Neuroimmunology: Behavioral Effects
Summary and Keywords
Bidirectional interactions between the immune system and central nervous system have been acknowledged for centuries. Over the past 100 years, pioneering studies in both animal models and humans have delineated the behavioral consequences of neuroimmune activation, including the different facets of sickness behavior. Rodent studies have uncovered multiple neural pathways and mechanisms that mediate anorexia, fever, sleep alterations, and social withdrawal following immune activation. Furthermore, work conducted in human patients receiving interferon treatment has elucidated some of the mechanisms underlying immune-induced behavioral changes such as malaise, depressive symptoms, and cognitive deficits.
These findings have provided the foundation for development of treatment interventions for conditions in which dysfunction of immune-brain interactions leads to behavioral pathology. Rodent models of neuroimmune activation frequently utilize endotoxins and cytokines to directly stimulate the immune system. In the absence of pathogen-induced inflammation, a variety of environmental stressors, including psychosocial stressors, also lead to neuroimmune alterations and concurrent behavioral changes. These behavioral alterations can be assessed using a battery of behavioral paradigms while distinguishing acute sickness behavior from the type of behavioral outcome being assessed. Animal studies have also been useful in delineating the role of microglia, the neuroendocrine system, neurotransmitters, and neurotrophins in mediating the behavioral implications of altered neuroimmune activity. Furthermore, the timing and duration of neuroimmune challenge as well as the sex of the organism can impact the behavioral manifestations of altered neuroimmune activity. Finally, neuroimmune modulation through pharmacological or psychosocial approaches has potential for modulating behavior.
Over multiple centuries, the idea that physical functions dictate behavior has garnered attention from philosophers, scientists, physicians, and veterinarians. Humorism, the concept that the balance among four basic fluids in the human body dictates temperament, dates back to the ancient Greeks and Romans. This concept was later abandoned, and clear documentation of the drive toward a mechanistic understanding of the means by which the immune system bidirectionally interacts with the brain, and thereby behavior, began in the 20th century. In his memoir, The Stress of My Life, Hans Selye recounts his observation of what he termed “the syndrome of being sick” during his second year at the University of Prague in 1926. He noted that no matter the diagnosis, patients presented with a cluster of shared symptoms: “they are all indisposed, they look tired, have no appetite, gradually lose weight, they do not feel like going to work, they prefer to lie down rather than to stand up” (p. 56). It was this epiphany early in his training that led to his first publication on the topic in Nature in 1936. The work entitled “A Syndrome Produced by Diverse Nocuous Agents” described the generation of a similar phenotype as observed in ill patients that could be elicited by a variety of aversive agents in laboratory animals. Selye later termed this phenomenon “biologic stress.” Selye notes in his memoir that his original naming of the phenomenon was incorrect and a product of his novice status with the English language. Selye in fact meant “strain” and not “stress” as the terms were originally defined in physics. “Strain” refers to the response of the object, and “stress” refers to the force that is imposed on the object. However, by the time Selye became aware of his translation mistake, “biologic stress” had been widely accepted, and there was no option of correcting his original mistake. Therefore, he created a second term, “stressor,” to refer to the challenge that imposes “biologic stress” on the organism.
The biological mediators of stress have been widely studied for more than a century, and although this cluster of biological responses certainly accounts for some of the influences of the immune system on brain and behavior (Figure 1), direct effects of the immune system on the brain can precipitate changes in behavior. The appreciation of these immunological mechanisms was also born out of the observation of sickness behavior. The chronological history of the establishment of the concept of sickness behavior was masterfully synthesized by R. W. Johnson in 2002. In his synopsis, he noted the key discoveries essential to the development of the sickness behavior concept. In the 1960s, work by N. E. Miller employed operant conditioning in rats to determine whether sickness behavior was a motivational state or simply a consequence of energy depletion from the pathogenic agent. Miller demonstrated that while endotoxin-injected rats would no longer bar-press for water, they would consume freely-available water, and they would bar-press to stop moving. Collectively, Miller’s work suggested that endotoxin-injected rats were “motivated” to inhibit activity, and it was not a simple manifestation of energetic depletion (Holmes & Miller, 1963; Miller, 1964). The next critical finding was the demonstration that fever and the promotion of fever were adaptive when an organism was infected with a pathogen. A series of studies by Kluger and colleagues demonstrated that lizards given a pathogen preferred warmer environments (lizards are ectothermic and therefore take on the temperature of their environment), and that their survival after infection was promoted by access to a warmer environment (Vaughn, Bernheim, & Kluger, 1974; Kluger & Vaughn, 1978; Kluger, 1991). These findings were complemented by work demonstrating that fever may inhibit pathogen growth by providing less optimal growth conditions (Kluger, Ringler, & Anver, 1975). Additional studies assessed the potential adaptive quality of anorexia and the biological mediators of anorexia. Interleukin-1 β (IL-1β) was the first cytokine, a soluble messenger of the immune system, established as anorectic (Plata-Salaman, Wilson, & French-Mullen, 1998). Further work assessed the degree to which anorexia was adaptive by allowing pathogen-treated rats to either free-feed or by force-feeding the rats. Rats that were free-fed reduced their consumption postinfection, and rats that were force-fed a caloric content equivalent to that of a noninfected animal were more likely to die from the pathogen. These data suggested that short-term anorectic effects of pathogens are adaptive (Murray & Murray, 1979). After establishing these associations, the framework for mechanistic studies was in place. Further studies demonstrated that IL-1β was sufficient to increase slow-wave sleep (Krueger, Walter, Dinarello, Wolff, & Chedid, 1984) and induce reduced food intake, weight loss, and reduced social behavior (Johnson et al., 1997). Collectively, these IL-1β-induced behaviors recapitulate sickness behavior and demonstrate a mechanism by which the immune system can alter brain function and thereby behavior. Conversely, in 1975, a seminal paper from Ader and Cohen demonstrated that the immune system is subject to classical conditioning, establishing the influence of the central nervous system function on the immune system function (Ader & Cohen, 1975). Collectively, these early works show that interactions between the immune and central nervous systems are bidirectional and have potent behavioral implications.
