Abstract
The female brain is highly dynamic and can fundamentally remodel throughout the normal ovarian cycle as well as in critical life stages including perinatal development, pregnancy and old-age. As such, females are particularly vulnerable to infections, psychological disorders, certain cancers, and cognitive impairments. We will present the latest evidence on the female brain; how it develops through the neonatal period; how it changes through the ovarian cycle in normal individuals; how it adapts to pregnancy and postpartum; how it responds to illness and disease, particularly cancer; and, finally, how it is shaped by old age. Throughout, we will highlight female vulnerability to and resilience against disease and dysfunction in the face of environmental challenges.
1. Introduction
The female brain is remarkably dynamic, responding uniquely to the early life environment, aging and to various life stages in between. In this review we will highlight the key themes the psychoneuroimmunology research community is contributing to the understanding of the female brain (Figure 1). In particular, we focus on specific life stages. First, we outline how the female brain develops and how this development can be perturbed by environmental influences, particularly by neuroimmune challenges. Next, we address how the healthy adult female brain is dynamically remodeled as circulating sex hormones change. Pregnancy is an important part of many females’ lives wherein the neuroimmune system changes fundamentally to protect the growing fetus and we discuss the latest work on how the brain adapts. As females mature and age, they face unique challenges, including susceptibility to sex hormone-responsive diseases (and treatments) around menopause that are associated with persistent behavioral comorbidities, like breast cancer and age-related cognitive decline. Here we outline some of the female-specific psychoneuroimmune changes that occur at these times (Figure 1). With this review, it is our deliberate intention to present what is known about female neuroimmunology without, where possible, invoking a comparison to males. Until very recently, there has been a conspicuous paucity of research focusing solely on females, despite meta-analysis demonstrating female mouse models are not more variable than males, even when cycle stage is not controlled for (Prendergast et al., 2014). For example, with the exception of reproductive topics, female-only studies accounted for 20% or fewer of the papers published in 2009 (Beery and Zucker, 2011). As our discussion shows, female brains and neuroimmune responses can be very different from those of males. However, simply pursuing a comparative approach in research design is restrictive as it tends to limit any investigation of females to how they do, or do not, differ from males and discourages exploration of female-unique responses. Thus, neglecting to specifically study females in biomedical research restricts our understanding of women’s health and disease progression to assumptions that they are indistinct from that of men, and limits the possibilities of creating female-specific therapies and pharmaceuticals. This oversight may be very costly, not just in terms of research and healthcare dollars, but also in terms of human suffering and understanding potential applied health advantages of females (Krukowski et al., 2018; Rummel, 2018). We envisage that as our understanding of female psychoneuroimmunology progresses, so will our capacity to tailor drug delivery systems to accommodate monthly and even circadian sex hormone fluctuations; to prevent pre-term birth by strategically enhancing a woman’s adaptive neuroimmune responses to pregnancy; and to identify and mimic how females are relatively protected against early life challenges. The findings discussed here suggest we are beginning to make headway into this important topic.
Figure 1.
Summary diagram of the key changes in the psychoneuroimmunology of the female brain across the lifespan. Across the lifespan, from the perinatal stage to advanced age, females exhibit dramatic shifts in sex steroid hormones. These range from very low (during the perinatal period), to moderate, oscillating levels (during young adulthood), to very high (during late pregnancy), to precipitously declining levels (with cancer treatments) and finally, to gradually declining levels (in menopause and into advanced age). These hormonal shifts play an important role in the behavioral phenotype demonstrated at each developmental stage, altering behaviors such as mood and cognition. Preclinical studies have informed our understanding of the neuroimmune phenotype that is characteristic of each stage of life, and which may be modulated by fluctuations in sex hormones. Reproduced with the permission of The Ohio State University.
2. Perinatal development of the female brain
The basics of female brain development
In mammals, female-typical brain development begins with the process of sex determination, driven by sex chromosomes. With a sex chromosome complement of XX, female development proceeds along a ‘default process’, so called because it occurs in the absence of active hormonal signals, but not because it does not involve active regulation by sex chromosome genes (Blecher and Erickson, 2007). In the absence of intervening signals from the Y chromosome, primordial gonadal tissue differentiates into the ovaries (Blecher and Erickson, 2007). The ovaries are relatively quiescent during development in comparison to the testes, only beginning to secrete substantial amounts of the female typical hormones, estrogens and progestins, at puberty (Jost et al., 1973). Despite this quiescence, female mice that lack aromatase, the enzyme responsible for producing estrogens, display disrupted sociosexual behavior in adulthood; but these behavioral changes can be normalized by prepubertal treatment with estrogens (Bakker and Baum, 2008; Brock et al., 2011). These data indicate that female-typical hormones contribute to female brain development early on (Blecher and Erickson, 2007; McCarthy and Arnold, 2011). The source of the hormones in question could be extragonadal, as the brain synthesizes significant amounts of estrogens (Konkle and McCarthy, 2011; McCarthy, 2008).
One X chromosome in each female cell is silenced via the process of X-inactivation (Gartler and Riggs, 1983). Thus, every female tissue is mosaic, either expressing paternal or maternal X-chromosome genes. The pattern of X-inactivation across brain regions and neuron subtypes is not uniform (Gregg et al., 2010; Wu et al., 2014), and such mosaicism may be a major (and totally unexplored) source of variability across brain cells that is relevant for individual differences in the behavioral function of females. The process of X-inactivation is also not entirely complete, and both immune and epigenetic regulatory genes have been shown to escape inactivation in different female tissues (Carrel and Willard, 2005). There is a high concentration of immune-related genes on the X chromosome, and, if they escape inactivation, these could underlie the female-biased risk for autoimmunity (Bianchi et al., 2012). A fascinating study in mice shows the maternal X gene for interleukin (IL)-18 is more highly expressed in the female prefrontal cortex than in the male (Gregg et al., 2010), but the mechanistic role of this or other X-chromosome immune genes have not been explored in the context of female brain development.
