Frontiers in Neuroendocrinology xxx (2012) xxx–xxx

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Frontiers in Neuroendocrinology

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Review

The immune system and developmental programming of brain and behavior

Staci D. Bilbo ⇑, Jaclyn M. SchwarzDepartment of Psychology and Neuroscience, Duke University, 572 Research Drive, Box 91050, Durham, NC 27708, USA

a r t i c l e i n f o a b s t r a c t

Article history:Available online xxxx

Keywords:MicrogliaCytokinesChemokinesCognitionHippocampusToll-like receptorsInfectionSensitive periods

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⇑ Corresponding author.E-mail address: staci.bilbo@duke.edu (S.D. Bilbo).

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The brain, endocrine, and immune systems are inextricably linked. Immune molecules have a powerfulimpact on neuroendocrine function, including hormone–behavior interactions, during health as well assickness. Similarly, alterations in hormones, such as during stress, can powerfully impact immune func-tion or reactivity. These functional shifts are evolved, adaptive responses that organize changes in behav-ior and mobilize immune resources, but can also lead to pathology or exacerbate disease if prolonged orexaggerated. The developing brain in particular is exquisitely sensitive to both endogenous and exoge-nous signals, and increasing evidence suggests the immune system has a critical role in brain develop-ment and associated behavioral outcomes for the life of the individual. Indeed, there are associationsbetween many neuropsychiatric disorders and immune dysfunction, with a distinct etiology in neurode-velopment. The goal of this review is to describe the important role of the immune system during braindevelopment, and to discuss some of the many ways in which immune activation during early braindevelopment can affect the later-life outcomes of neural function, immune function, mood and cognition.

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1. Introduction

Interactions among the brain, endocrine, and immune systemsare now well accepted. Though immune processes within the brainare not identical to those occurring in the periphery, the brain hasresident immune cells, namely microglia, which produce cytokinesand other inflammatory molecules in response to disturbances inhomeostasis in a manner similar to peripheral immune cells. Othercentral nervous system (CNS) cells, including perivascular macro-phages, astrocytes, endothelial cells, oligodendrocytes, and neu-rons also produce cytokines and chemokines and express theirreceptors, during normal brain function as well as in response toinjury, infection, or illness. In addition to resident immunocompe-tent cells, there are multiple pathways by which peripherally-de-rived immune factors can affect the brain, and in turn by whichthe brain can impact peripheral immune responses. These includethe autonomic nervous system (ANS), activation of the ‘‘stress axis’’(the hypothalamic–pituitary–adrenal (HPA) axis), and cytokines,chemokines, and leukocytes that travel or signal across the (BBB).The neural and hormonal pathways by which the neuroendocrineand immune systems interact and communicate during infectionor illness have been extensively reviewed (Bellinger et al., 2008;Costa-Pinto and Palermo-Neto, 2010; Dantzer et al., 2000; Elenkovet al., 2000; Webster Marketon and Glaser, 2008; Nance and Sand-ers, 2007; Rabin et al., 1990; Rivest, 2010; Turnbull and Rivier,1999). The primary goal of this review is to discuss the role of

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hwarz, J.M. The immune systeme.2012.08.006

immune molecules, primarily cytokines and chemokines, in nor-mal brain development, and to highlight the mechanisms by whichearly-life events may alter this normal developmental trajectoryvia their specific impact on cytokine expression, and thereby im-pact later-life neuroendocrine-behavioral interactions.

2. Neuroendocrine–immune communication

Beyond its traditional role in host defense, the immune systemis now considered a diffuse sensory organ, which works in concertwith the neuroendocrine system to achieve and maintain homeo-stasis throughout the entire body (Husband, 1995; Vitkovic et al.,2000). Immunocompetent cells are located throughout virtuallyevery organ of the body, including the brain and other endocrinetissues, and sophisticated interactions occur among these cells,via hormones, neurotransmitters, and soluble protein messengerscalled cytokines. Cytokines have autocrine and paracrine actionswithin local tissues, as well as hormonal actions via their releaseinto the blood stream and subsequent signaling to the CNS (Buttsand Sternberg, 2008; Deverman and Patterson, 2009). Many cyto-kine families have been identified, including the tumor necrosisfactors (TNFs), interferons (IFNs), interleukins (IL-1 through 26),transforming growth factor (TGF), colony-stimulating factors(CSFs), platelet-derived growth factor (PDGF), epidermal growthfactor (EGF), fibroblast growth factor (FGF), macrophage inflamma-tory proteins (MIPs), macrophage migration inhibitory factors(MIFs), and insulin-like growth factors (IGFs). An equally lengthylist of chemokines has been described, a subset of cytokinesthat mediate cell adhesion, chemotaxis, and leukocyte trafficking.

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Chemokines are separated into four categories including the C–Cchemokines, the C–X–C chemokines, the C chemokines, and oneCX3C chemokine (Cardona et al., 2008). Chemokines tend to beclassified by their structural characteristics more than theirfunction. Nerve growth factor (NGF), brain-derived neurotrophicfactor (BDNF), and hormones such as leptin, prolactin, and growthhormone have also been characterized for their cytokine-likefunctions (Hanisch, 2002; Lord, 2002; Redelman et al., 2008).Cytokines are generally described for their pro-inflammatory vs.anti-inflammatory roles during the course of an immune response;however, many cytokine actions are pleiotropic and depend highlyon the cytokine environment around them. In addition, there are anumber of endogenous cytokine receptor antagonists (e.g., IL-1ra)that are released in conjunction with cytokines, which modulatetheir production and function.

2.1. Cytokines and the brain

Cytokines have neuromodulatory properties within the brainduring infectious and inflammatory processes; however, they arealso constitutively expressed in healthy brain tissue and regulatesuch homeostatic mechanisms and behaviors as sleep, memory,and metabolism (Farrar et al., 1987; Kubota et al., 2000; Vitkovicet al., 2000; Yirmiya and Goshen, 2011). One of the best-describedobservations demonstrating the profound effects cytokines canhave on brain function is in the expression of sickness behavior(Dantzer et al., 1998a,b; Dantzer and Kelley, 2007). Sick animalsexhibit several well-characterized behavioral changes, includingreductions in food and water intake, activity, exploration, in-creased sleep, and reduced social and sexual interactions (Hart,1988). These so-called sickness behaviors are not mediated bythe infectious pathogens themselves, but rather they are a criticalcomponent of the immune response orchestrated by the immunesystem via the release of cytokines (Dantzer et al., 1998a,b; Dant-zer and Kelley, 2007). Cytokines induce physiological (e.g., fever)and behavioral changes via their actions within the brain (Dantzeret al., 1998a). As a result, preventing the synthesis of cytokines, orthe binding of cytokines to their receptors within the brain pre-vents the expression of sickness behavior even in the presence ofa peripheral immune challenge (Dantzer et al., 1998a; Palin et al.,2008). Conversely, administering individual cytokines directly intothe brain, in the absence of a peripheral infection, will induce sick-ness behavior (Dantzer and Kelley, 2007); e.g., direct injection ofIL-1b into the ventricles of the brain induces the full range of sick-ness behaviors (Anforth et al., 1998). Numerous studies have nowdemonstrated that these behaviors, rather than being pathologicalconsequences of infection, are organized, adaptive strategies thatare critical to host survival (Blatteis, 2007; Dantzer and Kelley,2007). As such, sickness behavior reflects an overall change inthe motivational/behavioral state of the individual that is orga-nized by the nervous, endocrine, and the immune systems.

Cytokine receptors have been characterized in microglia, astro-cytes, neurons, endothelial cells, and oligodendrocytes, ubiqui-tously throughout the CNS of mammals, although relativedensities for individual receptors vary by brain region (see Dever-man and Patterson (2009), Rostene et al. (2011b), Sorce et al.(2011), Veenstra and Ransohoff (2012) and Vezzani et al. (2011)for review). Cytokines are produced within the brain by numerouscell types in response to virtually any perturbation of CNS homeo-stasis, including trauma, stroke, ischemia, neurodegeneration, orinfection (Ban et al., 1993; Hopkins and Rothwell, 1995; Rothwelland Hopkins, 1995). Cytokines are also produced within the brainin response to peripheral cytokine production or infectious stimuli,indicating that cytokine signals are transmitted from the peripheryinto the brain. This transmission may occur via several routes,including neurotransmission following cytokine binding to their

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receptors on vagal afferents (Andersson and Tracey, 2012; Dantzeret al., 1998a; Goehler et al., 2000; Johnston and Webster, 2009);signaling across the BBB – e.g., via endothelial cells, astrocytes,and microglia within the BBB that recapitulate the immune signalfrom the periphery by secreting their own cohort of cytokines intothe brain (Skaper et al., 2012; Verma et al., 2006; Wiese et al.,2012); crossing into the brain at circumventricular organs wherethe BBB is permeable or leaky (e.g., area postrema (Wuchertet al., 2008); or finally, active transport across the BBB by special-ized transporters (Banks and Erickson, 2010; Banks et al., 1995).These routes of transmission have been extensively reviewed(Banks and Erickson, 2010; Banks et al., 1995; Dantzer and Kelley,2007; Maier and Watkins, 1998; Mignini et al., 2003; Quan andBanks, 2007; Rivest, 2003; Wrona, 2006). We touch on aspects ofbrain development that significantly impact these transmissionpathways, and the implications for long-term function, in subse-quent sections of this review.

3. Early-life programming of brain and behavior by immunedisruption

In recent years, scientists and medical professionals have iden-tified similarities between sickness behaviors caused by an acuteillness and the behaviors expressed by individuals with certainneuropsychiatric disorders (Fig. 1) (Dantzer and Kelley, 2007;Dantzer et al., 2008). In particular, the behavioral and physiologicalsymptoms of depression are strikingly similar to the list of sicknessbehaviors described above including decreased food intake, de-creased activity, increased sleep disturbances, and decreased so-cial/sexual interactions; suggesting that many psychiatricdisorders may involve a dysregulation of immune function evenin the absence of an overt immune challenge (Dantzer, 2006; Paceand Miller, 2009). However, depression is not the only psychiatricdisorder with a well-described link to immune dysregulation.These include schizophrenia, anxiety and stress disorders, majordepressive disorder, autism, and learning disabilities (Horniget al., 1999; Nelson and Willoughby, 2000; Rantakallio et al.,1997; Shi et al., 2009). For instance, individuals with schizophreniahave abnormal levels of IL-1b, IL-6, growth factors (e.g. BDNF), andneuregulin within the brain and body (Muller and Ackenheil, 1998;Muller and Schwarz, 2010; Nawa and Takei, 2006), indicating thatthese individuals have not only abnormal immune function butalso differences in proteins critical for synapse formation and func-tion within the brain. Individuals with posttraumatic stress disor-der (PTSD) have increased levels of circulating inflammatorymarkers, increased reactivity during skin antigen tests, lower T cellcounts, and increased global methylation of immune genes (Baueret al., 2010; Pace and Heim, 2011; Smith et al., 2011). Individualswith autism spectrum disorders and Rett syndrome have alteredcytokine profiles circulating within the periphery, low immuno-globulin levels, and altered T cell activation (Ashwood et al.,2010, 2011; Bauer et al., 2010; Goines and Van de Water, 2010;Pace and Heim, 2011; Smith et al., 2011).

Notably many of these neuropsychiatric disorders also have aknown or suspected developmental origin. The developing brainis exquisitely sensitive to both endogenous and exogenous signalsthat may significantly alter the developmental trajectory of cells,neural circuits, and associated behavioral outcomes. Indeed,increasing evidence suggests diverse experiences during the pre-or postnatal period, including maternal stress, nutrition, trauma,or infection, may profoundly modulate or ‘‘program’’ developingneural circuits, with the result that adult outcomes includingbehavior are significantly and often permanently affected (Bilboand Schwarz, 2009; de Boo and Harding, 2006; Fatemi and Folsom,2009; Owen et al., 2005).

and developmental programming of brain and behavior. Front. Neuroen-

Fig. 1. Adaptive and pathological neuroimmune function similarly increases brain cytokine production and influences behavior. Systemic infection produces a peripheralcytokine response, which in turn produces a cytokine response in the brain. Cytokines within the brain induce a well-characterized set of adaptive behaviors that are intendedto help fight infection, including reduced appetite (food and water intake), increased sleep and decreased overall activity, reduced social interactions, and altered cognitivefunction. Many neuropsychiatric or mood disorders exhibit a similar set of behavioral symptoms that have become prolonged or exaggerated, including chronic metabolicdisorders or decreased appetite, chronic sleep disturbances/fatigue, altered social interactions, withdrawal/depression, and decreased cognitive function (e.g. learningdisabilities, dementia, and delirium). Not surprisingly, many neuropsychiatric disorders are also associated with altered immune/neuroimmune function.

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A link between perinatal infection and neuropsychiatric disor-ders may have first been proposed in 1891, when Thomas Cloustensuggested there might be an infectious origin to what he describedas ‘‘adolescent insanity’’. Since then, many researchers have notedthe strong relationship between early-life infection and the later-life onset of schizophrenia (Fruntes and Limosin, 2008; Meyeret al., 2005). The specific mechanisms by which infections maylead to psychopathology include direct infection of the developingfetus and subsequent abnormal neural development, the genera-tion of auto-antibodies by the mother that subsequently react withfetal neural tissue, and alterations in cytokine production, whichmay be an underlying component of all three mechanisms (Pearce,2001). Elevated levels of pro-inflammatory cytokines generated bythe maternal or fetal immune system have been associated withabnormal fetal brain development and an increased risk of neuro-developmental disorders (Cai et al., 2000; Meyer et al., 2006a; Panget al., 2003; Urakubo et al., 2001). For instance, concentrations ofIL-1b, IL-6, and TNFa are elevated in infants with severe perinatalcomplications or bacterial meningitis (Miller et al., 1990; Mustafaet al., 1989), and concentrations strongly correlate with the occur-rence of neurological sequelae. Similarly, increased levels of IL-6 inamniotic fluid, the result of increased inflammation from bacterialinfection in late pregnancy, correlates significantly with increasedrates of mortality and brain injury (Yoon et al., 1995). There areseveral reports in humans that maternal influenza infection in-duces cytokine synthesis via the activation of the maternal im-mune system, the fetal immune system, and the placenta, each ofwhich has been linked to increased risk of schizophrenia in the off-spring (Brown et al., 2004; Hillier et al., 1993; Mortensen et al.,1999; Urakubo et al., 2001). Recent advances in maternal and peri-natal medicine have greatly increased survival rates among moth-ers suffering infections or trauma in developed countries; however,these studies establish that infections, despite the low risk ofdeath, nonetheless leave an enduring mark (Bilbo, 2011). In an ef-

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fort to determine the mechanisms underlying such changes, anumber of animal models of early-life immune activation havebeen developed and characterized.

3.1. Animal models of early-life immune activation

3.1.1. Polyinosinic:polycytidylic acid (Poly IC)Poly IC is a synthetic double-stranded RNA molecule that is

commonly used as a viral mimetic. Poly IC is recognized by the pat-tern recognition receptor, toll-like receptor (TLR) 3, which specifi-cally recognizes double stranded RNA, the genetic information formany viruses (Alexopoulou et al., 2001). Perinatal poly IC exposurecauses a robust febrile response, a profound increase in cytokineproduction, and HPA axis activation (Fortier et al., 2004; Miltonet al., 1992; Rotondo et al., 1988). Based on the significant link be-tween maternal influenza virus and the increased risk of schizo-phrenia in human offspring, several researchers have studied thelong-term consequences of perinatal poly IC exposure on physiol-ogy and behavior in rodent models. Treatment of newborn rat pupswith poly IC has significant effects on adult immune responses,including an attenuated febrile response and an exaggerated corti-costerone response to an adult immune challenge (Ellis et al.,2006). Similar to behavioral symptoms seen in individuals withschizophrenia and autism, offspring that were prenatally treatedwith poly IC display significant deficits in pre-pulse inhibitionacoustic startle response, decreases in exploratory behavior in bothopen-field and novel-object tests, and decreases in social interac-tions as adults (Hsiao and Patterson, 2011; Meyer et al., 2006a,b;Meyer et al., 2008; Pantelis et al., 2003; Shi et al., 2003). Cognitiveimpairments resulting from prenatal immune activation includedeficits in reversal learning of a previously learned task (Hanet al., 2011). In addition, rats or mice exposed to poly IC prenatallyhave an impaired ability to ignore irrelevant environmental stim-uli, one of the central deficits in humans with schizophrenia. This

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is manifested in humans and rodents as a lack of latent inhibition.Latent inhibition is a phenomenon whereby repeated pre-exposureto an inconsequential stimulus (such as a tone) can decrease thecapacity for that same stimulus to signal significant consequenceslater (Zuckerman et al., 2003; Zuckerman and Weiner, 2005). Nota-bly many of these behavioral deficits caused by early-life poly ICexposure can be reversed by acute administration of antipsychotic(clozapine and chlorpromazine) and psychomimetic drugs such asketamine (Shi et al., 2003), which is why this animal model is her-alded as a strong model for schizophrenia.

3.1.2. Lipopolysaccharide (LPS)LPS, the cell wall component of gram-negative bacteria, has

been used to mimic infection in many animal studies because itinitiates a well-characterized immune response via the activationof TLR4. Within the immature rat brain, LPS induces a rapid and ro-bust increase in cytokine expression characterized by a robust in-crease in the expression of many cytokines and chemokines,including IL-1b, IL-6, TNFa, CXCL1, CXCL2, CXCL10, CCL2 andCCL7, among others, as well as a marked increase in circulatingcorticosterone (Fidel et al., 1994; Golan et al., 2005; Ortega et al.,2010; Schwarz et al., 2012; Urakubo et al., 2001; Walker et al.,2004). Treatment of either pregnant dams or neonatal pups withhigh doses of LPS is linked to overt white matter damage, de-creased oligodendrocyte development, hypo-myelination of neu-rons (Cai et al., 2000; Fan et al., 2005; Pang et al., 2003), andenhanced behavioral pain responses in adulthood (Hodyl et al.,2010). Lower doses of LPS given during the perinatal period also in-duce a number of long-term changes in the brain, both biochemicaland behavioral.

Interestingly, prenatal exposure to LPS causes a decrease instress responsivity and a blunted immune response to subsequentimmune challenges during the neonatal period in rats (Hodylet al., 2008; Mouihate et al., 2010). In contrast, treatment of pupspostnatally with LPS causes an increase in circulating corticosteronefollowing a stressor, and a decrease in the expression of sicknessbehaviors and fever following an adult immune challenge (Ellis

Fig. 2. Neonatal infection in male rats produces a number of long-term physiological afollowing an adult immune challenge, such as LPS, when compared to control rats (Bilboan acute stressor, when compared to control rats (Bilbo et al., 2008b). Neonatally-infectcontrol rats (Bilbo et al., 2008b).

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et al., 2005, 2006; Walker et al., 2006, 2008). Rats exposed to endo-toxin postnatally also show changes in behavior in adulthood suchas increased anxiety, and exaggerated acoustic startle responses(Walker et al., 2004, 2008). Based on both models of LPS adminis-tration during the perinatal period (pre vs. postnatal), it is apparentthat the time point at which the immune challenge occurs is crit-ically important for determining the long-term effects on neuroim-mune function and behavior.

3.1.3. Escherichia coli (E. coli)E. coli is a primary cause of infection in low-birth weight prema-

ture infants in the US, and infections in premature infants are asso-ciated with significant delays or alterations in neurodevelopment(Adams-Chapman and Stoll, 2006; Stoll et al., 2004). We haveextensively characterized the impact of neonatal E. coli infectionin rats on later-life brain and behavior (Bilbo, 2010; Bilbo et al.,2005a,b, 2006, 2007, 2008a,b, 2010; Bland et al., 2010a,b; William-son et al., 2011). Infection of rat pups on postnatal day (P)4 (rela-tively comparable to a preterm human) with E. coli markedlyincreases circulating cytokines in the periphery (IL-1b, IL-6, TNFa)and increases circulating corticosterone for at least 48 h after infec-tion (Bilbo et al., 2005a). Within the brain, neonatal E. coli infectionincreases IL-1b mRNA and protein at 24 h (Bilbo et al., 2005a), aswell as the expression of a host of other genes important for IL-1b signaling, including Caspase 1 (which cleaves IL-1b into its ac-tive form), IL-18, and the IL-1 type 1 receptor (Schwarz and Bilbo,2011). As adults, rats infected neonatally with E. coli exhibit a num-ber of physiological and behavioral changes, including vulnerabil-ity to cognitive impairments, sensitized fever to an LPS challenge,decreased corticosterone responses to a stressor, and decreased so-cial interactions (Bilbo, 2010; Bilbo et al., 2005a, 2008b, 2010)(Fig. 2).

3.2. Early-life immune activation and later-life cognition

The impact of an early-life immune challenge has been wellcharacterized for later-life cognitive abilities, and we focus on that

nd behavioral changes. Neonatally-infected rats exhibit a sensitized fever responseet al., 2010). Neonatally-infected rats have an attenuated corticosterone response toed rats also exhibit decreased social interactions with other rats when compared to

and developmental programming of brain and behavior. Front. Neuroen-

Fig. 3. Neonatal immune activation can have direct long-term effects on neuronal function or indirect long-term effects on neuronal function via alterations in neuroimmunefunction. Neonatal immune activation directly affects neuronal function by reducing neurotransmitter function (including GABA in the hippocampus and glycine in theprefrontal cortex), decreasing the expression of pre-synaptic proteins in the hippocampus, inhibiting long-term potentiation, and producing a differential neuronal activationpattern during a learning task such as the novel object recognition task. Neonatal immune activation indirectly alters neuronal function by producing long-term changes inneuroimmune function that in turn negatively impact neuronal function. Decreased tonic inhibition of microglia via altered expression of neuronal inhibitory signals,including fractalkine (via its receptor CX3CR1) and CD200, also results in exaggerated cytokine responses, which impact neuronal function.

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literature here. Cytokine receptors are distributed throughout thebrain, but the hippocampus has one of the highest densities ofmicroglia and receptors for IL-1b, a cytokine that has been wellcharacterized in relation to cognition (Cunningham and De Souza,1993; Schneider et al., 1998). The hippocampus is a brain regioncritical for learning and memory, as well as a host of other behav-iors important for survival such as emotion. Notably, the hippo-campus is also particularly vulnerable to damage from eventsthat occur during development or in adulthood, such as chronic/se-vere stress, epilepsy, stroke, hypoxia/ischemia, or cardiac arrest(Fujioka et al., 2000; Petito et al., 1987; Salmenpera et al., 1998;Sapolsky et al., 1987). Thus, one might predict that the developinghippocampus may also be particularly vulnerable to early-life im-mune activation.

There are two potential pathways by which perinatal immuneactivation may influence neural function and its associated behav-ioral outcomes such as learning and memory: (1) early-life im-mune activation could permanently alter or disrupt thedevelopment of neural pathways important for learning and mem-ory, or, (2) early-life immune activation could re-program adultimmune function, affecting how an adult responds to a subsequentimmune challenge via either prolonged or exaggerated pro-inflam-matory cytokine production or decreased anti-inflammatory regu-lation, which would indirectly impair the neural processesimportant for cognition (Fig. 3).

3.2.1. Long-term consequences of early-life immune activation: directeffects on cognition

Many labs have investigated the direct effects of perinatal im-mune activation on the neural circuits underlying cognition (op-tion #1 above), and have demonstrated that perinatal immuneactivation can significantly affect the development of specific neu-ral processes such as neurotransmission and synaptic plasticityimportant for learning and memory (Bitanihirwe et al., 2010; Itoet al., 2010; Oh-Nishi et al., 2010; Ozawa et al., 2006; Winter

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et al., 2009; Yang et al., 2000). Prenatal exposure to Poly IC causesreduced basal neurotransmission of dopamine and glutamate, aswell as reduced levels of the inhibitory transmitter GABA, withinthe hippocampus, and reduced glycine within the prefrontal cor-tex, a brain region critical for working memory. The authors ofthese studies attribute the cognitive/behavioral inflexibility ofthese offspring exposed prenatally to Poly IC to the observedchanges in neurotransmitter function (Bitanihirwe et al., 2010).Maternal immune activation using Poly IC also causes a reducedfrequency and increased amplitude of miniature excitatory post-synaptic potentials within the hippocampus of the offspring, indic-ative of significant differences in baseline glutamatergictransmission (Ito et al., 2010). There is a distinctly different patternof neuronal activation within the hippocampus of prenatally in-fected rats during an object recognition task, indicating that notonly is neurotransmission different but the overall function ofthe neuronal circuit is significantly altered (Ito et al., 2010). Lastly,maternal Poly IC treatment also causes decreases in pre-synapticproteins within the hippocampus of offspring suggesting differ-ences in synapse number; these offspring also have impairedlong-term potentiation (LTP), a process of synaptic strengtheningimportant for learning, within the CA1–CA3 pathway of the hippo-campus (Oh-Nishi et al., 2010).

3.2.2. Long-term consequences of early-life immune activation:indirect effects on cognition

Other experiments have been designed to explicitly test option#2 above; i.e. whether early-life immune activation can alter theadult neuroimmune response to a subsequent immune challengethereby indirectly affecting the neural circuitry underlying learningand memory. To test this possibility, rats infected neonatally withE. coli or its vehicle were tested in a modified version of contextualfear conditioning known as the context pre-exposure task (Barrien-tos et al., 2004). This paradigm assesses the rat’s memory for a re-cently explored context. In this task, when a rat is placed into a

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specific context and immediately shocked, it displays little or noconditioned fear (freezing) to the context. This absence of fear tothe context is thought to occur because the animal does not havethe opportunity to sample the environment and thus store a repre-sentation of its features (a hippocampal dependent process) priorto an immediate shock (Rudy et al., 2004; Rudy and O’Reilly,2001). If, however, a rat is pre-exposed to the context for severalminutes the day before, an immediate shock the following day willproduce substantial freezing on a subsequent test day (Fanselow,2000; Rudy and O’Reilly, 2001; Westbrook et al., 1994).

Using this paradigm, adult rats from each neonatal treatmentgroup (control vs. E. coli infection) received no injection, saline,or a low dose of LPS (which by itself does not typically cause mem-ory impairments) immediately following the context pre-exposure.If the adult LPS challenge causes an exaggerated or prolonged im-mune response in neonatally infected rats that would interferewith learning the context, then only rats that experience the com-bination of a neonatal infection and LPS after context pre-exposurewould display impaired memory. However, if neonatal E. coli infec-tion directly alters the development of neural pathways that sup-port memory formation, one would predict that neonatallyinfected rats should display impaired memory regardless of theadult immune challenge. Results demonstrated that only rats thatexperienced the combination of neonatal infection and subsequentLPS exposure displayed impaired memory for the explored context(Bilbo et al., 2005a). In contrast, neonatally infected rats that didnot receive an adult immune challenge at the time of contextpre-exposure did not exhibit memory deficits. Taken together,these data support the hypothesis that neonatal immune activa-tion increases the risk of cognitive deficits indirectly, via long-termprogramming of neuroimmune responses that subsequently inter-fere with the cellular processes of learning and memory. Interest-ingly, these data are in good accord with the ‘‘two-hithypothesis’’ of schizophrenia, which posits that the combinationof an underlying vulnerability (likely instantiated early in life) plusa later-life (typically young adult) precipitating event (e.g., stress,infection) is required for the manifestation of the illness (Choyet al., 2009; Keshavan, 1999; Keshavan and Hogarty, 1999; May-nard et al., 2001; Pantelis et al., 2003). From these data, one mightask: (1) How is the adult immune response different in an animalexposed to an early-life immune challenge; and (2) How does thisimpact behavior?

3.2.3. Cytokines and neural functionA growing body of evidence implicates a role for cytokines in

normal, non-pathological, synaptic plasticity mechanisms withinthe brain and associated learning and memory behaviors (McAfo-ose and Baune, 2009). TNFa is important for activity-dependentsynaptic scaling within the hippocampus (Beattie et al., 2002;Stellwagen and Malenka, 2006). Moreover, TNFa, as well as multi-ple interleukins (e.g., IL-6, IL-1, IL-10) and prostaglandins canmarkedly impact cognitive function, primarily memory (reviewedin Yirmiya and Goshen (2011)). Similarly, IL-6 has been implicatedin LTP maintenance (Balschun et al., 2004). High frequency stimu-lation in the hippocampus increases IL-6 mRNA expression (Jan-kowsky et al., 2000). Treatment of rat hippocampal neuronalcultures with IFNc during the peak of synaptogenesis reducesspontaneous excitatory-postsynaptic currents (EPSCs) and in-creases spontaneous inhibitory PSCs several weeks later (Brasket al., 2004).

IL-1b in particular has been well characterized for its role incognition. IL-1b is induced within the hippocampus in responseto fear conditioning (Goshen et al., 2007), and in hippocampalslices during the induction of LTP. However, IL-1b is also necessaryfor the maintenance of LTP of hippocampal synapses (Ross et al.,2003; Spulber et al., 2009b). Mice lacking endogenous IL-1b or its

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receptor exhibit markedly impaired hippocampal-dependentlearning and memory, and similarly transgenic over-expressionof the endogenous IL-1 receptor antagonist (IL-1ra) impairs LTPas well as hippocampal-dependent memory in the water mazeand fear-conditioning paradigms (Goshen et al., 2007; Spulberet al., 2009a,b).

In contrast to these data, exaggerated IL-1b within the brain isalso strongly associated with memory impairment. IL-1b is verytightly regulated during the course of the immune response withinthe normal brain. Patients with AIDS-related dementia, cancer,chronic inflammatory diseases (e.g., Alzheimer’s), or autoimmunediseases often exhibit exaggerated levels of IL-1b co-occurring withcognitive impairment (Gallo et al., 1989; Griffin et al., 1989;Meyers, 2000). Exogenously applied IL-1b inhibits LTP within hip-pocampal slices (Cunningham et al., 1996; Katsuki et al., 1990), andsimilarly, a systemic injection of a high dose of LPS inhibits LTP ofthe hippocampal perforant pathway in vivo (Vereker et al., 2000).This effect is blocked by inhibition of Caspase-1, the enzyme nec-essary for cleaving IL-1b into its biologically active form (Verekeret al., 2000), suggesting that IL-1b is the mechanism by whichperipheral LPS administration inhibits LTP in vivo. Rats injectedwith high levels of IL-1b directly into the dorsal hippocampus alsodisplay memory impairments (Barrientos et al., 2002; Pugh et al.,1999). These data suggest that cytokines, in particular IL-1b, arenecessary for normal cognitive function, specifically influencingthe synaptic mechanisms underlying learning and memory withinthe hippocampus. Moreover, the physiological level of IL-1b withinthe hippocampus is critically important, as too little or too muchIL-1b can equally impair learning and memory, consistent with ahormesis function observed for many hormones and biochemicalevents within the body and brain (Goudochnikov, 2011; Mattson,2008).

Based on the critical role for IL-1b in normal learning processes,and the learning and memory deficits seen in neonatally infectedrats following an adult immune challenge, subsequent experi-ments have explored whether IL-1b production within the hippo-campus is exaggerated or prolonged in adult rats infectedneonatally with E. coli. The expression of IL-1b and its associatedfamily of proteins is relatively low in the normal healthy brain.IL-1b protein within the hippocampus of neonatally infected ratsis not detectable and not significantly different than control ratsin the absence of an adult immune challenge, indicating that neo-natal infection does not result in chronically elevated IL-1b levelswithin the brain (Bilbo et al., 2005a). However, in response toLPS treatment, neonatally infected rats exhibit a prolonged andexaggerated expression of IL-1b protein specifically within the hip-pocampus and the adjacent parietal cortex (Bilbo et al., 2005a). Atthe messenger RNA level, the genes encoding for IL-1b, IL-1b con-verting enzyme (caspase-1), and the IL-1b type I receptor, are allsignificantly elevated following LPS treatment within the hippo-campus of neonatally-infected rats compared to controls. In addi-tion, mRNA for the anti-inflammatory IL-1ra is not significantlyelevated in neonatally infected rats above controls (Bilbo et al.,2007). Thus, early-life infection appears to program a shift in theneuroimmune system towards an exaggerated pro-inflammatoryresponse, specifically an exaggerated increase in IL-1b within thehippocampus, during the course of an immune challenge in theadult brain. Based on these data and the literature suggesting thatthe level or duration of IL-1b is important for learning and mem-ory, one might hypothesize that this exaggerated IL-1b responsewithin the hippocampus of neonatally infected rats could impairlearning of the context in the fear conditioning task. In supportof this hypothesis, blocking the synthesis of IL-1b using a cas-pase-1 inhibitor at the time of LPS administration completely pre-vents the contextual memory deficit described above in neonatallyinfected rats (Bilbo et al., 2005a). Thus, exaggerated IL-1b within

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the hippocampus in response to an immune challenge can criti-cally interfere with memory formation and, moreover, the riskfor dysregulation of immune responses and associated behavioraldeficits is capable of being programmed by early-life immuneactivation.

3.2.4. Interim conclusionsThe accumulated evidence from each of the described models of

perinatal immune activation (Poly IC, LPS, and E. coli) providesinteresting interpretations of the ‘‘big picture.’’ Although the mech-anism of action underlying distinct immune challenges may be dif-ferent (TLR3 vs. TLR4 activation), the end results of early-lifeimmune activation share similarities. First, all models of perinatalimmune activation produce a robust increase in cytokine expres-sion at the time of the challenge. Thus, increased cytokine produc-tion during the perinatal period emerges as a common mechanismby which many of these long-term changes in neuroimmune func-tion and behavior may be programmed for the life of the individ-ual. Notably, while researchers often use LPS as an immunechallenge to mimic the effects of E. coli, the two stimuli can elicitvery distinct cytokine profiles and behavioral outcomes in adult-hood. Namely, E. coli produces a robust yet pathway-specific in-crease in gene expression (focused on the IL-1b family ofproteins) following infection, whereas LPS produces a robust yetvery broad cytokine and chemokine response following adminis-tration (Schwarz and Bilbo, 2011). Therefore, the identification ofcommon cytokines that are elevated within the developing brainby these distinct immune challenges may guide future researchaimed at understanding how the incidence of seemingly disparateinfections and injuries in humans has been positively linked withthe incidence of neuropsychiatric disorders and cognitiveimpairment.

A second similarity among disparate perinatal immune chal-lenges is their induction of long-term changes in behavior in adult-hood. Some of these appear direct, and others indirect via long-term changes within the immune system as discussed previously.However, it should be noted that baseline cytokine expressionwas never analyzed in the adult offspring exposed to Poly IC prena-tally. An alternate conclusion for the described alterations in thoseanimals is that perinatal immune activation alters the baselinefunction or expression of neuroimmune molecules (even in the ab-sence of an adult immune challenge), and in so doing indirectly af-fects the endpoints measured, including basal neurotransmission,LTP, and synapse formation within the adult hippocampus.

4. Mechanisms underlying enduring consequences of early-lifeimmune challenge

Microglia are the innate immune cells of the brain. They are ra-pid responders to any disruption of homeostasis or immune chal-lenge, and are major producers of cytokines, chemokines, andother neuromodulators within the brain. They express a widenumber of surface and nuclear receptors, including those for com-plement proteins (CD11b), cytokines and chemokines (e.g., TNF,CCL2), as well as major histocompatibility (MHC) molecules,immunoglobulins, toll-like-receptors (TLRs), cell adhesion mole-cules, and many others (see Garden and Moller (2006) and Hanisch(2002) for review). Microglia in the normal adult brain have a rest-ing, highly ramified morphology, with low levels of ‘‘activationmarkers’’ (e.g., CD11b, MHC II) on the cell surface. However, theterm ‘‘activation’’ marker is somewhat of a misnomer, given thatresting microglia are by no means dormant or inactive. Increasingevidence suggests a role for microglia in normal synaptic plasticitymechanisms within the adult brain, including interactions withextracellular matrix composition and geometry, and dendritic

Please cite this article in press as: Bilbo, S.D., Schwarz, J.M. The immune systemdocrinol. (2012), http://dx.doi.org/10.1016/j.yfrne.2012.08.006

spine remodeling and elimination (Tremblay and Majewska,2011; Tremblay et al., 2011). These cells are very dynamic, evenwhen resting (Nimmerjahn et al., 2005), and continually surveytheir microenvironments by extending and contracting processesinto nearby synapses, with a frequency that is activity-dependent(Tremblay et al., 2010; Wake et al., 2009). For instance, they sam-ple individual synapses more frequently following visual stimula-tion, or in response to injury, and are likely responsible forsynapse removal via phagocytosis (Tremblay et al., 2010). Microg-lia have receptors for multiple neurotransmitters and neuromodu-lators, including those important for learning and memory (e.g.,ATP, norepinephrine, glutamate) (Pocock and Kettenmann, 2007),suggesting a rapid and direct role for these cells in normal cogni-tion. Many excellent reviews have been published on microgliafunction and biology, which goes beyond the scope of the currentmanuscript to extensively review here (Garden and Moller, 2006;Hanisch, 2002; Streit, 2002a,b; Streit et al., 2005).

4.1. Glial priming

Microglia are an excellent candidate for inducing long-termchanges within the brain, because these cells have the capacityto become and remain chronically sensitized or ‘‘primed’’ (Townet al., 2005). In response to injury or immune stimulation, microg-lia up-regulate a number of these surface receptors, includingthose for complement proteins, MHC II (important for antigen pre-sentation), and cytokines, which in turn initiate both repair andcytotoxic processes via interactions with numerous other CNS celltypes (e.g., astrocytes, neurons) (Rostene et al., 2011a). Microglialpriming has been implicated in Alzheimer’s, Parkinson’s, and Hun-tington’s diseases, as well as in normal aging (Barrientos et al.,2006; Bilbo, 2010; Cunningham et al., 2005; Frank et al., 2006a;Godbout and Johnson, 2009; Lynch, 2010; Perry, 2004). The charac-teristics of priming are not well defined, though primed glia havebeen characterized in situ by an activated morphology with en-larged cell bodies and short, thick processes. An important featureof priming is that these cells do not constitutively over-producepro-inflammatory mediators within the brain. Rather, the pro-inflammatory response produced by primed glia to a subsequentchallenge (e.g., systemic infection) is significantly exaggeratedwhen compared to resting/quiescent glia that receive the samechallenge (Perry et al., 2003). Thus, it is hypothesized that primedglia adopt a prolonged sensitized state, presumably following ini-tial activation by insult or injury (Perry et al., 2010; Streit et al.,2009). We hypothesize based on our research that the subsequentchallenge (i.e., ‘‘second hit’’) may occur temporally quite distantfrom the initial precipitating event; however, in general thedynamics of priming are relatively unknown. Note that there isalso evidence that microglia become dystrophic with age in con-trast to sensitized, which exhibit stripped or disembodied pro-cesses and are impaired in their normal homeostatic functions(Streit et al., 2009; Streit and Xue, 2009). In either case, becausemicroglia are believed to be long-living cells, glial pathology hasthe capacity to significantly alter neural function and behavior,perhaps over the entire lifespan.

Though the priming literature has largely been focused onmicroglia (similar to macrophages in the peripheral immune sys-tem (Johnson et al., 1983; Martinez et al., 2008; Pace et al.,1983), there is some evidence that astrocyte function is alteredby a prior inflammatory challenge; for instance, astrocytes cul-tured with discrete cytokines (IL-1b or TNFa), or with microglia-conditioned media exhibit sensitized responses to subsequentTLR2 ligands (Henn et al., 2011). Moreover, rats given kainic acid(KA) on P15 exhibit a lower threshold to induce seizures followinga subsequent exposure to KA on P45, along with long-term

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increases in the astrocyte markers GFAP and S100B, in addition togreater microglial activation (Somera-Molina et al., 2007).

The concept of glial priming is striking in its similarity to thepattern of cytokine expression and cognitive impairment in adultrats infected on P4 with E. coli, in which a sensitized IL-1b responseand memory deficit is only observed following the subsequentchallenge later in life. Indeed, we now have strong evidence thatearly-life infection with E. coli leads to long-term sensitization/priming of microglia within the brain. The microglial surface anti-gens CD11b and MHC II are markedly increased within the hippo-campus in response to infection on P4, and this increase issustained into adulthood (Bilbo et al., 2005a, 2007). In contrast,there were no acute or long-term changes in basal GFAP expressionfollowing neonatal infection. However, increased microglial mar-ker expression could indicate an increase in cell number, as op-posed to a change in their reactivity, consistent with thedefinition of ‘‘priming’’. Notably, by adulthood the total numberof microglia, astrocytes, & neurons within the hippocampus doesnot differ as a consequence of neonatal treatment. However, themorphology of microglia in neonatally-infected rats is very differ-ent in adulthood; cells are larger and amoeboid-like, with thickerprocesses, consistent with priming (Bland et al., 2010b). This differ-ence is apparent basally, indicating a long-term effect of the infec-tion alone. More recently we have confirmed and extended thischaracterization of glia using flow cytometric analysis of rapidlyisolated microglia from rats in each condition. To do this, rats fromeach neonatal treatment were injected as adults with saline or LPS,and the hippocampus was collected 24 h later. Microglia were rap-idly isolated (Frank et al., 2006b; Henry et al., 2008), and stainedwith an APC-conjugated CD11b antibody. Cell size (forward lightscatter) and CD11b+ expression were assessed using flow cytome-

Fig. 4. Learning increases IL-1b protein within hippocampal microglia, which is modulaadulthood with saline or lipopolysaccharide (LPS) 24 h prior to either a learning expfootshock), or a control procedure which consisted of footshock only (without context ethe hippocampus of separate groups of rats from each neonatal condition, 2 h after eachrats from both neonatal conditions that received a saline injection as adults, IL-1b protcompared to context alone or shock alone. Neonatally-infected rats that received LPS 24response to learning (context + shock); ��p < 0.01 compared to control rats. These data inneonatally-infected rats that receive an adult immune challenge have dysregulation of IL-sole source of IL-1b in these experiments (Williamson et al., 2011). (B) In a separate set oeach neonatal condition that received saline 24 h prior to the learning experience showassociation between the shock and the context. Control rats that received LPS 24 h priorstrong memory. In contrast, neonatally-infected rats that received LPS 24 h prior to conindicating impaired memory only in this ‘‘2-hit’’ group (neonatal infection + adult immuproduced by microglia within the hippocampus at the time of learning and is requiredalone), IL-1b is not produced in detectable levels. In neonatally-infected rats, long-termresults in significantly exaggerated levels of IL-1b following a learning experience, whinterfere with the consolidation of the learning experience and result in memory deficiinverted U), in a normal, active phenotype in which IL-1b is produced during normal leaexaggerated levels of IL-1b are observed in response to learning, but only in neonatally-inrepresented from Williamson et al. (2011)).

Please cite this article in press as: Bilbo, S.D., Schwarz, J.M. The immune systemdocrinol. (2012), http://dx.doi.org/10.1016/j.yfrne.2012.08.006

try. Again, total cell number did not differ, whereas microglia wereboth larger and exhibited increased CD11b+ expression on a percell basis in neonatally-infected rats (Williamson et al., 2011), con-sistent with our previous in situ findings (Bland et al., 2010b).

4.2. Microglia are the source of exaggerated IL-1b in neonatally-infected rats

These collective data suggest that changes in the function ofmicroglia, rather than simply changes in number, underlie their in-creased reactivity in neonatally-infected rats. Consistent with thisinterpretation, rapid isolation and separation of microglia (CD11b+cells) from other CNS cell types (CD11b-cells; e.g., astrocytes, neu-rons) using magnetically activated cell sorting (MACS�) for analy-sis of IL-1b expression indicates that microglia are the sole sourceof exaggerated IL-1b in neonatally-infected rats within the brain.Most exciting, these experiments also revealed that CD11b+ cellsare the source of IL-1b during hippocampal-dependent learning. Asdescribed above, systemic infection with E. coli on P4 leads tomarked hippocampus-dependent memory impairment in adult-hood, but only if these animals receive a low dose LPS challengeafter learning. The impairment is causally linked to exaggeratedCNS IL-1b production, as preventing IL-1b synthesis within thebrain completely prevents the memory impairment (Bilbo et al.,2005a). Curiously, LPS 24 h prior to learning also impairs long-termcontextual memory in neonatally-infected but not control rats de-spite the fact that hippocampal IL-1b is largely undetectable inboth groups by 24 h after an LPS injection (Bilbo et al., 2005a,2006). These data led us to test the hypothesis that learning itselfinduces IL-1b protein within the hippocampus, which is differen-tially modulated in NI rats. To test this, rats treated with PBS or

ted by neonatal infection. (A) Neonatally-infected rats and controls were treated inerience (fear conditioning, consisting of 2 min context exploration followed by axploration) or context exposure only (no footshock). IL-1b protein was measured inof these conditions (shock alone, context alone, or context + shock/fear learning). Inein was only increased after the learning experience (context + shock); �p < 0.001,h prior to behavioral testing exhibited an exaggerated IL-1b response, but only in

dicate that normal learning induces the synthesis of IL-1b in the hippocampus, but1b at the time of learning. Subsequent experiments revealed that microglia were thef rats, fear memory for the context was assessed 72 h after conditioning. Rats fromrobust freezing behavior (fear) at the 72 h test, indicating that they remember the

to conditioning also show robust freezing behavior (fear) at the 72 h test, indicatingditioning exhibit significantly decreased freezing (fear) in the context (��p < 0.05),ne challenge; see (Williamson et al., 2011). (C) Our working model is that IL-1b isfor normal memory formation. In the absence of learning (shock alone or context

changes in neuroimmune function (microglial priming, see Williamson et al., 2011)ich are ‘‘unmasked’’ by the adult LPS challenge. These exaggerated levels of IL-1bts. The cartoon illustrates microglia in a quiescent phenotype (left-hand tail of therning to support memory (center), and in a sensitized/primed morphology in whichfected rats that receive LPS as adults (right-hand tail of the inverted U). All data are

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E. coli on P4 were injected with saline or LPS as adults, and fearconditioned 24 h later. IL-b was detectable at low but physiologicallevels within the hippocampus 2 h after contextual fear condition-ing in both groups of rats (Williamson et al., 2011). In contrast, IL-1b was not detected within the cortex, confirming that IL-1b is sig-nificantly and selectively elevated within the hippocampus at thetime of context learning. Importantly, IL-1b was undetectablewithin the hippocampus following either exposure to the context(with no shock) or footshock alone, suggesting that IL-1b is onlysynthesized within the hippocampus during a learning experience.Most importantly, this learning-induced increase in hippocampalIL-1b levels was significantly exaggerated in neonatally-infectedrats that were previously injected with LPS (Williamson et al.,2011) (Fig. 4).

These data indicate that LPS given 24 h prior to learning andmemory causes a significant shift in microglial function in neona-tally-infected rats such that learning itself results in exaggeratedIL-1b production, which impairs learning and memory. Consistentwith this interpretation, inhibiting microglia with minocyclineeither at the time of LPS treatment or at the time of learning can re-verse the memory impairment in neonatally-infected rats (Wil-liamson et al., 2011). These collective data have led to threeconclusions: (1) microglia have a critical role in learning and mem-

Fig. 5. Immune molecules play a ubiquitous role in neural development. Microglia, acontinually communicate via cytokines, chemokines, neurotransmitters and other factorimmune function have now been implicated in neural development; representative exa(2009) for comprehensive reviews). (1) Many cytokines are important for progenitor c(BMP)/transforming growth factor beta (TGFb) family of cytokines is critical for neural inimportant for progenitor cell maintenance and proliferation (Derouet et al., 2004; Greggcell populations and proliferation of dividing cells within the brain (Lathia et al., 2008),Cytokines such as IL-1b and the IL-6 family of proteins have a demonstrated role in cytogexpression peaks during astrocytogenesis, which is dependent on the presence of amoeboas primitive yolk sac macrophages beginning around E9–10 (Ginhoux et al., 2010); macrthis recruitment (Ginhoux et al., 2010; Sasaki et al., 2000). (3) Chemokines, in particularregions, including the cerebellum (Ma et al., 1998; Zou et al., 1998). (4) MHC I is critical fmany other brain regions (Corriveau et al., 1998; Datwani et al., 2009; Shatz, 2009).dependent synaptic scaling (Stellwagen and Malenka, 2006). (5) Complement proteins,these proteins via the complement receptor 3 (CD11b), and phagocytose the labeled synaprimary phagocytic cells of the CNS, and thus have an important role in phagocytosing apand most abundantly within the developing brain (Ferrer et al., 1990). Programmed cell d2002b).

Please cite this article in press as: Bilbo, S.D., Schwarz, J.M. The immune systemdocrinol. (2012), http://dx.doi.org/10.1016/j.yfrne.2012.08.006

ory via the production of IL-1b, (2) microglial dysfunction (exag-gerated IL-1b) results in cognitive dysfunction, and (3) early-lifeevents can significantly impact cognitive function later in life vialong-term programming of microglial function.

5. Beyond infection: immune molecules and neuraldevelopment

A wide number of immune signaling molecules including cyto-kines, chemokines, MHC molecules, complement proteins, andTLRs have been identified for their critical roles in neural develop-ment (Deverman and Patterson, 2009) (Fig. 5). Many of these mol-ecules are glial-derived (microglia and astrocytes), or theycritically interact with glial function to guide normal development.We and others (Deverman and Patterson, 2009; Tremblay et al.,2011) have hypothesized that the colonization pattern of thedeveloping brain by glia, and the large number of immune mole-cules important for brain development, has important implicationsfor a wide number of insults or environmental stimuli that mightactivate the developing immune system either directly or indi-rectly, and in so doing exert enduring effects on neural functionand behavior, and the evidence is mounting in support of thishypothesis.

strocytes, and neurons share a common molecular language within the CNS, ands (center circle). Many of the same molecules originally identified for their roles inmples are conceptualized here (see Boulanger (2009) and Deverman and Pattersonell maintenance, proliferation, and differentiation. The bone-morphogenic proteinduction (Gaulden and Reiter, 2008). The gp130 receptor and associated ligands are

and Weiss, 2005; Mehler et al., 1995). TLR3 is important for maintaining progenitorand HMGB1, a known ligand for TLR4, impacts cell survival (Zhao et al., 2011). (2)enesis within the developing brain (Bowen et al., 2011; Nakanishi et al., 2007). IL-1bid microglia (Giulian et al., 1988b). Microglia begin to colonize the developing brainophage colony-stimulating factor (M-CSF) and the CSF-1 receptor are important forCXCL12 and its receptor CXCR4, guide the migration of new neurons in many brainor the activity dependent formation of synapses within the visual cortex, and likelyTNFa released by astrocytes promotes synaptic transmission and affects activity-C1q and C3, tag synapses for elimination (Stevens et al., 2007). Microglia recognizepses as a mechanism of synaptic pruning (Schafer et al., 2012). (6) Microglia are theoptotic debris following programmed cell death, a process that occurs continuouslyeath likely plays a major role in recruitment of microglia into the CNS (Wang et al.,

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5.1. Role of microglia in neurodevelopment

Microglia originate early in the life of the fetus and are poten-tially very long-lived, meaning they may have the capacity to re-side in the brain for most of the life of the animal (Male andRezaie, 2001). Microglial progenitor cells begin colonizing the ro-dent brain around embryonic day (E) 9–10 via the infiltration ofprimitive macrophage precursors from the yolk sac (Chan et al.,2007; Ginhoux et al., 2010; Male and Rezaie, 2001). These primi-tive microglia enter the parenchyma via the blood stream and ven-tricles (Cuadros and Navascues, 1998). Microglia are detectableusing immunohistochemical staining for the antigen Iba1 withinthe developing rodent brain around E13 or 14; they are initially lo-cated within the embryonic brain around subcortical regions suchas the hippocampus and around the corpus callosum (Wang et al.,2002a; Xu et al., 1993). From that point, microglia migrate to theirfinal destination within the brain where they continue to prolifer-ate. Similar to the rodent brain, colonization of microglia withinthe human brain is an orchestrated response that occurs early infetal development alongside maturation of the nervous system(Chan et al., 2007). In humans, the first cells with the characteris-tics of a macrophage appear within the yolk sac and mesenchyme(embryonic cells that will eventually develop into the circulatoryand lymphatic system) around the 4th week of gestation. Vascular-ization of the neural plate commences at around 5 weeks of gesta-tion and within the 5th and 6th week of gestation many of theseyolk-sac derived cells appear within and just outside these newlyformed blood vessels (see Male and Rezaie (2001) for review).

To date, it is not well known what factors drive the infiltration andmigration of immature microglia into the parenchyma. Someresearchers have noted that the invasion of microglia within thedeveloping brain coincides with naturally occurring cell death dur-ing early brain development (Ashwell, 1990, 1991; Perry et al.,1985). Moreover, chemokines such as macrophage colony stimulat-ing factor (M-CSF) and the CSF-1 receptor (Ginhoux et al., 2010; Sasa-ki et al., 2000), and intercellular cell adhesion molecule (ICAM)-2(Ginhoux et al., 2010; Rezaie et al., 1999), may play a role. Many otherchemokines (e.g., monocyte chemoattractant protein (MCP)-1) havean important role in microglial migration and neural developmentwithin the healthy brain (Cowell and Silverstein, 2003; Cowellet al., 2006; Cross and Woodroofe, 1999; Rezaie and Male, 2002).We have recently identified a significant number of chemokines thatare up-regulated within the rat hippocampus and cortex at birthwhen compared to the adult brain, including CCL2, CCL3, CCL6,CCL7, CCL12, and Chemokine (C–X–C motif) ligand 6 (CXCL6) (Sch-warz et al., 2012). One might hypothesize these cytokines are impor-tant for attracting primitive macrophages and immature microgliainto the brain from the periphery during early brain development.

Within the adult brain, microglia have a distinct ramified mor-phology represented by thin, long processes and small cell bodies.In contrast, microglia within the embryonic human and rodent brainhave a larger, round, amoeboid morphology, similar to the morphol-ogy of microglia seen in the adult brain following activation or injury.From embryonic development to early postnatal development, andfrom adolescence to adulthood, microglia shift their morphologyrapidly and dramatically in a brain region-dependent manner. Thisprocess has been explored predominantly within subcortical regionsof the rodent brain and the retina (Cuadros and Navascues, 1998;Schwarz and Bilbo, in press). From birth to P4, cells change their mor-phology rapidly as they develop from a round amoeboid shape to ashape characterized by a smaller cell body with thinner, longer pro-cesses. However, even in the juvenile and adolescent rodent brain,microglia within certain brain regions continue to show a more acti-vated morphology suggesting that these brain regions and themicroglia within them are continuing to undergo maturationalchanges (Cuadros and Navascues, 1998; Schwarz and Bilbo, in press).

Please cite this article in press as: Bilbo, S.D., Schwarz, J.M. The immune systemdocrinol. (2012), http://dx.doi.org/10.1016/j.yfrne.2012.08.006

Taking into consideration the morphology of immature microgliaand the increased production of cytokines within the developingbrain, one might assume that the primary role of microglia withinthe developing brain is related to their role as brain macrophages,specifically that they are actively engaged in the phagocytosis of cel-lular debris of apoptotic cells as well as the induction of apoptosis inother cells (Bessis et al., 2007; Marin-Teva et al., 2004; Wang et al.,2002a). However, recent work suggests that microglia have a muchmore complex role in the developing brain. Microglia now havedemonstrated roles in cellular differentiation and axon guidance(see Boulanger (2009) and Deverman and Patterson (2009) for re-view). Moreover, a critical role for microglia in developmental syn-apse elimination has recently been described (Schafer et al., 2012).C1q and C3, proteins within the classical complement cascade ofthe immune system, localize to synapses within the postnatalmouse brain intended for elimination (Stellwagen and Malenka,2006). Microglia that express the complement receptor (CD11b)for C3 are activated for phagocytosis of these ‘‘opsonized’’ or labeled,synapses (Schafer et al., 2012; Stevens et al., 2007; Tremblay et al.,2011). Interestingly, a lack of CX3CR1 (fractalkine) receptor onmicroglia transiently reduces the number of microglia within theearly postnatal brain (P8–P15), and impairs synapse elimination inmice (Merrill, 1991). Defects in synaptic function have been linkedto a large number of mental health disorders, including depression,anxiety, and cognitive disruption, and pruning defects (either overor under pruning) are linked to autism and schizophrenia (Keshavanet al., 1994; Luscher and Isaac, 2009; Saugstad, 2011).

5.2. Role of astrocytes in neural development

Astrocytes are derived from specific populations of progenitorcells (see Zhang and Barres (2010) for review) toward the end ofembryonic development. During mammalian nervous systemdevelopment, neural progenitor cells (NPCs) generate neurons firstand astrocytes second, though the switch that guides this determi-nation is brain-region dependent (for review see Freeman (2010)).The differentiation of NPCs into neurons first and astrocytes secondrequires a discrete turning on and turning off of particular genes,such as gfap or s100b, using epigenetic mechanisms includingDNA methylation (Takizawa et al., 2001). Interestingly, a recentexperiment determined that co-culture of neural progenitor cellswith microglia can promote the differentiation of neural progeni-tors into astrocytes (Gu et al., 2011). Protoplasmic astrocytes beginto sprout processes within the final weeks of embryonic develop-ment and the first weeks of postnatal development, and theydevelop long processes relatively rapidly. By P7, astrocytes withinthe hippocampus display thin processes similar to filopodia thatoften terminate with small bulbous structures, with usually oneprimary but sometimes more primary, thicker processes (Bushonget al., 2004). One week later, astrocytes within the hippocampusdisplay much greater ramification of their processes, though manyof these processes are still thin and filopodial in nature; and by P21,astrocytes display multiple primary processes, thinner processesare more ramified/mature, and astrocytes have established distinctboundaries from neighboring astrocytes. Astrocytes have a crucialfunction in synaptogenesis and synaptic scaling, through therelease of diffusible factors and the production of extracellularmatrix proteins (see Eroglu and Barres (2010) for review). Mostsynaptogenesis occurs after birth and depends significantly onastrocyte function. A single astrocyte can associate with nearly2 million synapses (Freeman, 2010), making up the ‘‘tripartite syn-apse’’ (Araque et al., 1999), and their role in synaptic plasticitymechanisms within the adult CNS is now well accepted (Araqueand Navarrete, 2010; Pfrieger, 2010; Sharif and Prevot, 2010).Astrocytes express many neurotransmitter receptors, allowingthem to rapidly perceive and respond to synaptic activity (Stipursky

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et al., 2011). Astrocytes also produce the TNFa that mediates synap-tic scaling following prolonged periods of inactivity within the HP(Beattie et al., 2002; Stellwagen and Malenka, 2006). D-serinerelease from astrocytes is necessary for HP LTP (Hennebergeret al., 2010; Yang et al., 2003). Importantly, a recent report showedthat IL-1 type 1 receptor expression in astrocytes is also necessaryfor HP-dependent LTP and long-term memory (Ben Menachem-Zi-don et al., 2011). Moreover, these cells are immunocompetent andrespond to injury or infection in many ways that are analogous tomicroglia. In response to injury or immune stimulation, astrocytesexhibit hypertrophy and proliferation, a process known as reactivegliosis or astrocytosis, which has been implicated in a number ofneurological disorders with discrete developmental origins, includ-ing seizures (Somera-Molina et al., 2007), ischemia (Sullivan et al.,in press), and cortical injury (Burns et al., 2009).

5.3. Cytokines

A large number of cytokines have been characterized for theirimportance in many neurodevelopmental processes including neu-rogenesis, neuronal and glial cell migration, proliferation, differen-tiation, and synaptic maturation and pruning (Fig. 5). These includemembers of the gp130, bone morphogenetic protein (BMP), andtransforming growth factor beta (TGFb) super-families, ‘‘cyto-kine-like’’ hormones such as leptin, growth hormones, and prolac-tin, as well as many traditionally defined ‘‘pro-inflammatory’’cytokines (e.g., IL-1b, TNFa) (Bouret et al., 2012; Deverman andPatterson, 2009; Garay and McAllister, 2010; Larsen and Grattan,2012; Merrill, 1991, 1992; Pathipati et al., 2011). The basal expres-sion of many cytokines early in development is significantly higherwhen compared to the adult brain. Coinciding with the appearanceof amoeboid microglia during early brain development, research-ers have reported a naturally occurring increase in cytokines. Forexample, IL-1b is produced at detectable levels within the cortexfrom approximately E14 to P7 (Giulian et al., 1988a), in contrastto the adult brain in which levels are difficult to detect basally.In contrast, the cerebellum, which develops significantly later, justprior to birth in rodents, has a peak in IL-1b levels that occurs fromP2 to P14 (Giulian et al., 1988a). Specifically within the hippocam-pus, IL-1b is increased nearly 6-fold at birth when compared toadult hippocampus (Schwarz et al., 2012). Time dependence andregional specificity has also been demonstrated for the expressionof other cytokines during brain development, suggesting a physio-logical role for these cytokines in the development of specific braincircuits. Both IL-1b and TNFa are present early in the developingsheep brain, declining by birth and peaking again around the timeof synaptogenesis (Dziegielewska et al., 2000). IL-6 is important fornumerous developmental processes including prenatal CNS vascu-lar development (Fee et al., 2000), and IL-6 increases markedly instriatum, hippocampus, and cortex throughout development, sug-gesting a neurotrophic role for this cytokine within these brain re-gions (Gadient and Otten, 1994a,b). IL-11 is increased 10-foldwithin the hippocampus at birth when compared to adults (Sch-warz et al., 2012). Not surprisingly, there is a corresponding in-crease in cytokine receptors early in development whencompared to the adult brain. Specifically, IL-1 receptor 2, IL-2receptor b, IL-2 receptor c, and IL-6 receptor a are all significantlyup-regulated at P0 within the hippocampus when compared to theadult (Schwarz et al., 2012). These data suggest that elevated levelsof particular cytokines may coincide with important processes ofneurodevelopment in a brain region-dependent manner.

5.4. Chemokines

Chemokines are small 8–12 kD proteins important for T cell, Bcell, and hematopoietic cell development (Aiuti et al., 1997;

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Hernandez-Lopez et al., 2002; Ma et al., 1998; Nagasawa et al.,1994, 1996; Zou et al., 1998), and are critical mediators of chemo-taxis in the context of disease; e.g., recruitment of leukocytes tosites of insult or injury (Jones et al., 2010; Koziolek et al., 2009;Liu and Jiang, 2011; Nibbs et al., 2007). Increasing research hasidentified a ubiquitous role for chemokines in nervous systemfunction as well. For instance, CXCR2 increases GluR1 affinity forglutamate following transfection into human embryonic kidney(HEK) cells (Lax et al., 2002). Application of the CXCR2 ligand,CXCL2, onto cultured cerebellar Purkinje cells increases spontane-ous AMPA-type glutamatergic excitation (Lax et al., 2002). Thechemokine CX3CL1 (fractalkine) reduces AMPA-mediated currentsand alters EPSCs evoked by electrical stimulation of Schaffer collat-erals in hippocampal neurons, via interactions with its receptorCX3CR1, which is notably highly expressed on microglia withinthe brain (Lauro et al., 2008). Numerous other chemokines,including CCL2 (MCP-1), CCL3 (macrophage inflammatory protein(MIP)-1a), and CXCL12, have been identified for their roles inneurotransmission within the CNS as well, particularly within thehippocampus (Kuijpers et al., 2010; Nicolai et al., 2010).

In addition to playing critical roles in neurotransmission, che-mokines are important for neural stem cell migration within thebrain (Kolodziej et al., 2008; Tran et al., 2007), including the devel-oping brain. The chemokine CXCL12 (SDF-1) and its exclusivereceptor CXCR4 have a critical role in the migration of neurons totheir final destination. Mice lacking either CXCL12 or CXCL4 havedeficits in cerebellar development, as the temporospatial migrationof granule cells into the internal granule cell layer from the exter-nal layer is disrupted (Ma et al., 1998; Zhu et al., 2002; Zou et al.,1998). Since this discovery, others have discovered that CXCR4and CXCL12 regulate the migration of cells within other developingbrain regions including the proliferating cells of the dentate gyrus(Lu et al., 2002), GABAergic interneurons migrating into the cortex(Stumm et al., 2003), and gonadotropin-releasing hormone (GnRH)neurons migrating from the vomeronasal organ to their destinationwithin the hypothalamus (Schwarting et al., 2006). CXCL12 alsoregulates axonal elongation and branching within hippocampalneurons via interactions with its receptor (Pujol et al., 2005). Withmore sophisticated tools aimed at targeting individual chemokinesand their receptors, researchers will most likely identify manymore neurodevelopmental processes that are regulated by thesechemoattractant immune molecules. Notably, inflammatory stim-uli increase the proliferation of neural stem cells (NSCs) in the den-tate gyrus (Belmadani et al., 2006; Das and Basu, 2008), and NSCsexpress several chemokine receptors, including CXCR4, the recep-tor for CXCL12, and CXCR2, the receptor for CCL2/MCP-1 (Imitolaet al., 2004; Tran et al., 2007; Tran and Miller, 2003; Wideraet al., 2004), which has important implications for injury and re-pair, and long-term neurocircuitry organization and function.

5.5. MHC I

In addition to the members of the cytokine families, other im-mune molecules have a demonstrated role in neural development.MHC I proteins were described in the activity dependent formationof synapses within the visual cortex over a decade ago (Corriveauet al., 1998). MHC molecules are cell-surface ligands that are bestknown for binding T cells within the periphery to regulate theiractivation. However, they are also present on neurons within thedeveloping brain, where they are thought to be located postsynap-tically near glutamate receptors and to interact with a number ofputative pre-synaptic proteins expressed on axonal growth conesin the selection and guidance of activity-dependent synaptic for-mation and strengthening (Shatz, 2009). Since their initial identifi-cation within the visual pathway, MHC I family moleculeshave been identified in many neuronal types within the developing

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dorsal root ganglia, brainstem, hippocampus, and cerebellum, andmost likely MHC I has an important role in modulating synapseformation within all of these brain regions. The MHC I family ofgenes is in general an attractive candidate for guiding synapticspecificity because of its enormous diversity (Shatz, 2009).

5.6. Complement proteins

The classical complement cascade within the peripheral im-mune system consists of a large number of proteins, includingthe initiating molecule C1q and downstream effector C3, whichorganize interactions between cells of the innate and adaptive im-mune system in order to aid in pathogen detection and elimination(Murphy et al., 2008). As described above, a role for these sameproteins in developmental synapse elimination, or pruning, withinthe CNS has recently been recognized. Complement proteins arewidely expressed within neurons of the developing brain, particu-larly during periods of active synaptic remodeling (Stevens et al.,2007). C1q or C3 deficient mice exhibit impairments in synapseelimination, along with disordered layer segregation within thelateral geniculate nucleus of the developing visual system. The pre-diction is that these same molecules are important in a number ofdevelopmental disorders as well; e.g., psychiatric disorders inwhich defective synapse elimination has been implicated, includ-ing autism and schizophrenia (Stephan et al., 2012), although thisremains to be directly demonstrated.

5.7. PAMPs, DAMPs and toll-like receptors

The innate immune system represents a complex set of tissues,cells, and molecules critical for the detection, containment, andelimination of a large number of pathogens, insults, and damageto cells. Pathogen-associated molecular patterns (PAMPs) are a di-verse set of evolutionarily-conserved molecules present on micro-organisms such as bacteria and viruses, which are recognized by

Fig. 6. The list of factors hypothesized to activate immune cells via toll-like receptors (Twhich identify the pathogen-associated molecular patterns (PAMPs) of specific pathogensnegative bacteria, lipopolysaccharide (LPS), which is also found on E. coli. The role of theassociated molecular patterns (DAMPs). These include a novel subset of proteins that arealarmins, which are putatively recognized by TLRs, including both TLR4 and TLR2. ProteProteins, and high mobility group box (HMGB) 1. In addition, the list of exogenous or enever-expanding. These include drugs of abuse (e.g. opiates, amphetamines, and ethanol

Please cite this article in press as: Bilbo, S.D., Schwarz, J.M. The immune systemdocrinol. (2012), http://dx.doi.org/10.1016/j.yfrne.2012.08.006

the innate immune system via the activation of the endogenouspattern recognition receptors (PRRs), most notably the TLRs. Thepattern recognition receptor TLR3 is expressed by neural progeni-tor cells in the developing cortex and regulates the proliferation ofthese cells (Lathia et al., 2008). In vitro studies suggest TLR2 and 4are important for stem cell fate determination, and mice lackingTLR2 exhibit impaired neurogenesis, whereas mice lacking TLR4exhibit enhanced neurogenesis (Rolls et al., 2007). These data areespecially intriguing given that the Toll family of receptors wereinitially characterized in Drosophila for their role in embryonicneural patterning, but are inseparable from the immune systemin mammals (Anderson et al., 1985). Importantly, the function ofsome TLRs, including TLR2 and 4, extends beyond that of PAMPrecognition to ‘‘danger’’ associated molecular patterns (DAMPs)recognition more broadly (Matzinger, 2002). DAMPs includeendogenous ‘‘alarmins’’ that are released in response to cellularor tissue distress (Bianchi, 2007). There are many putative factorsthat have been identified as alarmins, including hyaluronan, highmobility group box (HMGB) 1, and heat shock proteins (see Bianchi(2007) for review).

A few of these alarmin molecules have an established role inbrain development, neural function, and behavior. Most notably,HMGB1 is a ubiquitous component of chromatin which can be re-leased by necrotic cells, is retained by apoptotic cells, and is ac-tively secreted by cells undergoing an inflammatory challenge orbiological stress (Muller et al., 2004). However, HMGB1 is alsohighly expressed in the developing brain of vertebrate and non-vertebrate species (Fig. 6), and is the only HMGB to be releasedeven in the absence of immune activation (Guerin et al., 2009;Huang et al., 2005; Kinoshita et al., 1994; Rauvala and Pihlaskari,1987). Years ago, it was determined that HMGB1 can induce neu-rite outgrowth from embryonic forebrain cultures derived fromrats (Rauvala and Pihlaskari, 1987). More recently, it has beendetermined that HMGB1 is necessary for the survival and differen-tiation of catecholaminergic neurons during the development of

LRs), in particular TLR4. Toll-like receptors are innate pattern recognition receptors. For example, TLR4 recognizes the immunologically active cell wall pattern of gram-se receptors has recently expanded to include the broader recognition of ‘‘danger’’produced and released by nearby cells undergoing cell death or distress, known asins that have been identified as alarmins thus far include hyaluronan, Heat Shock

vironmental factors that are hypothesized to activate TLR4 (directly or indirectly) is), saturated dietary fats, and other toxins (e.g. air pollution).

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the forebrain in zebrafish (Zhao et al., 2011). Thus, similar to otherimmune molecules previously discussed, alarmin molecules ap-pear to have a critical role in the development of functional circuitswithin the brain.

HMGB1’s role in neural function and behavior is exemplified ina recent experiment which determined that over-expression ofHMGB1, caused by a functional knockout of Single-Ig-interleu-kin-1 related receptor (SIGIRR), a protein that constitutivelydown-regulates HMGB1 expression, causes significant impair-ments in hippocampal function in adults (Costello et al., 2011).Specifically, these mice show deficits in novel object recognition,spatial reference memory, and LTP. Blocking TLR4, one of the in-nate immune receptors activated by HMGB1, completely blocksthese deficits caused by exaggerated expression of HMGB1 signal-ing (Costello et al., 2011), suggesting that these effects of HMGB1are exclusively driven by the activation of the innate immune sys-tem. These data support the hypothesis that dysfunction of the im-mune system – including in this case the dysregulation of alarminproteins – can cause significant cognitive impairment even in theabsence of an overt immune challenge.

5.8. Is there a sensitive period for the long-term consequences of early-life immune activation?

The development of the brain involves an exquisitely timed setof events that ultimately lead to the formation of functional cir-cuits required for complex behaviors. Thus the consequences ofan immune challenge early in life for potentially lifelong behav-ioral outcomes will undoubtedly vary depending on the ongoingdevelopmental processes at the time of insult. We have recently re-viewed this evidence (Bilbo and Schwarz, 2009). As described inthe previous section, the morphology, function, and synthesis ofimmune molecules from glial cells are markedly different duringearly postnatal development as these cells continue, themselves,to develop and direct the development of the cells around them.We have thus hypothesized that the distinct colonization patternof microglia into the developing brain represents a sensitive periodfor long-term changes in their function as well as associated cogni-tive and behavioral outcomes; if true, then a challenge later in lifeshould not have the same impact. Indeed, E. coli infection on P30, atime when the majority of microglia are in a mature ramified statein males (Schwarz et al., 2012), does not enduringly impact IL-1bexpression, nor does it impact cognition in adulthood, either ba-sally or following an LPS challenge (Bilbo et al., 2006). Beyondchanges in glia, and in immune molecules expression within thedeveloping brain as described previously, there are numerousother factors that likely impact the long-term consequences of im-mune disruption or challenge early in life, including the maternalimmune response, and the placental and blood–brain barriers.

5.8.1. The maternal–fetal interfaceThe maternal immune system and placenta are two critical fac-

tors that can distinguish or differentially impact the neurodevelop-mental outcomes of the offspring exposed to an immune challengeprenatally. Pregnancy is associated with many changes in thematernal immune response (see Robinson and Klein (2012) for re-view). Over the course of pregnancy, there is a gradual shift fromcell-mediated (Th1) to humoral (Th2)-dominant responses, a de-crease in inflammatory macrophages and cytokines production,decreased febrile responses, and an increase in regulatory T cells,changes that are hypothesized to prevent fetal rejection (Mouihateet al., 2008; Robinson and Klein, 2012). However, these changesalso affect disease pathogenesis, including susceptibility to infec-tious diseases that are often increased (Robinson and Klein,2012). Interestingly, maternal immune activation, while altered,nonetheless results in a robust increase in certain cytokines (e.g.,

Please cite this article in press as: Bilbo, S.D., Schwarz, J.M. The immune systemdocrinol. (2012), http://dx.doi.org/10.1016/j.yfrne.2012.08.006

IL-6) within the maternal blood stream (Shatz, 2009). Cytokinesproduced by the maternal immune system may in turn gain accessto the fetal brain, via the placenta. The placenta is the first func-tional organ of the fetus (Pasca and Penn, 2010), and research on‘‘fetal programming’’ increasingly focuses on the placenta as a cru-cial source of variation in the development and physiology of thefetus in response to environmental change (reviewed in Godfrey(2002), Jansson and Powell (2007) and Myatt (2006)). The majorityof this research has focused on the impact of maternal stress ormaternal nutrition on fetal outcomes, via changes in metabolicpathways (e.g., leptin, insulin) (Armitage et al., 2004; de Boo andHarding, 2006; Jansson and Powell, 2007). However, a significantliterature on the role of placental endocrine–immune interactionsis emerging. Maternal antibodies and immune cells contact the lin-ing of the syncytiotrophoblast layer of the placenta, which in turnincreases cytokine production. In addition, the placenta has its ownmacrophages, known as Hofbauer cells, which are capable of pro-ducing cytokines and chemokines (Faulk and Hunt, 1989). Whilethere is debate about whether maternal cytokines cross the pla-centa, cytokines that are produced directly by the placenta includeIL-1, IL-2, IL-6, IL-8, and IL-10, interferons and TNFa, and likelymany others (Hsiao and Patterson, 2011; Pasca and Penn, 2010).There is a current upsurge in interest into the mechanisms bywhich placental cytokine expression may impact fetal develop-ment; recent evidence suggests an impact on fetal growth viadownstream modification of growth factors, such as IGF-1 (Hsiaoand Patterson, 2011), and leptin (Bolton et al., in press; Dahlgrenet al., 2001; Latzin et al., 2011; Vickers et al., 2005; Wright,2010). In sum, the placenta has the capacity to produce its own ar-ray of cytokines, which can enter the fetal circulation and therebymodulate or interfere with ongoing fetal growth and neurodevel-opment (Hsiao and Patterson, 2011; Pasca and Penn, 2010). Nota-bly, imbalanced cytokine production within the placenta has beenobserved during maternal infection, but also in response to pre-eclampsia, prenatal stress, and exposure to air pollution (Boltonet al., in press; Latzin et al., 2011; Williamson et al., 2011), suggest-ing the implications of placental neuroendocrine–immune interac-tions extend well beyond infection.

5.8.2. Blood–brain barrier (BBB)The BBB is a collection of endothelial cells, astrocytes, pericytes,

and microglia that separate the circulating blood and the extracel-lular fluid of the brain via the integrity of the tight junctions be-tween these cells. The BBB must effectively bring nutrients andoxygen into the brain while effectively keeping out any foreignor invading substances that might be damaging to sensitive neuraltissue. It is becoming more evident that the integrity of the BBB hasa major role in the pathophysiology of many neuropsychiatric dis-orders (Muller and Ackenheil, 1998; Yarlagadda et al., 2009; for in-stance), the passage of cytokines and chemokines through the BBBcan not only affect neural function and behavior but also causeconsiderable damage to neural tissue. In general, dogma states thatcytokines are large enough molecules that their passage across theBBB does not occur. However, it is now understood that certaincytokines can cross the BBB via saturable transport (Banks et al.,1993, 1995, 2002; Gutierrez et al., 1993). Specifically, the BBBhas selective cytokine binding sites that convey the cytokine acrossthe barrier via transporters (see Banks and Erickson (2010) for re-view). In addition, cytokines increase the permeability of the BBB(Pan and Kastin, 2001, 2008; Pan et al., 2003), thereby increasingthe likelihood of cytokine transport across. Thus, while a rareoccurrence, in the event of trauma caused by hypoxia/ischemiaor severe inflammation, metabolic changes such as diabetes, oreven drugs of abuse, the composition of the BBB can change (Haw-kins and Davis, 2005) and circulating cytokines from the peripherymay enter the brain and affect its function.

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The developing brain represents a new set of challenges to thedogma regarding BBB permeability. The BBB is significantly morepermeable during early brain development, as it is relativelyunderdeveloped at this time. In general, tight junctions are presentearly in development such that the BBB is developed enough tokeep out the majority of large proteins (see Saunders et al.(1999) for review). However, the capacity for some lipid-insolublemolecules to enter the developing brain is greater than in the adultbrain (Barichello et al., 2012; Saunders et al., 1999, 2000). Neonatalinfection with E. coli, for example, causes a significant increase inthe gene expression of cytokines within the brain itself (Bilboet al., 2005a; Schwarz and Bilbo, 2011), but also a robust increasein the serum protein levels of many cytokines (IL-1b, IL-6, andTNFa) (Bilbo et al., 2005a). It is likely that the invasion of cytokinesand chemokines from the peripheral immune system into the brainis greater in the developing brain than in the adult brain. Moreover,E. coli enters the brain directly following peripheral infection of thenewborn rat (Bilbo et al., 2005a), but not in the adult. Such directaccess of pathogens can in theory activate microglia directly viapathogen recognition receptors (e.g., TLRs), as opposed to indi-rectly via cytokines. As a result, the potential risk for damage froma peripheral immune challenge might be much greater in the neo-nate than in the adult.

6. Conclusions and future directions

In summary, we have reviewed the evidence that the immunesystem is critically involved in neural and endocrine function, inboth sickness and in health. During brain development, a largenumber of immune molecules are implicated in various aspectsof ‘‘building a brain’’, including neural cell differentiation, migra-tion, synapse formation and refinement, and programmed celldeath. Microglia produce or express receptors for many of thesemolecules, and are especially active beginning in mid-gestationand throughout the perinatal period. For this reason, we havehypothesized that development represents a sensitive period forimpacting microglial function, and subsequent brain and behav-ioral development. However, many outstanding questions remain.

For instance, many developmental disorders exhibit a strikingsex difference in their etiology and prevalence. Males are morelikely to be diagnosed with disorders that present at birth or earlyin childhood, such as autism and learning disabilities. In contrast,females are more often diagnosed with disorders that arise aroundthe onset of adolescence or puberty (see Bao and Swaab (2010) forreview). This epidemiology suggests that there are sex-basedneurobiological differences, which are likely to arise during devel-opment, that either directly promote specific neuropsychiatric dis-orders or increase the susceptibility to environmental factors thatlead to such disorders. At present, no sex-based differences havebeen described that can fully explain the sexual dimorphism ofneuropsychiatric disorders. However, there are sex differenceswithin the placenta in response to a wide number of environmen-tal variables (reviewed in Howerton and Bale (in press)). For in-stance, prenatal stress induces larger changes in genes importantfor fetal growth in males compared to females (Mueller and Bale,2008). Moreover, we have recently reported a marked sex differ-ence in the colonization of the developing brain by microglia (Sch-warz and Bilbo, in press; Schwarz et al., 2012), wherein femaleshave 5-fold fewer microglia in brain regions important for cogni-tion during the first postnatal week compared to males. Notably,females also do not exhibit the same enduring impact of anE. coli infection on P4; i.e., exaggerated cytokine production andmemory deficits are not observed in adult females infected on P4(Bilbo et al., 2012), potentially due to a blunted microglial-derivedinflammatory response to the initial infection. Interestingly, the

Please cite this article in press as: Bilbo, S.D., Schwarz, J.M. The immune systemdocrinol. (2012), http://dx.doi.org/10.1016/j.yfrne.2012.08.006

sex difference in microglial colonization observed in the neonatalbrain reverses entirely just prior to adolescence, in the juvenilebrain, and this sex difference is maintained into adulthood. Microg-lia within the female brain also appear to have a more activatedmorphology than the microglia within the male brain just priorto adolescence and into adulthood, suggesting that microglia with-in the juvenile/adolescent female brain may have a very differentfunctional output from the microglia in the male brain at this time.Whether and how sex steroids impact these sex differences in pla-cental function and microglial development remain to be defined.

Another important question is a critical one for intervention,and that is whether long-term ‘‘programming’’ effects would beobserved under less ‘‘impoverished’’ laboratory conditions. For in-stance, we have recently determined that 6 weeks of limited dailyenvironmental enrichment in adult rats, independent of any early-life manipulation, increased microglial and astrocyte surface anti-gen expression within the dentate gyrus of the hippocampus(which may indicate an increase in their density), but notably de-creased the pro-inflammatory cytokine response to a systemicLPS challenge compared to standard housing controls (Williamsonet al., 2012). However, the implications for behavior, if any, remainto be determined. We have also demonstrated that a neonatal‘‘handling’’ paradigm, which increases the quantity and quality ofmaternal care, reverses some but not all aspects of neonatal infec-tion on adult function. Glial priming appears to be largely pre-vented; however, handling is unable to decrease anxiety orincrease learning and memory in neonatally-infected rats, whichis characteristic of this paradigm in normal control animals (Bilboet al., 2007). Nonetheless, these data have intriguing implicationsfor the prevention or reversibility of immune activation early inlife. Again, the answer likely depends on the timing of exposure,and the underlying neurodevelopmental processes at play, in com-bination with genetic factors.

Taken together, we propose that this field warrants further re-search into the role that sex and brain regional dependent mecha-nisms may play in hormone–immune interactions, glialcolonization/differentiation, number, and function, and their po-tential contribution to neural and cognitive dysfunction. Enduringconsequences for the brain may be due to cell-intrinsic changeswithin microglia, or to changes in a plethora of other immune mol-ecules that we now know are critical for normal brain development.How and when immune molecules interact with hormones, such assex steroids, metabolic factors such as leptin, insulin and growthhormones, which are all critical for proper neural and behavioraldevelopment, is clearly underexplored. In sum, because immunemolecules are also critical for behavioral outcomes, including cog-nition, mood, and social interactions, an impact on their functionby diverse challenges early in development is a candidate mecha-nism of risk or resilience for neuropsychiatric disorders, as well asa novel target for behavioral or pharmacological interventions.

Acknowledgments

The authors acknowledge the funding sources for much of thework discussed in this review, including R01 DA025978 and R01MH083698 to S.D.B., and F32-DA030136 to J.M.S.

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