Sickness behavior is now generally accepted to consist of a set of behaviors that promote successful suppression of ongoing infection in the body. These include changes to homeostatic regulation of physiological processes, including energy availability, feeding and sleeping patterns, as well as an altered motivational state that includes pain, depressed mood, social withdrawal, and cognitive alterations (Hart, 1988; Dantzer, O’Connor, Freund, Johnson, & Kelley, 2008). While sickness behavior is primarily thought of as an adaptive mechanism that optimally allocates the body’s resources to fully fight off infection, some behavioral symptoms that arise from prolonged activation of the neuroimmune axis, such as anxiety and cognitive deficits, may not be directly involved in this coping strategy. As early as 1964, in a paper by Solomon and Moss, psychiatric disease has been associated with sickness behaviors (Solomon & Moss, 1964). The role of a dysfunctional immune system in neuropsychiatric disease, in particular depression, has been further established by pioneering studies from Miller and Raison (Raison, Capuron, & Miller, 2006; Miller, Maletic, & Raison, 2009).
The pathways that link immune function to behavior have been extensively studied and characterized. There are known mechanisms that link immune function to behavior and expands beyond pathogen-related sickness behavior to the maladaptive manifestation of immune influences on the brain, such as in neuropsychiatric disorders. Although much has already been established, this burgeoning field will continue to grow and ultimately lead to more appropriate therapies. Provided here are both the critical framework needed to integrate new findings as they develop and a springboard for generating new ideas for pursuit of additional studies.
Neuroimmune Axis and Its Effectors and Mediators
Once believed to be immune-privileged, the brain is now recognized to extensively interact with the immune system via multiple mechanisms that allow extravasation and relay of inflammatory signals from the periphery. The behavioral consequences of neuroinflammation are believed to arise largely from signaling of cytokines—soluble hormones released by immune cells. The pro-inflammatory cytokines IL-1β, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) serve as primary mediators of brain-immune communication, and their role in sickness behavior has been studied extensively. In addition, inflammatory stimuli can lead to the release of prostaglandins—lipid mediators crucial to various aspects of the sickness behavior—from many different cell types (Pecchi, Dallaporta, Jean, Thirion, & Troadec, 2009). All of these peripheral inflammatory molecules can activate receptors localized within the central nervous system (CNS) (Rothwell, Luheshi, & Toulmond, 1996), thus leading to neuroinflammation and accompanying changes in behavior.
Interestingly, these inflammatory mediators can be released as a result of both pathogens (“classical inflammation”) and the body’s endogenous danger signals in the absence of pathogens (“sterile inflammation”). When the body is infected by microorganisms such as bacteria and viruses, peripheral immune cells recognize specific components called pathogen-associated molecular patterns (PAMPs) displayed by these invading pathogens (Tang, Kang, Coyne, Zeh, & Lotze, 2012). PAMPs activate toll-like receptors (TLRs) and other pathogen recognition receptors on a variety of immune cell types. In the absence of pathogen-induced inflammation, many environmental and cellular stressors can also lead to pro-inflammatory outcomes (Chen & Nunez, 2010). This is accomplished by the recognition of danger-associated molecular patterns (DAMPs) present on many endogenous molecules, including heat shock proteins, uric acid, RNA, DNA, and S100 proteins.
Neural Pathways Underlying Immune-Induced Behavioral Changes
Brain-immune crosstalk occurs through a neural route mediated by innervation of peripheral tissue and lymphoid organs as well as a humoral route mediated by peripherally derived inflammatory molecules. It is generally believed that differences in the conveyance of inflammatory signals to the brain parenchyma give rise to time- and brain region-dependent behavioral alterations (Rothwell et al., 1996; Dantzer, Konsman, Bluthe, & Kelley, 2000; Dantzer et al., 2008). Signals received from afferent nerves constitute a rapid-acting pathway that may account for the so-called first wave of sickness behavior that peaks 2–6 hours following peripheral administration of antigen (Dantzer et al., 2008). In contrast, propagation of humoral factors through the brain via volume transmission or secondary mediators may lead to a delayed second wave of behavioral changes that include depressed mood, which is present at 24 hours following the initial stimulus. Although the neural and humoral routes must converge to fully orchestrate immune-induced behavioral and physiological alterations, the mechanisms and timing of such convergence have not been fully elucidated (Dantzer, 2006). Immune activation within these seemingly distinct neural circuits underlying physiological and behavioral aspects of sickness is nonetheless intricately integrated via immune, endocrine, and neurotransmitter mechanisms to orchestrate and modulate the full range of sickness behavior.
The Vagal Nerve
The brain receives inflammatory signals through the vagus—the tenth cranial nerve—which innervates visceral organs, including the gut and the liver (Pavlov & Tracey, 2012). In addition to relaying viscerosensory information, the vagus therefore also mediates in part the effects of gut microbiota on brain function (Goehler, Lyte, & Gaykema, 2007). Involvement of the vagus in sickness behavior is evidenced by vagotomy experiments, which demonstrated attenuated behavioral responses to peripherally administered cytokines (Bluthe, Michaud, Kelley, & Dantzer, 1996; Luheshi et al., 2000). The vagus projects primarily to the nucleus tracteus solitarius (NTS) and ventrolateral medulla, major relay nuclei in the brainstem that send catecholaminergic projections to forebrain regions involved in autonomic regulation and behavioral responses (Gaykema & Goehler, 2011). In particular, the NTS and ventrolateral medulla heavily project to the hypothalamus, thus initiating the well-established neuroendocrine response to immune activation as well as changes to autonomic regulation. In addition to having reciprocal connections to the hypothalamus, the NTS and ventrolateral medulla send projections to limbic structures such as the amygdala and bed nucleus of stria terminalis (Gaykema, Chen, & Goehler, 2007)—areas that are important to orchestrating various aspects of sickness behavior such as fear and pain. The affective and cognitive aspects of sickness behavior are generally believed to be mediated by brain circuits and mechanisms at least partially distinct from those underlying the physiological aspects of sickness behavior (Kent et al., 1992; Konsman, Luheshi, Bluthe, & Dantzer, 2000; Luheshi et al., 2000). Accordingly, subdiaphragmatic vagotomy prevents the cytokine-induced corticosterone response (Fleshner et al., 1998), c-Fos activation of limbic structures, and reduction in social exploration; however, it does not prevent activation of the preoptic area and accompanying fever (Konsman et al., 2000; Luheshi et al., 2000). Similarly, while subdiaphragmatic vagotomy suppresses conditioned taste aversion induced by peripheral administration of IL-1β and lipopolysaccharide (LPS) (Goehler et al., 1995), it does not impact the cytokine-induced reduction in food intake (Porter, Hrupka, Langhans, & Schwartz, 1998).
The hypothalamus is the master regulator of homeostasis in the body and regulates multiple physiological functions such as feeding, sleeping, energy allocation, and febrile response that are relevant to sickness behavior. The hypothalamus is divided into largely distinct nuclei that mediate each behavior. For example, the medial preoptic area of the hypothalamus, a region that controls the febrile response (Roth & De Souza, 2001), and the arcuate nucleus that regulates food intake (Reyes & Sawchenko, 2002), have each been demonstrated to be activated by peripheral inflammatory stimuli. Prostaglandin signaling in the medial preoptic area also mediates inflammation-induced hyperalgesia (Heinricher, Neubert, Martenson, & Goncalves, 2004), whereas intracerebroventricularly administered IL-1β increases non-REM sleep by activating the ventrolateral and medial preoptic nuclei (Baker et al., 2005). The paraventricular nucleus (PVN) of the hypothalamus is a key region in the neuroendocrine response (Lopez, Akil, & Watson, 1999), and it modulates affective behavior via the release of endocrine mediators. The neuroimmune axis is intricately regulated by endocrine systems, particularly the hypothalamic-pituitary-adrenal (HPA) axis, the endocrine core of the stress system. Immune stimuli lead to a neuroendocrine response mediated by the HPA axis, which serves as a negative feedback mechanism to suppress ongoing inflammatory processes (Bellavance & Rivest, 2014). Activation of the HPA axis results in the release of corticotropin-releasing factor from the hypothalamus, adrenocorticotropic hormone from the pituitary gland, and cortisol from the adrenal glands. Cortisol serves as a potent anti-inflammatory mediator by acting on glucocorticoid receptors expressed on immune cells (Cronstein, Kimmel, Levin, Martiniuk, & Weissmann, 1992; Fantidis, 2010; Chinenov, Coppo, Gupte, Sacta, & Rogatsky, 2014).
PAMPs, Cytokines, and Pathogen-Initiated Inflammation
The humoral route of brain-immune communication occurs through leakage of inflammatory signals (PAMPs and cytokines) in the blood directly into the brain via a permissive blood-brain barrier (BBB), or by acting on the endothelial cells forming the BBB. Furthermore, cells of the circumventricular organs and the choroid plexus receive peripheral inflammatory signals and relay this information to adjacent parenchyma. These cells can also be induced to produce cytokines and prostaglandins themselves and project to brain regions, including the NTS and PVN of the hypothalamus that are important to behavioral changes (Quan, 2014). Parenchymal microglia and neurons express receptors for cytokines and prostaglandins predominantly within the brainstem nuclei, forebrain autonomic nuclei, and limbic structures (Rothwell et al., 1996). Following activation of their immune receptors, these parenchymal cells locally produce their own inflammatory signals and thus are able to propagate this cytokine transmission to yet deeper brain structures.
DAMPs and Sterile Inflammation
As previously mentioned, many environmental and cellular stressors trigger inflammatory outcomes via the process of “sterile inflammation” in the absence of pathogens. While mechanistically distinct from neuroinflammation that results from invading pathogens, sterile neuroinflammation nonetheless results in the induction of shared pro-inflammatory mediators (Fleshner, Frank, & Maier, 2017). Sterile inflammation may be useful for maintaining neuronal homeostatic functions and synaptic plasticity; yet it can turn maladaptive in disease conditions such as chronic stress. The behavioral impact of these stressors can be mediated via DAMPs that activate inflammasomes (Fleshner et al., 2017). One of the best characterized DAMPs, high-mobility group box 1 (HMGB1), can activate a variety of pattern recognition receptors such as TLRs (Chen & Nunez, 2010). Importantly, HMGB1 can be induced by psychological stressors and facilitates stress-induced priming of the neuroinflammatory response (Frank, Weber, Watkins, & Maier, 2015). Other DAMPs, including uric acid and ATP, can activate the NLRP3 inflammasome that has also been linked to stress-induced neuroinflammation (Weber, Frank, Tracey, Watkins, & Maier, 2015).
Behavioral Effects of Neuroimmune Activation: Evidence From Humans
A high prevalence of depression, anxiety, and cognitive deficits are common comorbidities in a variety of chronic inflammatory conditions, including cancer and its treatment, cardiovascular disease, metabolic disease, HIV/AIDS, and autoimmune and neurodegenerative disorders. Harkening back to Selye’s early observations, neuroimmune and endocrine mechanisms have been proposed to underlie these behavioral changes as a shared pathway among these seemingly unrelated medical conditions (Irwin & Miller, 2007) (Figure 2). It is still unclear whether behavioral alterations ensue from a generalized inflammatory response in the brain that is common to all inflammatory disorders, or whether some of these medical conditions lead to highly localized, region-specific neuroinflammation that results in a unique set of behavioral symptoms in each disorder. For example, infection with HIV leads to a chronic, low-grade inflammation in the body and the brain, and triggers a set of behavioral deficits that have come to be called HIV-associated neurocognitive disorders (HAND). While these behavioral alterations are recognized to be caused by the presence of HIV and associated inflammation, the core behavioral symptoms of HAND—dementia, anxiety, and depression—are not unique to HIV/AIDS. Indeed, similar affective and cognitive deficits are present in late-stage neurodegenerative diseases such as Parkinson’s disease in a manner that corresponds with the level of inflammatory markers (Lindqvist et al., 2013).
Some of the most compelling evidence for the behavioral impact of neuroimmune activation are offered by work conducted in patients receiving interferon therapy for the treatment of viral infections and certain types of cancer. Interferon-α increases depressive symptoms in up to 50% of patients receiving it, which has given rise to the cytokine hypothesis of depression (Raison et al., 2006). The cytokine hypothesis of depression is supported by observations that patients with depression exhibit elevated levels of inflammatory cytokines (Alesci et al., 2005; Dowlati et al., 2010), self-reported cognitive deficits, fatigue, and abnormal appetite (Capuron et al., 2002; Capuron & Miller, 2004). Furthermore, production of cytokines such as TNF-α decrease in antidepressant responders following treatment (Lanquillon, Krieg, Bening-Abu-Shach, & Vedder, 2000). Of the various symptoms of sickness behavior, the impact of neuroimmune activation on affective behavior has been investigated most extensively (Capuron & Miller, 2011). Elevated exposure to cytokines has been hypothesized to be an important mediator in the behavioral alterations observed in depressed patients (Dantzer & Kelley, 2007) and in prediction of the anxiety response following treatment with LPS (Lasselin et al., 2016). Accumulating evidence suggests that the impact of inflammatory signals on higher-order behavior involves forebrain regions. For example, cytokine-induced malaise symptoms including fatigue, anhedonia, and psychomotor slowing are linked to altered dopamine signaling and metabolism in the basal ganglia, which are subcortical structures crucial to motivation, reward, and locomotor activity (Felger & Miller, 2012). Additionally, in one study, activation of the anterior cingulate cortex, a region implicated in anxiety and alarm, corresponded with cognitive dysfunction in patients receiving interferon-alpha for the treatment of hepatitis C virus (Capuron et al., 2005).
In addition to clinical manifestations of behavioral deficits, subclinical changes in affect and cognition have also been demonstrated following peripheral administration of antigens, thus confirming the causal relationship between neuroimmune activation and behavioral changes even at a nonpathological level of immune activation (Schedlowski, Engler, & Grigoleit, 2014). For example, low doses of endotoxin given to healthy human subjects temporarily lead to depressed mood, a feeling of social isolation, anxiety (Eisenberger, Inagaki, Mashal, & Irwin, 2010; Engler et al., 2015), and anhedonia that correlates with reduced ventral striatum activity in response to reward cues (Eisenberger et al., 2010). Among healthy males administered a typhoid vaccination, higher levels of circulating IL-6 were correlated with slower reaction times in a cognitive task (Brydon, Harrison, Walker, Steptoe, & Critchley, 2008). Similarly, aging, via a decrease in optimal anti-inflammatory defense in the brain, can lead to subclinical deficits in affect and cognition (Deary et al., 2009; Corona, Fenn, & Godbout, 2012).
Common Animal Models of Neuroimmune Alterations
While much has been learned from studies in humans, animal models have been useful in assessing the behavioral consequences of neuroimmune alterations, particularly in developing a mechanistic understanding of behavioral changes. Following are some of the common models of neuroimmune activation in rodents and the ways in which their behavioral consequences are assessed.
Direct Immune Stimulation
A variety of experimental models have been employed to investigate the behavioral and molecular consequences of neuroimmune activation. Endotoxin- or cytokine-induced sickness behavior serves as an animal model for neuropsychiatric conditions, including depression, schizophrenia, bipolar disorder, and anxiety. Because of its ability to induce a robust activation of the neuroimmune axis, administration of the bacterial toxin LPS remains the most commonly used model (Hopkins, 2007). LPS is a component of the cell wall of Gram-negative bacteria and is recognized by TLR4. Additionally, administration of Poly I:C, a synthetic double-stranded RNA, which is a viral PAMP (Gandhi, Hayley, Gibb, Merali, & Anisman, 2007), intestinal infection with the bacterial PAMP Campylobacter jejuni (Goehler et al., 2005), and direct stimulation with pro-inflammatory cytokines (De La Garza, 2005) have been demonstrated to trigger neuroimmune activation and behavioral changes. Furthermore, inducible overexpression of cytokines and cytokine receptors in key brain regions of transgenic mice have successfully been used to demonstrate the behavioral consequences of cytokines in the brain (Hein et al., 2012). These transgenic animals display cytokine-specific alterations in neuroinflammatory profiles, which lead to wide-ranging structural, functional, and behavioral deficits that may be unique to each cytokine and its region of expression (Campbell, Hofer, & Pagenstecher, 2010).
Psychosocial and Environmental Stressors
The ability of psychosocial and environmental stimuli to engage the neuroimmune axis has long been recognized, and as such, the impact of acute and chronic stress on neuroinflammation and concurrent behavior has been extensively investigated. Various stress paradigms, including social dominance hierarchy (Aghajani et al., 2013), chronic unpredictable stress (Munhoz et al., 2006), chronic adolescent stress (Pyter, Kelly, Harrell, & Neigh, 2013), and repeated social defeat (Wohleb et al., 2011), have been shown to lead to robust increases in pro-inflammatory cytokines and chemokines systemically and also in the prefrontal-limbic circuitry that underlies affective-like behavior. One mechanism via which exposure to stressors could lead to pro-inflammatory signaling and associated behavioral deficits involves altered glucocorticoid signaling. Under homeostasis, the glucocorticoid receptor exerts potent anti-inflammatory actions, and some studies have found glucocorticoids to be protective of central nervous system damage from inflammation. However, there is substantial evidence that prolonged exposure to elevated glucocorticoids can have detrimental and pro-inflammatory consequences. For example, chronic administration of dexamethasone, a synthetic glucocorticoid receptor agonist, increases the expression of pro-inflammatory cytokines (Hu et al., 2016). This seemingly contradictory role of glucocorticoids may stem from a reduction in expression or activity of the glucocorticoid receptor, resulting in an impaired ability of glucocorticoids to suppress inflammation (Pace & Miller, 2009; Horowitz & Zunszain, 2015; Hu et al., 2016).
Environmental factors such as diet can also impact behavior via altering the microbiome composition and brain-gut communication. Several animal models involving germ-free animals as well as high fat diet consumption have helped establish the microbiome–brain link (Cryan & Dinan, 2012). Transplantation of microbiota from high fat diet-fed mice into chow-fed, nonobese C57BL/6 mice led to the development of deficits in exploratory, cognitive, and stereotypic behavior (Bruce-Keller et al., 2015). These behavioral changes were accompanied by decreased intestinal barrier, increased markers of inflammation in both plasma and colon, as well as microglial activation, upregulation of TLR expression, and decreased expression of the synaptic marker synapsin-1 in the brain. Conversely, intermittent fasting can reverse chronic LPS-induced inflammatory markers as well as accompanying cognitive deficits in the Barnes maze and inhibitory avoidance test (Vasconcelos et al., 2014).
Behavioral Consequences of Neuroimmune Alteration in Rodent Models
The most common types of behavioral assessments in animal models of immune activation and sickness behavior measure behavioral despair (as indicated by immobility in the forced swim or tail suspension tests), anhedonia (reduced intake of sucrose solution), anxiety-like behavior (reduced central tendency in the open field, reduced time spent in the open arm of the elevated plus maze), and reduced sociability. Cognitive tests assessing spatial memory (Morris water maze) and memory of novel objects can also be utilized (York, Blevins, Baynard, & Freund, 2012). One complication in the study of behavioral consequences of neuroinflammation is the delineation of changes to affective and cognitive behavior from acute alterations in sickness behavior. Because many of the measures of affective and cognitive behavior depend on motor activity such as the forced swim test or the tail suspension test, it is difficult to delineate the contribution of specifically depressive-like symptoms versus the manifestation of sickness behavior, a symptom of which is also decreased mobility. By assessing affective behaviors at time points in which animals no longer exhibit altered motor function due to inflammatory challenge, it is possible to tease apart affective behavior from reduced mobility due to sickness (Frenois et al., 2007). Following is a summary of the findings from animal models on affective, cognitive, and motor behaviors (Figure 3).
Many studies show that immune challenge with LPS administration increases depressive-like behavior in rodents (Frenois et al., 2007; Lin et al., 2017). Increased immobility in the tail suspension test, increased immobility and decreased struggling in the forced swim test, and reduced sucrose intake as behavioral metrics have all been used to quantify depressive-like behavior following LPS administration (Frenois et al., 2007). A single challenge dose of LPS can increase depressive and anxiety-like behavior in mice (Anderson, Commins, Moynagh, & Coogan, 2015). The effects of immune challenge are further complicated by age and timing specificity, topics that will be covered in greater detail in subsequent sections. For example, early life immune challenge (LPS administered on PND 14) increases anxiety behavior in adolescent mice but increases depressive-like behavior in adult mice (Dinel et al., 2014). In addition to peripheral administration of endotoxin, brain region-specific alteration of cytokine expression can also have distinct implications on affective behavior. For example, sustained expression of IL-1β in the dorsal raphe increases risk-taking and manic-like behavior (Howerton, Roland, & Bale, 2014).
Multiple LPS-exposures have been found to impair neurogenesis and spatial memory in mice (Dinel et al., 2014). Rats that were neonatally exposed to LPS exhibit impaired memory in adulthood when exposed to an additional immune challenge (Bilbo et al., 2005). Memory impairment following LPS exposure can be attenuated by preventing microglial activation during fear conditioning (Williamson, Sholar, Mistry, Smith, & Bilbo, 2011). Impaired spatial memory is also associated with increased hippocampal cytokine expression in diabetic obese mice (Dinel et al., 2011). The behavioral impact of inflammatory signaling in the hippocampus on cognitive behavior is further illustrated by evidence that IL-1β overexpression in the hippocampus impairs contextual and spatial memory (Moore, Wu, Shaftel, Graham, & O’Banion, 2009; Hein et al., 2010).
Motor Behavior and Autonomic Functions
As lethargy and fatigue are two of the core symptoms of sickness behavior, tests evaluating locomotor function can reveal the impact of neuroimmune activation. Peripheral administration of LPS reduces locomotor activity of rodents in a dose-dependent manner (Yirmiya, Rosen, Donchin, & Ovadia, 1994). Similarly, LPS administration reduces feeding behavior of rodents (Langhans, Harlacher, Balkowski, & Scharrer, 1990) and disrupts sleep (Schiffelholz & Lancel, 2001). And more specifically, peripheral administration of specific cytokines such as IL-1 reduces locomotor activity and feeding behavior, and induces weight loss (Otterness, Golden, Seymour, Eskra, & Daumy, 1991). Chronic administration of dexamethasone, a synthetic glucocorticoid, results in decreased exploratory behavior and locomotor activity in mice, coupled with increased expression of the inflammatory transcription factor nuclear factor-κB, IL-1β, and IL-6 in the hippocampus and frontal cortex (Hu et al., 2016). Furthermore, stimulant-induced locomotor behavior is also susceptible to alteration via immune activation. Locomotor activity in response to dopaminergic agonists is altered in female rats with prior LPS exposure (Tenk, Foley, Kavaliers, & Ossenkopp, 2007).
Mechanisms Mediating the Behavioral Effects of Neuroimmune Activation
Throughout the following section, mechanisms and molecular players that mediate or interact with neuroimmune activation are discussed. Specific mechanisms that have potential to mediate the behavioral effects of neuroimmune activity are detailed.
Immune-competent cells in the central nervous system are a potential mediator of neuroimmune-induced behavioral changes. Microglia are the primary immune-competent cells that reside in the central nervous system and respond to pathogens, cellular damage, and endogenous danger signals. Following a neuroimmune stimulus, activated microglia can be detected by expression of ionized calcium binding adaptor molecule 1 (IBA-1). While microglial activation and expression of IBA-1 have been detected following various immune challenges, the precise role of microglial activation on the behavioral effects of neuroimmune activation is incompletely understood. Administration of a challenge dose of LPS increases depressive and anxiety-like behaviors and increases expression of hippocampal IBA-1 in mice (Anderson et al., 2015). Blockade of microglial activation following chronic stress, another neuroimmune activator, attenuates stress-induced depressive-like behaviors (Kreisel et al., 2014). While many studies use IBA-1 as a marker to detect microglial activation, detailed morphometric studies have also been used to assess microglial structure and their relation to behavioral endpoints. Hyper-ramification of microglia, characterized by elongated cellular projections, has been associated with impaired working memory, but a causal role of microglial structure has not been established (Hinwood et al., 2013).
In addition to the brain’s resident immune cells, under extreme immune compromise, peripheral leukocytes are known to enter the brain via incompletely understood mechanisms (Ransohoff & Engelhardt, 2012). Lymphoid organs are innervated by descending sympathetic nerves and serve as reservoirs for immune cells that can be deployed upon demand. While the bone marrow contains hematopoietic stem cells that can eventually differentiate into any type of immune cell, the spleen also acts as a reservoir for undifferentiated monocytes that exit the spleen and circulate upon receiving relevant differentiation signals (Swirski et al., 2009). The infiltration of these peripheral immune cells into the brain has been shown to be an important mediator of stress-induced neuroimmune activation and accompanying behavioral changes such as anxiety-like behavior (London, Cohen, & Schwartz, 2013; Wohleb et al., 2014).
HPA Axis and Glucocorticoid Signaling
Variations in HPA axis activity and its regulation have long been implicated in the behavioral effects of immune activation (Kapcala, Chautard, & Eskay, 1995). The HPA axis regulates the body’s response to stress, and its dysregulation has been implicated in the development of affective disorders (Fernandez-Guasti, Fiedler, Herrera, & Handa, 2012). Adrenal glucocorticoids act in a negative feedback loop to cease HPA axis activation, mediated by the glucocorticoid receptor. Inflammatory cytokines activate the HPA axis, and prolonged exposure may contribute to the development of glucocorticoid resistance, the reduced ability of the glucocorticoid receptor to suppress inflammation, and HPA-axis overactivity, which is associated with depression (Kapcala et al., 1995; Postal & Appenzeller, 2015). Glucocorticoid receptor activity is susceptible to cytokine-mediated disruptions, and studies have found that cytokines reduce activity of the glucocorticoid receptor and promote glucocorticoid resistance via altered glucocorticoid receptor expression, impaired translocation efficiency, or alterations in phosphorylation, among other mechanisms (Pariante et al., 1999; Capuron & Miller, 2004; Hu, Pace, & Miller, 2009; Pace & Miller, 2009). Alterations in glucocorticoid receptor activity may also be mediated by altered expression of receptor isoforms. Exposure to the inflammatory cytokine TNF-α alters the ratio of expression of the inactive β isoform of the glucocorticoid receptor to the active α isoform, a consequence of which may be reduced glucocorticoid activity (Webster, Oakley, Jewell, & Cidlowski, 2001). Since the glucocorticoid receptor has potent anti-inflammatory activity, cytokine-induced glucocorticoid resistance may shift the balance away from glucocorticoid signaling to pro-inflammatory processes, an alteration that has the potential to contribute to behavioral effects by enhancing neuroinflammatory signaling (Horowitz & Zunszain, 2015).
Alterations in glucocorticoid signaling have been found in tandem with behavioral changes following immune activation. Early-life immune challenge (at postnatal day [PND] 14) increases anxiety-like behaviors in adolescent mice and depressive-like behaviors in adult mice. These animals also exhibit decreased phosphorylation of the glucocorticoid receptor in the prefrontal cortex, a region involved in regulation of HPA-axis activity. Increased expression of inflammatory cytokines (TNF-α, IL-1β) in HPA-related regions (prefrontal cortex, hypothalamus, hippocampus) may further contribute to dysregulation of the system (Dinel et al., 2014). The hippocampus, a region involved in HPA-axis regulation as well as affective and cognitive disorders, is susceptible to increases in inflammatory cytokines following exposure to LPS, which can be exacerbated by previous exposure to chronic adolescent stress (Pyter et al., 2013) or prenatal stress (Diz-Chaves, Pernia, Carrero, & Garcia-Segura, 2012).
Neurotransmitter systems interact with the immune system by acting at neurotransmitter receptors present in immune-competent cells. The responses that these neurotransmitters can elicit are varied and depend on the specific context of neurotransmitter activation (Levite, 2008). Immune activity is also able to alter the activity of specific neurotransmitter systems throughout the brain. Reuptake of serotonin may be a mediator in the interaction of neurotransmitters and cytokines in the development of affective disorders. Serotonin reuptake is a mechanism commonly utilized in antidepressant treatment, and alterations in this reuptake process may contribute to the affective complications of neuroimmune activity (Haase & Brown, 2015). Expression and activity of the serotonin reuptake transporter are susceptible to expression of inflammatory cytokines. Specifically, pro-inflammatory cytokines have been found to increase expression and activation of the serotonin reuptake transporter (Morikawa, Sakai, Obara, & Saito, 1998; Mossner, Daniel, Schmitt, Albert, & Lesch, 2001; Zhu, Blakely, & Hewlett, 2006). Serotonergic metabolism can also be altered by exposure to inflammatory cytokines (Clement et al., 1997; Wichers & Maes, 2002; van Heesch et al., 2013). Indoleamine 2,3 dioxygenase, an enzyme that degrades tryptophan, regulates the ability of serotonin to be synthesized. LPS administration has been found to increase expression of indoleamine 2,3 dioxygenase, and inhibition of this enzyme reverses LPS-induced depressive-like behaviors assessed by the sucrose preference test (Fu et al., 2010; Lawson et al., 2013). Furthermore, the serotonergic system is susceptible even to inflammation outside the central nervous system. Systemic administration of LPS is able to alter serotonergic signaling (Couch et al., 2013).
Norepinephrine signaling in the sympathetic nervous system serves as the primary means of neural control of immune function (Nance & Sanders, 2007). Although adrenergic signaling is traditionally thought to exert immunosuppressive effects in pathogen-initiated inflammation (Lorton & Bellinger, 2015), accumulating evidence suggests that adrenergic signaling can stimulate pro-inflammatory outcomes under conditions of stressor-induced sterile inflammation. For example, acute psychosocial stress-induced NFκB activity in healthy volunteers was found to be mediated by the α1 adrenergic receptor (Bierhaus et al., 2003). In mice exposed to social defeat stress, increases in microglial activation and concurrent anxiety-like behavior have been demonstrated to be mediated by β2 adrenergic signaling (Wohleb et al., 2011). In contrast to the classical PKA-dependent adrenergic signaling pathway, these pro-inflammatory consequences of norepinephrine can be mediated via a PKA-independent cascade involving p38 and ERK (Bierhaus et al., 2003; Tan et al., 2007). Another mechanism of pro-inflammatory adrenergic signaling involves the release of DAMPs as secondary mediators. Following tail shock stress in rats, signaling via α1 adrenergic receptor can increase plasma levels of the DAMP Hsp72 (Johnson et al., 2005) as well as IL-1β and IL-6 (Johnson et al., 2005). Taken together, these data suggest that adrenergic signaling is a critical mediator of stress-induced neuroinflammation and behavioral alterations.
Neurogenesis and Neurotrophic Factors
Neurogenesis has been extensively studied in the study of affective disorders and is also implicated in mediating the behavioral effects of immune activation (Musaelyan et al., 2014). Neurogenesis is impacted by the presence of inflammatory cytokines (Borsini, Zunszain, Thuret, & Pariante, 2015), and impairment of microglial activation reverses stress-induced impairments in neurogenesis, suggesting a connected role among neuroimmune activation, microglial activation, and neurogenesis (Kreisel et al., 2014). While immune signaling is crucial to the normal development of the brain and synaptic plasticity (Boulanger & Shatz, 2004), under pathological conditions, dysregulated immune signaling may assume a maladaptive function, resulting in abnormalities in synaptic pruning and plasticity that ultimately lead to behavioral deficits. Furthermore, disruptions in the expression of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), has been extensively investigated in the pathogenesis of affective disorders and is additionally impacted by neuroimmune activity. Animals exposed to neonatal infection also exhibit decreased BDNF gene expression in the hippocampus following adult fear conditioning (Bilbo et al., 2008). Alterations to BDNF and other neurotrophic factors are associated with anxiety and depressive-like behaviors and thus may be involved in mediating the behavioral impact of neuroinflammatory signaling (Lipsky & Marini, 2007).
Factors Moderating Behavioral Outcomes Following Neuroimmune Activation
Duration of Neuroimmune Alteration
The duration or pattern of immune exposure is important in determining the resulting behavioral effects. Specifically, repeated immune insults have been found to alter behavior differently than single challenges. Male but not female rats exposed to prenatal LPS followed by an adult LPS challenge experience decreased locomotor activity in adulthood. Males who had not experienced the prenatal exposure do not exhibit altered locomotor activity in adulthood (Tenk, Kavaliers, & Ossenkopp, 2008). The route of administration of immune challenge further alters the behavioral consequences. Multiple exposures of intranasal LPS increase depressive-like behaviors in female but not male rats, while a single exposure of intraperitoneal LPS increases depressive-like behaviors in both males and females in the forced swim test (Tonelli, Holmes, & Postolache, 2008). Finally, genetic background also impacts the behavioral effects of neuroimmune activation. LPS administration increases depressive-like behavior in a strain-specific manner in mice (Painsipp, Kofer, Sinner, & Holzer, 2011).
There are noted sex differences in the interaction of the neuroimmune system and behavior. Sex steroids play a pronounced role in the regulation of the body’s response to immune activation. High concentrations of estrogen are immunosuppressive, while low levels of estrogen stimulate immune activity—this modulatory ability of estrogen may allow the female body to differentially regulate the immune response during her differential energetic and immune needs during pregnancy (Abrams & Miller, 2011).
In general, males tend to exhibit lower activation of the immune system following immune challenge compared to females; this can cause increased susceptibility to viral infection and damage from viral activity in males. Females, however, experience a greater risk of the harmful effects of prolonged immune activation following an immune challenge (Klein, 2012). Sex differences in innate ability to mount an immune response may contribute to sex differences in the behavioral implications of neuroimmune activation.
Sex differences in response to immune activation have been explored in animal models. Repeated intranasal LPS increases depressive-like behaviors in female but not male rats (Tonelli et al., 2008). However, in another study using a mild LPS exposure, males and females are differentially impacted depending on the behavioral test. Males exhibit reduced ambulatory activity and decreased food consumption following LPS exposure, although both males and females are impacted in other behavioral measures, specifically exploratory behaviors and sucrose consumption (Pitychoutis, Nakamura, Tsonis, & Papadopoulou-Daifoti, 2009). Neurotransmitter systems have been found to be differentially impacted by immune challenge and may contribute to sex differences in behavioral alterations following immune activation. Prenatal immune challenge has been found to increase serotonin in the amygdala and nucleus accumbens in female but not male mice (Bitanihirwe, Peleg-Raibstein, Mouttet, Feldon, & Meyer, 2010). Differential expression of microglia has also been implicated as a mechanism for conferring sex differences in the behavioral response to immune activity. Specifically, males and females exhibit different numbers and morphology of microglia at different ages; thus, this variation in microglial expression has been hypothesized to contribute to differences in temporal sensitivity to immune challenge (Schwarz & Bilbo, 2012). Sex differences in the behavioral response to immune activation are impacted by a number of factors, but the timing of the immune challenge is also an important modulator in determining the behavioral consequences of neuroimmune activation.
Timing of Neuroimmune Activation
The timing of neuroimmune activation is important in determining the behavioral effects, and sex differences in the behavioral response to neuroimmune timing are particularly pronounced. Developmental periods may be particularly susceptible to immune activation. Severe cases of maternal inflammation during pregnancy have been linked to a number of psychiatric disorders, including schizophrenia (Canetta et al., 2014) and autism (Atladottir et al., 2010) in the offspring, suggesting highly specific mechanisms that translate these maternal inflammatory signals to the child’s brain (Choi et al., 2016). Rodent studies indicate that males may be more susceptible to early life immune challenge, while females may experience greater damage from immune challenge later in life (Schwarz & Bilbo, 2012). Male rats exposed to infection as neonates exhibit impaired memory in adulthood when exposed to an immune challenge (Bilbo et al., 2005). Males but not females experience increased immobility in the tail suspension test and forced swim test following neonatal exposure to TNF-α, an inflammatory cytokine. Males also exhibit increased stress-induced corticosterone following neonatal TNF-α exposure. Females exhibit decreased entries and time in the light box only at a high dose of TNF-α (Babri, Doosti, & Salari, 2014). Alternatively, females may exhibit enhanced susceptibility to immune challenge later in life (Schwarz & Bilbo, 2012). Some of these changes may be mediated by different expression of cytokine receptors at different ages. Stimulation with LPS differentially alters expression of various cytokine receptors in young compared to old mice, thus contributing to differential sensitivity to immune stimulants (Utsuyama & Hirokawa, 2002; Kohman, Crowell, & Kusnecov, 2010).
Neuroimmunomodulation: Opportunities for Behavioral Impact
Pharmacological Modulation of the Neuroimmune Axis: Behavioral Implications
A recent meta-analysis of randomized clinical trials found that non-steroidal anti-inflammatory drugs (NSAIDs) and cytokine inhibitors can reduce depressive symptoms in patients who do or do not meet the diagnosis criteria for depression (Kohler et al., 2014). Similarly, animal studies have shown that NSAIDs suppress LPS-induced fever and reduced locomotor activity without affecting the expression of pro-inflammatory cytokines either centrally or peripherally (Teeling, Cunningham, Newman, & Perry, 2010). Interestingly, a number of commonly used immunosuppressants such as rapamycin have been shown to exert detrimental effects on mood and cognition in both humans and animal models (Bosche et al., 2015), thus suggesting potential adaptive or beneficial effects of inflammatory processes. As mentioned previously, antidepressant treatments may at least partially owe their beneficial effects to their impact on neuroinflammatory mechanisms.
Environmental and Psychosocial Interventions: Behavioral Implications
Lifestyle factors including diet, exercise, sleep, stress management, environmental enrichment, and cognitive exercise have all been shown to modulate the impact of neuroimmune activation on behavioral outcomes (Berk et al., 2013), especially in the aging population (Singhal, Jaehne, Corrigan, & Baune, 2014). Mind–body therapies including yoga, meditation, and tai-chi are also known to reduce pro-inflammatory cytokines (Bower & Irwin, 2016). Additionally, the relationship between immune activation and behavior may be modulated by a person’s socioeconomic status and early life experience (Miller et al., 2009; Miller, Chen, & Parker, 2011).
Bidirectional interactions between the immune system and central nervous system have been acknowledged for centuries. Over the past 200 years, great strides have been made toward understanding the biological underpinnings of immune-brain interactions. Multiple pathways have been identified, and appreciation of the mechanisms that mediate these interactions have provided the foundation for development of treatment interventions for conditions in which dysfunction of immune-brain interactions leads to behavioral pathology. The studies recapitulated here recount the known mechanisms which link immune function to behavior. The work explored expands beyond pathogen-related sickness behavior to the maladaptive manifestation of immune influences on the brain such as in neuropsychiatric disorders. Collectively, the information provided here establishes a framework for future study in behavioral neuroimmunology by providing a historical perspective of the field, detailing a synopsis of current knowledge and constructing a foundation for interpretation and integration of future related findings.
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