Neuroimmune contributors to normal female brain and behavioral development
Neuroimmune cells are key mediators of normal brain development. Microglia, the brain’s resident immune cells, in particular, are crucial to regulating developmental cell genesis (Cunningham et al., 2013; Shigemoto-Mogami et al., 2014), apoptosis (Marin-Teva et al., 2004; Wakselman et al., 2008), myelination (Hagemeyer et al., 2017), synaptogenesis and synaptic pruning (Miyamoto et al., 2016; Paolicelli et al., 2011; Schafer et al., 2012; Weinhard et al., 2018a). The process of sexual differentiation, too, is dependent upon neuroimmune cells and their signaling. For example, the anteroventral periventricular area of the hypothalamus (AVPV), is larger in female rodents than in males, and is crucial for female hormonal cycling later in life (Semaan and Kauffman, 2010; Sumida et al., 1993). Higher rates of developmental cell survival in the AVPV underlie this sex difference (Waters and Simerly, 2009), and the neuroimmune mediators, tumor necrosis factor (TNF) receptor 2 as well as nuclear factor κ-B (NFκB) protect neurons from cell death to lead to this brain region developing in a female-typical manner (Krishnan et al., 2009). In the nearby medial preoptic area (POA) of the hypothalamus, females have fewer activated microglia (microglia that are hypo-ramified, phagocytic, and inflammatory (Davalos et al., 2005; Nimmerjahn et al., 2005; Sominsky et al., 2018)) and mast cells than males, and active signaling by neuroimmune cells contributes to brain masculinization (Lenz et al., 2013; Lenz et al., 2018). But it is entirely possible that these cells are also crucial for the feminization process, given that the POA regulates maternal behavior and female hormonal cycling.
Females are also protected from male-typical brain sexual differentiation via epigenetic means. The POA is responsible for both female estrous cycling and maternal behavior as well as male copulatory behavior (Lenz et al., 2012). DNA methylation levels are higher in the female POA than in the male and interfering with methylation in females leads to significant increases in male-typical gene expression and masculinization of sexual behavior (Nugent et al., 2015). Treating females with an inhibitor of DNA methylation enzymes leads to masculinization of sexual behavior (Nugent et al., 2015), but also the expression of immune-related genes increases four-fold in the female brain (McCarthy et al., 2017), meaning that many of the genes that are epigenetically silenced in the female brain are related to the immune system. It follows that early life immune activation could elevate expression for these genes that are typically silenced, and thereby perturb the normal process of brain feminization.
During development, female microglia across many brain regions, including the hippocampus, amygdala, parietal cortex and hypothalamus, show a more ameboid morphology than they do in later life (Schwarz et al., 2012). Female microglia also show a transient peak in phagocytic tone in the developing hippocampus relative to males, including greater numbers of phagocytic cups on microglia and increased expression of genes related to phagocytosis, including Cd68, Tyrobp, Trem2, and Cybb (Nelson et al., 2017; Weinhard et al., 2018b). Microglia phagocytic cups target neural progenitor cells for phagocytic clearance in females more than in males (Nelson et al., 2017). Increased expression of phagocytic markers correlates, but has not yet been mechanistically linked, to lower synaptic marker density in females prior to puberty (Weinhard et al., 2018b).
Cells of the innate and acquired immune system have also been linked to female behavioral development. Temporary depletion of microglia in the first postnatal week, using liposomal clodronate, leads to decreased anxiety-like behavior, decreased behavioral despair, and decreased acute stress responsivity in adult females (Nelson and Lenz, 2017b; VanRyzin et al., 2016), suggesting that microglia contribute to the normal development of these behaviors. Although most studies of neuroimmune function and brain development have focused on innate immune cells, there is increasing evidence that cells of the acquired immune system, such as T cells, also contribute to brain and behavioral function, possibly via signaling in the meninges and across the blood brain barrier (Kipnis, 2016). T-cells have recently been implicated in female-typical brain development. Female T-cell receptor knockout mice lack T-cells congenitally, and show both increased volume of the bed nucleus of the stria terminalis (BNST) and amygdala relative to wildtype females, as well as decreased hippocampal volume and decreased anxiety-like behavior as adults (Rilett et al., 2015). The brain regions impacted by congenital T-cell deficiency are crucial to sociosexual behavior, the stress response, learning, and anxiety behavior, but the mechanisms through which T-cells impact behavioral development are unknown.
Female response to early life perturbations
Given that immune cells contribute to normal brain development in females, it becomes obvious that early life perturbations that impact neuroimmune function may program brain development and lifelong behavior. Animal studies have used various early life immune challenge paradigms to model this risk and determine the underlying mechanisms through which immune activation shifts behavioral development (Estes and McAllister, 2016; Meyer, 2014; Patterson, 2009). To challenge the developing immune system, many studies have used the bacterial endotoxin, lipopolysaccharide (LPS), delivered either systemically to pregnant dams, locally into the uterus, or systemically to offspring, but other commonly used challenges are the viral mimetic, Poly I:C, live bacterial infection (E. coli), or exogenous cytokine treatment. Likewise, other early life perturbations, such as perinatal stress exposure, early life overnutrition, maternal obesity, maternal or neonatal ethanol exposure, maternal allergic asthma, and exposure to environmental pollutant exposure and neonatal pain or injury, influence female neural and behavioral development in part by eliciting neuroinflammation or perturbing normal immune responses in the brain, as will be discussed below.
Making hard and fast conclusions about the effects of early life inflammation on brain development is challenging given the large numbers of studies performed, differences in inflammogens used, timing of challenge, and the endpoints assessed. This has led to a call for early life inflammation studies to be performed with greater rigor to facilitate comparisons across studies (Kentner et al., 2018). In general, females show a mild but measurable acute pro-inflammatory response within the brain in response to perinatal inflammatory challenges, including increased gene expression for pro-inflammatory cytokines and changes in microglia staining density, number, and expression of phagocytic markers (for thorough recent reviews of sex-specific effects of early life inflammation and mechanisms of inflammation-induced brain development, refer to (Bilbo et al., 2018; Nelson and Lenz, 2017a; Sominsky et al., 2018)). However, in some cases, the female neuroimmune response to early life perturbations is not in the ‘expected’ pro-inflammatory direction. For example, neonatal overnutrition decreases inflammatory gene expression in the developing hypothalamus of females, but eventually leads to adult increases in both microglia number, and inflammatory gene expression in the adult hypothalamus (Ziko et al., 2014). Clearly, it is crucial to assess females at different developmental stages following early life perturbations before we can make any broader conclusions about how neuroimmune function is impacted by experience.
Careful studies of female microglial function after inflammation have yielded some insight into the mechanisms through which early life inflammation impacts brain development. In response to prenatal Poly I:C exposure, electron microscopy analysis of microglia in females show that they increase association with myelinated axons (Hui et al., 2018). Interestingly, a study of myelination after intrauterine inflammation showed decreased myelin basic protein in the brains of female offspring (Makinson et al., 2017), suggesting a possible link between inflammation-induced activation of microglia and decreased myelination. Exposure to allergic asthma in utero leads to altered DNA methylation in microglia, specifically in gene modules that have been associated with neurodevelopmental disorders in humans (Vogel Ciernia et al., 2018). Female microglia also have a faster baseline maturation rate than males at the transcriptomic level, and their maturation is not accelerated by immune challenge with LPS, as it is in males, which may reflect female resilience to early life inflammation (Hanamsagar et al., 2017). These studies suggest that the normal developmental functions of female microglia are disrupted by early life perturbations. This may be a cause of behavioral changes seen in females following early life immune activation, though few studies to date have mechanistically linked microglial dysfunction after inflammation with shifts in the trajectory of behavioral development.
After various early life inflammation exposures, females show deficits in memory tasks, motor function, social interaction and/or social preferences, increased anxiety-like behavior, and sensory gating or response inhibition deficits, and vulnerability to arthritis (Aavani et al., 2015; de Theije et al., 2015; Henderson et al., 2017; Hui et al., 2018; Lin et al., 2012; Makinson et al., 2017; Meyer et al., 2008; Ratnayake et al., 2013; Smith et al., 2007; Vogel Ciernia et al., 2018; Zhang et al., 2012). Yet, in many other cases, females show resilience, especially relative to males. For example, both prenatal exposure to LPS or, later, LPS challenge in the second postnatal week, leads to decreases in juvenile social play in males, but does not impact play in females (Hoffman et al., 2016; Taylor et al., 2012). Following early prenatal stress exposure, males but not females show hyperactivity, anhedonia, and heightened hypothalamic-pituitary-adrenal (HPA) axis responses to stress (Bronson and Bale, 2014; Mueller and Bale, 2008). Similarly, postnatal overfeeding leads to long-term changes in satiety signaling in males that are not seen in females (Ziko et al., 2017). Interestingly, the female placenta does not mount nearly as robust an inflammatory response to stress as the male placenta and shows epigenetic differences from males that lead to stress-buffering effects, which may indicate that the placenta is a key factor in female resilience (Nugent and Bale, 2015; Nugent et al., 2018). The maternal microbiome may also play a role here, in that eliminating the dam’s microbiome in mice can lead to a sex-specific impact on the microglial transcriptome, with a minimal early effect in females (Thion et al., 2018).
A single inflammatory exposure is often not sufficient to produce long-term behavioral consequences, but isolated early life inflammatory exposures may ‘prime’ the immune system to react more robustly to subsequent ‘second hits’ of inflammatory events (stress, toxin exposure, immune challenge) later in life. In the context of multiple hits of early life inflammation, females again display resilience. For example, prenatal diesel particulate exposure coupled with early life stress, leads to elevated pro-inflammatory mediators in the male brain (Bolton et al., 2013); but in the female brain, the same double hit leads to elevations in the anti-inflammatory cytokine, IL-10 (Bolton et al., 2013). This suggests that the immune system response in the female brain may actually buffer against later behavioral effects via anti-inflammatory pathways. Indeed, while both males and females showed elevated anxiety-like behavior following this double hit, females show no evidence of learning deficits, whereas males do (Bolton et al., 2013). The same group has demonstrated that females exposed to both air pollution and high-fat diet prenatally do not display metabolic changes and insulin resistance, whereas males do (Bolton et al., 2014). Both early life exposure to intrauterine inflammation and prenatal alcohol (Makinson et al., 2017; Terasaki and Schwarz, 2016) similarly lead to enhanced inflammatory responses to later life immune challenge in males, but not in females. Thus, female resilience appears to be a recurrent theme across diverse early life inflammation studies.
There are of course exceptions to this generality. For example, female rats show a larger inflammatory response than males in adulthood following neonatal inflammatory injury (LaPrairie and Murphy, 2007). Similarly, females show a robust potentiation of experimental arthritis induction in adulthood following prenatal ethanol exposure, accompanied by T cell proliferation and peripheral inflammation (Zhang et al., 2012). These data match with the known female susceptibility to both pain and autoimmune conditions (Fairweather et al., 2008; Rosen et al., 2017). These ‘exceptions’ to female resilience lead to an interesting question that deserves careful research attention: To what extent do females show a ‘quantitative’ difference in the inflammatory response following early life immune activation, versus a ‘qualitative’ difference relative to males? This qualitative difference could lead females to be resilient to certain perturbations but more vulnerable to others. There are data from the adult sex differences literature to support this idea. For example, in adult rodents, females and males both mount robust mechanical pain hypersensitivity, but in females, this pain response is mediated by T cells, and in males, it is mediated by microglia (Sorge et al., 2015). In a prenatal immune activation model that activates the toll-like receptor (TLR)7 pathway and leads to equal changes in microglia density and morphology in males and females, female mice show many fewer gene expression changes in the striatum than males (a ‘quantitative’ sex difference), and male and female mice show highly divergent gene expression responses in the brain (a ‘qualitative’ sex difference) (Missig et al., 2019). Thus, future research must look for both quantitative and qualitative differences between the sexes and across windows of development to best understand female-specific neurobiology, both in the context of normal function, and in the context of resilience and risk to neurological dysfunction.
Early life inflammation is a risk factor for neurodevelopmental disorders, such as autism spectrum disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD), and Tourette’s syndrome (Estes and McAllister, 2016). Most of these same disorders affect females at a much lower rate than males (McCarthy et al., 2017). In the case of autism spectrum disorder, there is an hypothesis that being female is protective, in that females with autism typically have much higher genetic load than affected males (Jacquemont et al., 2014; Robinson et al., 2013). It is possible that blunted female neuroimmune responses to early life inflammatory perturbations could potentially underlie this apparent protection. Increased expression of microglial and astrocyte-specific genes is evident in the postmortem brains of autistic individuals, as well as in males relative to females irrespective of autism diagnosis (Werling et al., 2016). Thus, lower levels of glial-related gene expression in females could be the source of this buffering. This is a provocative hypothesis, but it has yet to be rigorously tested experimentally. For example, might recapitulating the female neuroimmune system in a genetic animal model of neurodevelopmental disorders confer protection against early life perturbations that induce behavioral changes that resemble human disorders? It would be a major breakthrough for neurodevelopmental disorder prevention or treatment if we were able to pinpoint what female-specific factor mediates this protection, or more generally, the factors that contribute to female resilience to early life inflammatory events.
3. The dynamic female brain and its neuroimmune changes across the ovarian cycle
By the time females pass adolescence, their brains have mostly structurally matured (Toga et al., 2006). Neuron numbers and pattern of connectivity, and microglia and astrocyte numbers and morphology are broadly similar at peri-adolescence to those in young adults (Schwarz et al., 2012; Stiles and Jemigan, 2010). At this phase of life, female sex hormones start to play a major role in brain dynamics and neuroimmune function. 17β-estradiol (E2) is the predominant circulating estrogen in females, and directly influences brain function through the estrogen receptors, ERα & ERβ, expressed on glia & neurons, including in the hippocampus (Azcoitia et al., 1999; Gonzalez et al., 2007; Santagati et al., 1994). In rodents, the estrous cycle lasts approximately four days, with a proestrous (follicular) phase where the ovarian follicles mature, characterized by high levels of E2, progesterone, prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH); an estrous (ovulatory) phase where the ovum is released and the sex hormones plummet; and metestrous and diestrous (luteal) phases where if the ovum is fertilized the corpus luteum secretes progesterone to maintain the pregnancy, or is resorbed if not (Goldman et al., 2007). In humans, this cycle is approximately 20-35 days long and differs primarily in that the endometrium is shed in menses rather than being resorbed. Remarkably, the hormonal changes associated with this cyclicity can fundamentally remodel the brain.
There is some early evidence that neuronal proliferation, or at least numbers of BrdU-incorporated cells, is dependent upon cycle stage and ovarian hormones, with rats having increased dentate gyrus proliferation and cell survival in the proestrous phase, when E2 levels are high, relative to the other phases (Tanapat et al., 1999). However, perhaps most remarkable, is that dendritic spine density is altered by up to 30% across the estrous cycle in the rodent hypothalamus and CA1 hippocampus (Frankfurt et al., 1990; Woolley et al., 1990). In the estrous phase when E2 and progesterone fall to their lowest levels, dendritic spines are robustly pruned. In the metestrous / diestrous phases, dendritic spine formation and maintenance is supported and the synaptic spines maintained and strengthened so that by proestrus spine density can be 30% higher in the CA1 and ventromedial hypothalamus than is seen in estrus (Frankfurt et al., 1990; Woolley et al., 1990). This dynamic remodeling is tied to sex hormone levels with high E2 and progesterone encouraging spine maintenance and sex hormone removal, such as with ovariectomy, leading to reduced spine density (Gould et al., 1990).
The synapse is considered the structural neuronal substrate from which information is transmitted. Thus, it is not surprising that, practically, this dynamic neuronal and spine remodeling may mean females use different cognitive strategies at different stages of the cycle to solve complex tasks (Korol et al., 2004; Paris and Frye, 2008). In the proestrous phase, when E2 and progesterone are high and dendritic spines dense, female rats are more likely to use a place strategy (using recall of learnt external spatial orientation) to solve spontaneous alternation and T maze tasks. In the estrous phase, when sex hormone levels are low, rats are more likely to use a response strategy (using recall of learnt body movements) (Korol et al., 2004). In both tasks, exploration and motivation are similar and the strategies used are equally effective in facilitating task learning (Korol et al., 2004). Pregnancy, when progesterone and its metabolites are elevated, can also improve performance in object recognition and place recognition tasks relative to non-pregnant states (Paris and Frye, 2008). Such dynamic changes may be part of a strategy whereby different life stages call for different cognitive priorities. Whether such dynamic remodeling of dendritic spines contributes to any real or perceived changes in cognitive priorities and attention in human pregnancy and lactation is yet to be determined (Barha and Galea, 2017).
Although sex hormones such as estrogen play an important role in this cyclical dynamic brain remodeling, they likely do so through interaction with the neuroimmune system. Thus, ovarian cycle stage can robustly influence neuroimmune health. Females are more vulnerable to exacerbations of several neuroimmune disorders at certain stages of the ovarian cycle. For example, females with disorders as diverse as inflammatory bowel syndrome or Parkinson’s disease exhibit worsening symptoms at menses, when ovarian hormones are low (Mulak et al., 2014); and oophorectomy prior to menopause can elevate the risk of Parkinson’s developing (Gillies et al., 2014). In rhesus macaques, vaccination responses have been linked to ovarian hormones, with ovariectomy reducing the T-cell cytokine and IgG response to Vaccina Ankara vaccination; E2 replacement partially restores this response (Engelmann et al., 2011). High antibody titres after vaccination in females may be associated with better protection, but also with more frequent side-effects (Furman et al., 2014; Klein et al., 2010; Vermeiren et al., 2013). In rodents, too, sex hormones have been implicated in peripheral mechanisms of differential immunomodulation throughout the ovarian cycle. As such, ovariectomy worsens peripheral diabetes symptoms and the inflammatory effects associated with diabetes (Stubbins et al., 2012), as well as the allergic reaction of the lung to ovalbumin; and E2 treatment reverses, while progesterone exacerbates this effect (de Oliveira et al., 2010).
There has been limited investigation of natural fluctuations in immune reactivity across the ovarian cycle (i.e. from studies other than with ovariectomy or E2 replacement), and even less work on central cyclical immune changes. Yet there is some human evidence that circulating inflammatory markers change across the menstrual cycle, with C-reactive protein (CRP) being low in the follicular phase (when sex hormones are high) (Gaskins et al., 2012; Lorenz et al., 2017). In rodent models, central cytokines can be differentially sensitive across the ovarian cycle. Hypothalamic IL-1 levels are unresponsive to foot-shock stress during metestrus but increase at the other stages (Arakawa et al., 2014). This effect is likely related to high progesterone at this time attenuating the hypothalamic immune response (Arakawa et al., 2014). Likewise, proestrus and estrus see an exacerbated infarct size in a mouse focal ischemia model; an effect that is IL-4-dependent (Xiong et al., 2015).
Although evidence for cycle-stage variations in brain immune cell populations is limited, there is work to suggest microglia and astrocytes are sensitive to substantial variations in sex hormones. Microglia express estrogen receptors (ERα and ERβ) and this expression is significantly reduced by peripheral immune challenge with LPS (Sierra et al., 2008). Experimental ovariectomy, i.e. withdrawal of the sex hormones as occurs with menopause (and to a lesser extent in the luteal phase), leads to inflammation associated with microglial and astrocyte activity (Benedusi et al., 2012; Siani et al., 2017). These changes are somewhat reversible with E2 replacement and are similar in rodents and humans (Sarvari et al., 2012; Sarvari et al., 2014). LPS-induced activation of microglia is modified by compounds that act at the estrogen receptor, with E2, tamoxifen, and raloxifene (selective estrogen receptor modulators) suppressing microglial activation in ovariectomized rats (Tapia-Gonzalez et al., 2008) in a mechanism that may involve E2-mediated inhibition of the inwardly rectifying K+ channel, Kir2.1 (Wu et al., 2016). Exogenous E2 mimetics given long-term after ovariectomy can even reduce microglial and astrocyte numbers (Lei et al., 2003). Notably, females are resistant to the neuroimmune and cognitive deficits imparted by galactic cosmic radiation and this resistance is associated with microglial resilience to the challenge (Krukowski et al., 2018). Paradoxically, female microglia display higher expression of inflammatory, apoptotic, and LPS-response genes than male microglia do (Thion et al., 2018) and therefore have stronger innate and adaptive responses to acute immune stimuli (Klein and Flanagan, 2016). Potentially this greater efficiency in the central immune response offers some protection against long-term negative effects of immune challenge in females, but may also underlie why females are resistant to the antinociceptive effects of morphine compared with males (Doyle et al., 2017). In states where microglia are highly active, such as juxtaposing beta-amyloid plaques in the APP23 Alzheimer’s mouse, reductions in endogenous E2 further activate the microglia; replacing estrogen reverses this effect (Vegeto et al., 2006). However, early work suggests chronically elevated estrogen may not be beneficial, with chronic estrogen replacement therapy after ovariectomy leading to impaired cognitive performance when the treatment is coupled with chronic inflammation (Marriott et al., 2002). As discussed in the next section, microglia also play an important role in modulating synaptic plasticity through pregnancy.
It is clear the female brain is highly sensitive to hormonal fluctuations across the ovarian cycle and at life stages of hormone withdrawal. However, our understanding of these processes is limited by the lack of research in this area. This sensitivity may lead to resilience to immune challenges and stress at phases when E2 is low and progesterone high. Such resilience is important to consider when scheduling treatments such as surgery or vaccinations to maximize safety and effectiveness. When our understanding reaches an appropriate level of sophistication, we can also envisage titrating pharmacological treatments across the cycle to exploit and avoid desensitizing this natural resilience.
4. Neuroimmunological changes in pregnancy
As the female matures, pregnancy is one significant life stage during which dynamic neuroimmunological changes play an important role. While it is well established that the peripheral immune system undergoes dramatic changes in pregnancy to ensure the fetus is tolerated by the maternal immune system (Aagaard-Tillery et al., 2006; Mor and Cardenas, 2010; Trowsdale and Betz, 2006), in recent years attention has turned to the neuroimmunological changes that occur in pregnancy. However, to date research in this area is relatively limited.
In adults, microglia play a key role in immune surveillance. They act as macrophages, eliminating microbes, cellular debris and dead neurons from the central nervous system and are the primary source of cytokine secretion in the brain, hence facilitating neuroinflammatory processes (Colonna and Butovsky, 2017). Microglia are also important in sculpting neuronal networks by dynamically modulating synaptic plasticity (Benarroch, 2013; Colonna and Butovsky, 2017; Schafer et al., 2012; Walker et al., 2014; Yirmiya and Goshen, 2011). However, it remains to be established if microglia are involved in remodelling the maternal brain in pregnancy. In late pregnancy, there is a reduction in the number of microglia in the brain, specifically in the medial prefrontal cortex, nucleus accumbens, basolateral amygdala and dorsal hippocampus, which seems to be a result of reduced proliferation, rather than increased apoptosis (Haim et al., 2017). In accordance, neuroimmune responses of the maternal brain to immune/inflammatory challenge are suppressed, especially in late pregnancy (Sherer et al., 2017). For example, up-regulation in gene expression for the cytokines, IL-1β and IL-6 in response to bacterial endotoxin LPS administration is markedly attenuated in the prefrontal cortex, preoptic area, hypothalamus and hippocampus of late pregnant rats, compared with non-pregnant females (Sherer et al., 2017). The functional role of these microglial changes in late pregnancy is not clear, however they may contribute to neuroplasticity in the maternal brain that promotes changes in maternal motivation, cognitive function and mood post-partum (Figure 1) (Galea et al., 2014; Hillerer et al., 2014; Kinsley and Lambert, 2008; Leuner and Sabihi, 2016), although this requires further study.
Fever plays an important role in the body’s defence against infection as the increase in body temperature above the normal range serves to provide an inhospitable environment in which microbes are less able to multiply. However, despite fever being considered as an important component of the immune response, in late pregnancy the febrile response to immune challenge is markedly suppressed (Harre et al., 2006; Mouihate et al., 2002; Mouihate et al., 2005). This change is likely to be adaptive, as prolonged exposure to fever/hyperthermia can negatively impact fetal development and offspring health (Brucato et al., 2017; Edwards, 2006; Fisher et al., 2010; Lowe et al., 2008), however it may come at a cost-compromising the mother’s ability to fight infection (Martin et al., 1995). The mechanisms underlying reduced febrile responses to immune challenge may involve suppression of pro-inflammatory and enhancement of anti-inflammatory processes. Indeed, in response to LPS administration, production of pro-inflammatory prostaglandins is reduced in late pregnancy (Imai-Matsumura et al., 2002), evidently as a result of reduced cyclo-oxygenase-2 (COX-2; one of the enzymes responsible for responsible for formation of prostaglandins) induction in the hypothalamus (Mouihate et al., 2002)); while the response of the anti-inflammatory cytokine, IL-1 receptor antagonist (IL-1Ra) is augmented (Ashdown et al., 2007). It is not known what induces the change in febrile responses in pregnancy. While ovarian hormones influence fever development across the estrous cycle (Mouihate et al., 1998), increased levels of E2 and progesterone in late pregnancy do not appear to mediate attenuated febrile responses before term (Finley et al., 2015).
Hormonal regulation of neuroimmune adaptations during pregnancy
Changes in the hormonal milieu in pregnancy are recognised as potentially underpinning the neuroimmune alterations described above (Figure 1). Pregnancy is characterised by considerably higher circulating concentrations of E2 and progesterone (Bridges, 1984; Brunton and Russell, 2010). Both estrogen and progesterone have central anti-inflammatory actions in pregnancy (Kipp et al., 2007). Indeed, treating virgin female rats with a combination of E2 and progesterone to simulate pregnancy results in reduced febrile responses to LPS, concomitant with reduced COX-2 expression in the hypothalamus (Mouihate and Pittman, 2003). Moreover, as mentioned earlier, microglia express receptors for estrogen (Habib and Beyer, 2015; Vegeto et al., 2001) and estrogen has been shown to suppress proliferation and activation of microglia, inhibit pro-inflammatory cytokine secretion and promote anti-inflammatory cytokine secretion (Bruce-Keller et al., 2000; Dimayuga et al., 2005; Vegeto et al., 2001). Hence increased circulating sex steroids in pregnancy may contribute to neuroimmunological alterations.
In addition to increases in circulating sex steroids, oxytocin has also been proposed as a potential candidate in modulating neuroimmune responses in pregnancy. In support, oxytocin has been reported to inhibit LPS-induced microglial activation and consequently reduce the release of pro-inflammatory mediators in vitro and in vivo (Yuan et al., 2016), and attenuate febrile responses to centrally administered IL-1α (Poulin and Pittman, 1993). However, given oxytocin release in the supraoptic nucleus (SON), paraventricular nucleus (PVN), mediolateral septum and dorsal hippocampus is similar between virgin females and late pregnant rats (Landgraf et al., 1992; Neumann et al., 1993) and is only increased in the ventral septal area (VSA) in late pregnancy (Landgraf 1992), it is unclear whether this modest increase in central oxytocin is physiologically relevant with respect to suppressing neuroimmunological responses. Nevertheless, immune challenge is known to activate centrally projecting oxytocin neurons (Matsunaga et al., 2000) and stimulate oxytocin release in the VSA and SON (Landgraf et al., 1990; Landgraf et al., 1995), so this may be important, although it is not yet known whether this central oxytocin response to immune challenge is altered in pregnancy.
Finally, given their potent anti-inflammatory actions we should also consider a role for glucocorticoids in suppressing neuroimmune responses in pregnancy. Basal concentrations of corticosterone in the circulation increase progressively from around mid-gestation in the rat (Atkinson and Waddell, 1995). Microglia express glucocorticoid receptors (Tanaka et al., 1997) and glucocorticoids inhibit microglial proliferation and suppress secretion of pro-inflammatory cytokines from microglia (Drew and Chavis, 2000; Tanaka et al., 1997). Thus, although HPA axis responses to immune challenge are suppressed in late pregnancy (discussed below) and glucocorticoids exert less potent anti-inflammatory actions in females than in males (Duma et al., 2010), elevated baseline glucocorticoid levels may contribute to attenuating neuroinflammatory processes.
There is still a lot we do not understand about the neuroimmune adaptations that occur in pregnancy and this is an area that warrants more research. Of particular interest is the potential that these changes may predispose women to postpartum mood disorders. Certainly, altered microglial activity and immune signalling have been implicated in anxiety and depression (Hodes et al., 2015; Kohler et al., 2018; Remus and Dantzer, 2016; Reus et al., 2015; Steiner et al., 2011; Yirmiya et al., 2015; Young et al., 2014). Whether neuroimmunological adaptations in pregnancy and the subsequent restoration in the postpartum period (Sherer et al., 2017) interact with the dramatic withdrawal of pregnancy-related hormones at birth, which has also been proposed to confer vulnerability to puerperal mood disorders (Bloch et al., 2000; Brunton et al., 2008), is not known but is an area that requires investigation.
Neuroendocrine responses to inflammatory challenge in pregnancy
Sex differences in HPA axis responses to stress, including immune challenge, are well established in rodents, with females typically displaying greater responses than males (Frederic et al., 1993; Seale et al., 2004). However, in late pregnancy, responsivity of the HPA axis and the magnocellular oxytocin system to a range of physical and psychological stressors is markedly attenuated, compared with the non-pregnant state (Brunton and Russell, 2008). It is generally considered that maintaining quiescence of the oxytocin neurons serves to minimise the risk of preterm birth and limiting activation of the HPA axis should conserve energy stores and protect the foetuses from adverse programming by exposure to excessive levels of maternal glucocorticoids (Brunton et al., 2014).
Of particular relevance here is that this phenomenon is also seen in response to acute immune/inflammatory challenges in late pregnancy (Brunton et al., 2005). In non-pregnant rats, systemic administration of IL-1β is a potent activator of the HPA axis, activating corticotropin-releasing hormone (CRH) neurons in the medial parvocellular PVN (mpPVN) (reflected by Fos induction), up-regulating mpPVN Crh gene expression and stimulating adrenocorticotropic hormone (ACTH) and corticosterone secretion (Brunton et al., 2012; Brunton et al., 2005; Buller et al., 2001; Ericsson et al., 1994; Sapolsky et al., 1987). Systemic IL-1β also activates magnocellular oxytocin neurons in the SON and PVN, increasing their electrical activity and stimulating oxytocin secretion from the posterior pituitary (Brunton et al., 2012; Brunton et al., 2006; Buller et al., 2001). In contrast, in late pregnancy both the HPA axis and the neurohypophysial oxytocin system are substantially less responsive to stimulation by acute inflammatory challenges such as LPS or IL-1β administration, compared with non-pregnant rats (Brunton et al., 2005; Brunton et al., 2006). Hence, in late pregnancy IL-1β fails to stimulate the HPA axis and has little effect on the electrical or secretory activity of the magnocellular oxytocin neurons (Brunton et al., 2012; Brunton et al., 2006). Moreover, centrally administered IL-1β depletes CRH content in the median eminence of virgin but not pregnant rats (Nakamura et al., 1998).
Central mechanisms involved in restraining the HPA axis and oxytocin system
Endogenous Opioids
Endogenous opioids are involved in restraining HPA axis and oxytocin responses to IL-1β in late pregnancy. As such, prior intravenous administration of the opioid receptor antagonist, naloxone, not only restores ACTH, corticosterone and oxytocin secretory responses to IL-1β, but in the hypothalamus increases the firing rate of oxytocin neurons and permits IL-1β-induced up-regulation of Crh mRNA in the mpPVN as well as Fos expression in the SON and PVN (Brunton et al., 2005; Brunton et al., 2006).
Brainstem noradrenergic neurons located in the nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM) play a crucial role in integrating cytokine signals from the periphery and relaying them to the hypothalamus (Buller et al., 2001; Ek et al., 1998; Ericsson et al., 1997; Ericsson et al., 1994; Ericsson et al., 1995; Rivest et al., 2000). These neurons project to the parvocellular CRH neurons in the PVN and magnocellular oxytocin neurons in the PVN and SON (Buller et al., 2001; Buller et al., 2004; Ericsson et al., 1994; Xu et al., 1999) and mediate HPA axis and oxytocin neuron responses to IL-1β (Buller et al., 2001; Ericsson et al., 1994; Melik Parsadaniantz et al., 1995). Systemic IL-1β increases Fos expression in the A2 region of the NTS to a similar extent in late pregnant and non-pregnant rats (Brunton et al., 2005). However, despite triggering noradrenaline release in the PVN of non-pregnant female rats, IL-1β fails to stimulate noradrenaline release in the PVN of late pregnant rats, unless naloxone is retrodialysed directly into the PVN (Brunton et al., 2005). These data indicate that in late pregnancy endogenous opioids act presynaptically on noradrenergic afferents to the PVN and inhibit IL-1β-induced noradrenaline release (Brunton et al., 2005). The source of the endogenous opioids is likely to be the A2 NTS neurons themselves, since mRNA expression for both proenkephalin-A (Penk) and μ-opioid receptor (Oprm1) are up-regulated in the A2 region of the NTS in late pregnant rats (Brunton et al., 2005). Given noradrenergic NTS neurons also relay signals from the birth canal to drive oxytocin secretion at parturition (Douglas et al., 2001; Herbison et al., 1997; Meddle et al., 2000), it is thought that limiting activation of this pathway in pregnancy by endogenous opioids ensures premature activation of the oxytocin neurons and hence preterm birth is avoided.
Allopregnanolone
The steroid milieu dramatically changes in pregnancy. As mentioned above, concentrations of E2 and progesterone in the blood are increased (Bridges, 1984; Brunton and Russell, 2010). In addition, concentrations of the neuroactive steroid metabolite of progesterone, allopregnanolone is also substantially increased in the blood and in the brain (Concas et al., 1998). Gene expression for both of the allopregnanolone-synthesising enzymes (5α-reductase; Srd5a and 3α-hydroxysteroid dehydrogenase; Akrlc4) is increased in the NTS in late pregnant rats, as is enzyme activity in the hypothalamus (Brunton et al., 2009). This is expected to lead to increased local allopregnanolone production in pregnancy (Paul and Purdy, 1992), which is considered to be important with respect to HPA axis and oxytocin neuron regulation. Indeed, administration of the 5α-reductase inhibitor, finasteride (at a dose shown to reduce central allopregnanolone content by 90%) (Concas et al., 1998) restores HPA axis responses to IL-1β in late pregnant rats; while treating virgin females with allopregnanolone to mimic pregnancy levels, suppresses HPA axis responses to IL-1β (Brunton et al., 2009). The same treatment regimens alter responsiveness of the magnocellular oxytocin neurons to an inflammatory challenge in a similar manner, revealing a role for allopregnanolone in also restraining activity of the oxytocin system in late pregnancy (Brunton et al., 2012).
Interestingly, treating virgin rats with either of the allopregnanolone precursors, progesterone or dihydroprogesterone (DHP) alone is not sufficient to suppress HPA axis or oxytocin responses to IL-1β (Brunton et al., 2012; Brunton et al., 2009), indicating that conversion of progesterone/DHP into allopregnanolone is of critical importance in suppressing these responses. This is likely achieved locally through up-regulation of the allopregnanolone synthesising enzymes in the NTS in pregnancy (Brunton et al., 2009).
Allopregnanolone and induction of endogenous opioid tone
Allopregnanolone plays a key role in the induction of the inhibitory endogenous opioid tone over the HPA axis and the oxytocin system in late pregnancy (Brunton et al., 2012; Brunton et al., 2009). As mentioned above, pregnancy is associated with increased Penk and Oprm1 gene transcription in the NTS (Brunton et al., 2009). This up-regulation of opioid-related gene expression in the NTS can be induced in virgin females by exogenous allopregnanolone administration; while blocking allopregnanolone synthesis in pregnant rats with finasteride, reduces Penk and Oprm1 gene expression to virgin levels (Brunton et al., 2009). Moreover, in non-pregnant females allopregnanolone administration induces endogenous opioid inhibition over the HPA axis, as naloxone administration reverses allopregnanolone-induced suppression of ACTH secretory responses to IL-1β (Brunton et al., 2009).
Thus, in summary, increased allopregnanolone production in pregnancy is of critical importance in inducing and sustaining an inhibitory endogenous opioid mechanism that limits excitation of both the HPA axis and the neurohypophysial oxytocin system by acute exposure to inflammatory stimuli, through inhibiting the excitatory noradrenergic input to the CRH and oxytocin neurons in the hypothalamus. This mechanism is predicted to minimise the risk of premature activation of the oxytocin neurons and consequently premature uterine contractions and preterm birth. Indeed, sustained inhibition of allopregnanolone production during the last week of pregnancy results in preterm birth and markedly reduces survival rates of the neonates (Paris et al., 2011b). Furthermore, preventing activation of the maternal HPA axis in pregnancy is also expected to conserve energy and limit exposure of the fetuses to excessive levels of maternal glucocorticoids, which can adversely program the offspring, predisposing them to disease (Brunton et al., 2014; Maccari et al., 2014). However, in spite of this, repeated immune challenge during pregnancy leads to preterm birth and fetal programming of the offspring (Paris et al., 2011a), indicating this inherent defence mechanism can be breached by repeated insults.
5. Female cancer effects on brain
Later life stages can also change the female brain in specific ways. As a woman ages she has increased risk of developing sex hormone-dependent diseases like cancer, including breast cancer, the most common malignancy in women. Cancer is associated with debilitating neurological and behavioral comorbidities, including self-reported fatigue (~90%), depression (~18%), anxiety (~10%), and cognitive impairments (~35%), occurring before, during, and long after successful treatment (Ahles et al., 2012; Ancoli-Israel et al., 2014; Pitman et al., 2018; Shankar et al., 2016). These behavioral comorbidities are associated with inflammation in clinical cancer research and neuroinflammation in preclinical cancer research, as previously reviewed (Santos and Pyter, 2018; Schrepf et al., 2015; Vichaya et al., 2015), suggesting that the underlying mechanisms include immune dysregulation. Indeed, non-CNS tumors (Schrepf et al., 2015), chemotherapy (reviewed in (Santos and Pyter, 2018)), and radiation (Ramanan et al., 2008) each independently induce inflammatory signaling in the brain (e.g., IL-1β, IL-6, Tnfα, iNOS, COX-2), in part by activation of microglia (ionized calcium binding adaptor molecule 1 (Iba1+), cluster of differentiation 68 (CD68+), or Cd11b mRNA) and astrocytes (Gibson et al., 2019), in models of cancer and cancer treatments, with negative behavioral outcomes. However, these recent reviews do not consider the role of sex or sex hormones in the behavioral or neuroimmune consequences of cancer.
Based on meta-analyses, people with breast cancer have a relatively low prevalence of major depression compared with other cancers. However, depression symptoms based on diagnostic interviews or self-report are relatively higher for cancers affecting females (breast, ovary, uterine, etc.) than for other types of cancer (Krebber et al., 2014). Similarly, females report more psychological distress but less diagnosed depression and anxiety when male and female cancers are directly compared (van’t Spijker et al., 1997). Finally, female cancer patients and female partners of cancer patients perceive more stress and lower quality of life than women in healthy couples, whereas men do not show this difference (Hagedoorn et al., 2000). These statistics indicate that behavioral comorbidities due to cancer may by modulated by sex-specific mechanisms.
In fact, approximately 70% of women diagnosed with breast cancer are post-menopausal (Danforth, 1991). Menopause, occurring in women at around age 50, is the complete and permanent cessation of menstrual cycles due to the natural depletion of ovarian oocytes resulting in a near complete depletion of estrogen (MedlinePlus, 2011) and is a significant risk factor for a variety of diseases. In Australian women with non-metastatic breast cancer, those without ovaries have higher depression and anxiety scores compared with those without ovariectomy (Sayakhot et al., 2011). Conversely, in breast cancer survivors, antidepressant treatment is associated with significantly higher prevalence and severity of menopausal symptoms (Gupta et al., 2006). Indeed, quality of life issues related to menopause and cancer treatment are difficult to differentiate, given that menopause often overlaps with cancer diagnosis (Schultz et al., 2005). Furthermore, 75% of breast tumors are responsive to estrogen and progesterone, such that these hormones promote tumor growth and progression. Thus, in addition to standard chemotherapy and radiation treatments, breast cancer patients are often treated with adjuvant endocrine therapy to inhibit tumorigenic endocrine (primarily estrogen) activity in tumor cells (Rugo et al., 2016). Overall, there is a lack of understanding of how menopause and long-term endocrine, chemotherapy, and radiation treatments may influence the brain to cause cancer behavioral comorbidities.
Studies of treatment-free breast cancer patients report no significant differences in cognition between pre-versus post-menopausal women (Torino et al., 2012; van Dam et al., 1998) , nor do breast cancer patients grouped based on lower versus average cognitive performance vary by menstrual status (Ahles et al., 2008). These findings indicate that endocrine therapy and chemotherapy may be necessary to precipitate otherwise insignificant behavioral comorbidities. Currently, most cancer studies are not designed to consider hormonal status as a potential modifier of behavioral comorbidities. For this review, we explore how these cancer-related endocrine pathways may influence neuroimmunology to confer negative behavioral consequences. Of note, most research on the interaction between hormones and cancer behavioral comorbidities are focused on cognitive function.
While most breast cancer patients are diagnosed after menopause, chemotherapy treatment also causes ovarian failure, amenorrhea, and reduced reproductive hormones in the majority of pre-menopausal women (Mehta and Graves, 1992; Reyno et al., 1992). Thus, “chemotherapy-induced menopause” may have similar negative effects on cognition as natural menopause (Zec and Trivedi, 2002). Furthermore, hot flashes, which are linked to estrogen deprivation, are correlated with anxiety in healthy women (Freeman, 2014). In fact, early chemotherapy-induced menopause may render pre-menopausal breast cancer patients more vulnerable to behavioral issues associated with reduced estrogen signalling in the brain than post-menopausal patients due to their extended estrogen deprivation period (Roy et al., 1996). Some studies indicate that cognitive performance following chemotherapy varies according to pre-treatment menopausal status (Conroy et al., 2013; Jenkins et al., 2006). For example, post-menopausal breast cancer patients report significantly greater difficulty with concentration and memory then pre-menopausal patients. However, when treatment modalities were considered, a reverse trend was observed, such that radiation was harsher on cognitive functioning in post-menopausal women and chemotherapy was harsher in premenopausal women (Schagen et al., 1999). Incomplete reporting on whether or not radiation was combined with chemotherapy or hormone therapy limits the conclusions. Of note, anxiety was reported in 38% of these patients and was associated with the self-reported cognitive problems (Schagen et al., 1999), suggesting that some of these conclusions focused on cognitive function may be extrapolated to mood. In contrast, other studies indicate that chemotherapy-induced menopause confers no negative consequences on cognitive function (Schagen et al., 2006; Vearncombe et al., 2011).
The primary recommendation for adjuvant endocrine therapy for pre-menopausal cancer patients is selective estrogen receptor modulators (SERMs; historically tamoxifen) which dysregulate estrogen signalling in tumor cells, while leaving estrogen signalling in other tissues intact (e.g., brain). In contrast, for the majority of breast cancer patients (i.e., postmenopausal), estrogen modulator therapy consists of aromatase inhibitors (AIs) alone or in combination with tamoxifen. AIs and SERMs have different mechanisms of action on estrogen receptors and AIs inhibit signalling both in the brain and periphery. AIs are prescribed for 5 years post-chemotherapy/radiation, but due to their effectiveness at tumor inhibition, prescription of these drugs has recently been extended for 10+ years. In contrast to chemotherapy, findings on cognitive effects of estrogen modulators are relatively sparse, underpowered, and inconclusive (Agrawal et al., 2010). The lack of understanding of how endocrine therapy impacts cancer-associated behavior is partially due to few studies differentiating between estrogen modulator treatment and chemotherapy or differentiating among the various estrogen modulator mechanisms of action (Jenkins et al., 2004). The effects of tamoxifen and AIs on cognitive function in breast cancer patients is reviewed elsewhere (Zwart et al., 2015).
Thus, hormonal status, history of hormone replacement therapy, and age all modify endocrine therapy effects on behavior. Estrogen modulators impair cognitive function even when given without chemotherapy (Ahles et al., 2010; Bender et al., 2001; Jenkins et al., 2004; Jenkins et al., 2008), although tamoxifen may be more detrimental (but possibly, reversible) than AI (Bakoyiannis et al., 2016; Phillips et al., 2010; Schilder et al., 2010). Post-menopausal breast cancer patients treated only with endocrine therapy (no chemotherapy) display poorer processing speed, verbal memory, and verbal ability than those without any treatment or healthy controls (Bender et al., 2007). However, the opposite effect is observed in premenopausal women, suggesting that prior hormonal status modulates the negative effects of endocrine therapy on behavior. Another well-designed study indicates that AIs confer both acute and long-term impairments in visual working memory, in particular (Bender et al., 2015). The potential more moderate effects of AIs on the brain/behavior compared with SERMS is unexpected given that AIs deprive the brain of estrogens produced in both the periphery and in the brain, whereas tamoxifen only inhibits peripheral estrogen synthesis. Objective cognitive results do not consistently correspond to self-reported results in these studies. Clearly, additional prospective studies are necessary to draw more robust conclusions (Wu and Amidi, 2017). Of note, some reports indicate that depression may explain cognitive impairment in breast cancer survivors more than endocrine therapy or chemotherapy (Seliktar et al., 2015). Finally, powerful clinical studies have indicated that endocrine therapy in otherwise healthy, post-menopausal women increases their risk of developing cancer and stroke and has adverse effects on cognition (Anderson et al., 2004; