In a similar vein, RMS alone appears to have no lasting effects Finally, one study found a decrease in IL-10 in RMS animals in on IL-10 expression in plasma (Grassi-Oliveira et al., 2016), whole-brain homogenates (Dimatelis et al., 2012). splenocyte culture with lipopolysaccharide (LPS) (Kiank et al., 2009), colon, and genitourinary tract (Pierce et al., 2014, 2016). Microglial activation and density. Included studies consis- As with IL-1β, Barreau et al. (2004) alone reported increased tently report that RMS leads to microglial activation. Three stud- IL-10, in the colon, liver, and spleen. ies measured microglial activation within 3 days after the To date, only one study has looked at microglial activation in conclusion of RMS, and all three demonstrated increased microg- adult animals not subjected to further stress (Ganguly et al., lial activation on morphological analysis, regardless of whether 2018). Here, no effects were found in relation to microglial soma they used a binary classification system (Roque et al., 2016; Saa- area, summed microglial process length, or microglial process vedra et al., 2017) or directly assessed soma area and arborization end-point count in the prelimbic PFC (Ganguly et al., 2018). In area (Baldy et al., 2018). This finding was consistent across both terms of microglial density, while one study reported an increase CNS regions examined: in the hippocampus, specifically the in CA3, dorsal striatum, and nucleus accumbens (Banqueri et al., hilus (Roque et al., 2016; Saavedra et al., 2017) and CA3 (Saave- 2019), another study found no effect in the prelimbic PFC dra et al., 2017), and in the medulla (Baldy et al., 2018). With (Ganguly et al., 2018). respect to microglia density, there is no consensus regarding the short-term effects of RMS. Some studies report decreased microglia density, including in CA3 and the hippocampal hilus Long-term effects of RMS in the presence of (Saavedra et al., 2017) and the prelimbic PFC (Majcher-Maślanka later-life stress et al., 2019), while others reported no effect in the hippocampal hilus (Roque et al., 2016) and increased microglia density in the Studies measuring the effects of RMS on IL-1β expression in medulla (Baldy et al., 2018). animals subjected to further stress commonly report increased IL-1β expression in RMS animals, including in the hippocampus (Amini-Khoei et al., 2017, 2019; Wang et al., 2017; Zhu et al., Long-term effects of RMS in the absence of 2017), PFC (Wang et al., 2017), paraventricular nucleus (PVN) later-life stress (Tang et al., 2017), striatum (Dallé et al., 2017), cerebrospinal The majority of studies have found no long-term effect of RMS fluid (Réus et al., 2013), colon (Amini-Khoei et al., 2019), kid- on IL-1β expression, in plasma (Kruschinski et al., 2008), lung ney (De Miguel et al., 2018), lung (Avitsur et al., 2006), and (Avitsur et al., 2006; Kruschinski et al., 2008), colon (Lennon serum (Réus et al., 2013; Wang et al., 2017). However, several et al., 2013), spinal cord (Genty et al., 2018), or hippocampus studies report no change or even decreased IL-1β expression in (Zhu et al., 2017). Only Barreau et al. (2004) reported increased RMS animals, although often in the context of a direct inflamma- IL-1β in adult RMS animals not subjected to further stress, in the tory insult, possibly suggesting a degree of psychosocial stress- colon, liver, and spleen. evoked immune cell habituation or exhaustion. While no effect of In the absence of later-life stress, RMS does not have signifi- RMS was found in serum (Avitsur et al., 2013; Breivik et al., cant effects on TNF-α expression in a range of regions and tis- 2015) or spleen (De Miguel et al., 2018), among animals sub- sues, including hippocampus (Banqueri et al., 2019; Zhu et al., jected first to mild psychosocial stress and then shortly after to 2017), dorsal striatum (Banqueri et al., 2019), PFC (Banqueri high-dose LPS, those who had undergone RMS had decreased et al., 2019), lung (Avitsur et al., 2006), colon (Lennon et al., serum IL-1β (Avitsur et al., 2013). In another case involving both 2013; Pierce et al., 2014), genitourinary tract (Pierce et al., psychological distress and a severe physical inflammatory insult, 2014), splenocytes (Kiank et al., 2009), or plasma (Barouei nerve compression trauma increased spinal cord IL-1β mRNA in et al., 2015; Grassi-Oliveira et al., 2016). However, Riba et al. control but not RMS animals (Genty et al., 2018). The experi- (2017, 2018) reported elevated levels of TNF-α in the small mental methodologies of the later-life stressors are summarised intestine of RMS animals sacrificed at PND 50. The reasons for in Supplemental Figure S2. 6 Brain and Neuroscience Advances Most studies in which animals underwent a second stress hippocampus, together with higher IL-1β (Wang et al., 2017), have reported an increase in TNF-α in RMS animals, although splenocytes cultured with LPS, along with non-significantly ele- generally in non-blood tissues rather than blood. Regarding just vated TNF-α (Kiank et al., 2009), the serum, together with the brain, an increase in TNF-α expression in RMS animals was increased IL-1β and TNF-α (Réus et al., 2013), and colon tissue, reported in the hippocampus (Amini-Khoei et al., 2017; Han alongside increased interferon gamma (Shao et al., 2019). et al., 2019; Pinheiro et al., 2015; Zhu et al., 2017), although in However, most studies have reported no effect of RMS on IL-10 Han et al. (2019), this difference was not tested statistically; the expression, including in whole blood cultured with or without PFC (Ganguly et al., 2019; Pinheiro et al., 2015), although only LPS or concanavalin A (Desbonnet et al., 2010; O’Mahony et al., in males but not females in Ganguly et al. (2019); the PVN (Tang 2009), serum (Breivik et al., 2015; Carboni et al., 2010; Wang et al., 2017); the striatum (Dallé et al., 2017); and the nucleus et al., 2017), plasma (Kruschinski et al., 2008), PFC (Pinheiro accumbens in males but not females (Ganguly et al., 2019). et al., 2015; Wang et al., 2017), colon (Pierce et al., 2014, 2016), Several studies, however, did not find any effect of RMS in the bladder (Pierce et al., 2016), and lung (Kruschinski et al., 2008), hippocampus (Viola et al., 2019; Wang et al., 2017) and PFC and an increase in IL-10 has been reported by three studies, in the (Amini-Khoei et al., 2019; Viola et al., 2019). Reports measuring genitourinary tract (Pierce et al., 2014), hippocampus (Pinheiro TNF-α expression in other non-blood tissues generally find et al., 2015), and bladder (Pierce et al., 2016). either increased expression or no change in RMS animals. While Only two included studies measured microglia activation or increases have been reported in large intestine tissue (Amini- density in RMS animals in the context of later-life stress. In ani- Khoei et al., 2019), the reproductive tract (Pierce et al., 2014), mals that received daily IP saline injections from PND 28 to 42, and lung (Avitsur et al., 2006), a lack of effect has been reported at 2 weeks after the conclusion of injections, RMS animals had in the bladder or colon (Pierce et al., 2014), lung (Kruschinski slightly but significantly reduced hippocampal microglial pro- et al., 2008), spleen (De Miguel et al., 2018), and splenocyte cul- cess length and count, consistent with a more activated pheno- ture with LPS (Kiank et al., 2009). In most studies that have type on average (Han et al., 2019). Among animals subjected to looked at TNF-α in blood in animals exposed to later-life stress, an additional 2 weeks of daily 2-h restraint stress from PND 42 to no effect of RMS has been shown, including in the serum (Avitsur 56, the same effects of MS on process length and number et al., 2013; Carboni et al., 2010; Wang et al., 2017), plasma described above were observed, but here the effects were robust (Barouei et al., 2015), and whole blood, with or without ex vivo enough to also be detected using a morphological classification- stimulation with LPS (Desbonnet et al., 2010; O’Mahony et al., based approach. Regarding microglia density, one study found 2009) or concanavalin A (Desbonnet et al., 2010). However, a that MS confers a vulnerability lasting at least into young adult- few studies have found a long-term effect of RMS on blood TNF- hood to a greater increase in spinal cord microglia in response to α, with two studies finding an increase (Do Prado et al., 2016; compression trauma of a nearby nerve (Mizoguchi et al., 2019). Réus et al., 2013), and one finding a decrease in females but not males, and only after low-dose but not high-dose LPS or saline Discussion administration (Avitsur et al., 2013). In animals subjected to later-life stress, in contrast to the rela- In this systematic review, we sought to establish a clearer picture tively consistent findings of increased IL-1β and TNF-α in RMS of the effects of ELS on the innate immune system by surveying animals, especially in non-blood tissue, the findings regarding cytokine and microglia findings in the most widely used animal IL-6 are mixed. Many studies have found no effect of RMS on model of ELS. RMS is considered to have etiological validity as IL-6, including in lung tissue or bronchoalveolar lavage fluid an analogue of human ELS because it occurs in a period of early (Kruschinski et al., 2008; Vig et al., 2010), the reproductive tract life analogous to early childhood in humans, and its effects are (Pierce et al., 2014), the bladder (Pierce et al., 2016), the colon mediated by reduced parental attendance to emotional and physi- (Fuentes et al., 2016; Pierce et al., 2014), the kidney and spleen cal needs, just as they are in caregiver neglect, the most prevalent (De Miguel et al., 2018), the hypothalamic PVN (Tang et al., form of human childhood maltreatment (Schmidt et al., 2011; 2017), the medial PFC (Viola et al., 2019), the spinal cord (Genty Semple et al., 2013). et al., 2018), plasma (Barouei et al., 2015; Kruschinski et al., Overall, RMS did not appear to cause a persistent production 2008), serum (Avitsur et al., 2013; Carboni et al., 2010), and of a pro-inflammatory state by immune cells, given that among whole blood cultured ex vivo with LPS (Desbonnet et al., 2010; included studies, where animals experienced no later-life stress, O’Mahony et al., 2009). However, there are a number of studies generally no long-term effect of RMS on cytokine expression that have reported an increase in IL-6 in RMS animals, specifi- was found. However, in the context of later-life stress, RMS ani- cally in the colon and bladder (Pierce et al., 2016), lung (Avitsur mals very commonly exhibited a more pro-inflammatory et al., 2006), whole blood cultured with concanavalin A but not cytokine expression profile than controls. The contrast between saline (Desbonnet et al., 2010), striatum (Dallé et al., 2017), and these two sets of findings suggests that RMS causes a long-last- hippocampus (Han et al., 2019; Zhu et al., 2017), albeit not tested ing sensitization of the mechanism by which an active psychoso- statistically in Han et al. (2019). Finally, one study reported cial stressor results in pro-inflammatory signalling in tissues decreased IL-6 expression in RMS animals, specifically in the (summarised in Figure 3). In this mechanism as presently under- medial PFC (Viola et al., 2019). stood, (1) the CNS makes an assessment of stressor intensity and As with IL-6, findings regarding IL-10 expression in animals generates a proportional systemic production of neurotransmit- exposed to a second stress are mixed. Consistent with a pro- ters and hormones such as noradrenaline, adrenaline, and corti- inflammatory state, five studies have reported decreased IL-10 sol, which then act directly and indirectly on (2) innate immune expression in RMS animals, in the striatum, concurrently with cells, which respond by altering their production of pro-inflam- increased IL-1β, IL-6, and TNF-α (Dallé et al., 2017), the ventral matory cytokines (Fleshner and Crane, 2017; Miller and Raison, Dutcher et al. 7 Figure 3. Hypothesised effects of early-life stress (ELS). The findings of this review suggest that ELS exerts a long-lasting augmentation to individuals’ physiological responsiveness to stressors. When exposed to stressors later in life, individuals with a history of ELS may exhibit elevated autonomic nervous or endocrine signalling, and/or elevated immune cell responses to that signalling, and in turn elevated pro-inflammatory cytokine expression. possible that individuals with a history of ELS exhibit a more 2016; Ulrich-Lai and Herman, 2009; Weber et al., 2017). It is intense stress–immune response to sample collection itself, in possible that the sensitising effects of RMS are mediated through which case findings suggesting elevated inflammation should be modification of either or both components of this mechanism. To interpreted not necessarily as reflecting a stable elevated baseline, our knowledge, only one study has been conducted to date that but instead as suggesting increased variability and peak daily pro- directly assessed these two possibilities. Kiank et al. (2009) har- inflammatory signalling or increased average inflammation over vested splenocytes, a rich collection of innate and adaptive time. These findings point towards opportunities for therapeutic immune cells, from RMS and control rats and performed an ex intervention in patients with a history of ELS, aimed at preventing vivo assessment of their cytokine production in response to LPS, or treating disorders thought to be caused or exacerbated by avoiding the confounding of the stress caused by in vivo LPS inflammation, such as major depression and cardiovascular dis- administration. They found differences in cytokine production by ease (Batten et al., 2004; Nanni et al., 2012; Steptoe and Kivimäki, immune cells between RMS and control animals only when both 2012). Identification and reduction of ongoing stressors, as well groups experienced later-life stress; in the absence of later-life as certain psychotherapeutic, meditation, and relaxation regimens, stress, LPS-stimulated cytokine production by immune cells was represent readily available non-pharmacological interventions completely unaffected by RMS. This suggests that rather than that, given our findings, may be particularly beneficial for patients priming innate immune cells to effect a greater pro-inflammatory with a history of ELS (Antoni et al., 2012; Creswell et al., 2012; response to activating signals, RMS may instead result in greater Morgan et al., 2014; Pace et al., 2009). nervous and/or neuroendocrine production of activating signals While we did not collect data directly examining the causal in response to later-life stress. Indeed, many studies in both role of ELS-associated inflammation with respect to any particu- humans and animals have reported long-lasting effects of ELS on lar disorders, our findings have some generalizable implications the brain which could result in increased autonomic and endo- regarding causality. Where long-term non-immunological effects crine responsiveness to stress. For example, RMS has been of RMS have been identified in animals not subjected to any fur- reported to increase neuron density in the amygdala (Bassey and ther stress, such as neurobiological effects (Matthews et al., 2001), Gondré-Lewis, 2019; Gondré-Lewis et al., 2016) and decrease our results suggest that ongoing pro-inflammatory signalling may parvalbumin-positive interneuron density in the medial prefron- be unlikely to play a causal role in those effects. However, the tal cortex (mPFC) (Do Prado et al., 2016; Grassi-Oliveira et al., immune system may still be causally involved in that the early-life 2016; Wieck et al., 2013), while human ELS has been shown to inflammation may have long-lasting effects on other systems or decrease dorsal mPFC volume in adulthood (Van Harmelen et al., processes, for example, neurodevelopment, which persist beyond 2010). However, in rodent models of adulthood stress, stress- the resolution of the early-life inflammation (Estes and McAllister, induced priming of immune cells has been demonstrated both to 2016; Knuesel et al., 2014). Intervention studies targeting the subsequent stressors (Audet et al., 2011) and inflammatory stim- immune system, particularly in early life, are necessary to eluci- uli (Frank et al., 2014; Wohleb et al., 2012), indicating that fur- date the precise consequences of RMS-associated inflammation, ther work is required to understand the role of immunological and this review provides clear guidance for such studies. In RMS priming in the elevated neuroimmune responsiveness that fol- animals, it should be expected that pro-inflammatory signalling lows ELS. will peak during or immediately after early-life or later-life stress Another implication of our findings is that the elevated inflam- exposure and rapidly decline in the absence of stress. Normalisation mation that has been identified in humans with a history of ELS of inflammatory signalling should be expected within several may be a direct result of (1) ongoing adulthood stress, on a back- weeks if not within 1 day (Roque et al., 2016), although recovery ground of (2) increased responsiveness to stress. Ongoing adult- may be slowed if animals are deprived of standard stress-relieving hood stress may, for example, result from everyday occupational, cage elements such as tunnels, nesting, and littermates (Do Prado financial, or relationship stressors, or from the consequences of et al., 2016). Therefore, both inflammation and its hypothesised one or more of the psychiatric disorders that individuals with a consequences should be measured during or immediately after history of ELS are at increased risk of developing. 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The author(s) declared the following potential conflicts of interest with Baldy C, Fournier S, Boisjoly-Villeneuve S, et al. (2018) The influence respect to the research, authorship, and/or publication of this article: of sex and neonatal stress on medullary microglia in rat pups. Experi- T.W.R. is a consultant and receives royalties from Cambridge Cognition; mental Physiology 103(9): 1192–1199. received research grants from GlaxoSmithKline and Shionogi; and is a Banqueri M, Méndez M, Gómez-Lázaro E, et al. (2019) Early life stress consultant for Greenfield Bioventures, Cassava, Heptares, and Arcadia. by repeated maternal separation induces long-term neuroinflamma- J.W.D. has received research grants from Boehringer Ingelheim Pharma tory response in glial cells of male rats. Stress (Amsterdam, Nether- GmbH and GlaxoSmithKline. S.K. is employed by GlaxoSmithKline. lands) 22(5): 563–570. E.T.B. is a consultant for Sosei Heptares. 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Journal

Brain and Neuroscience Advances – SAGE

Published: Dec 28, 2020

Keywords: Maternal separation; early-life adversity; depression; chronic stress; cytokines; immune system; neuroimmune responsiveness

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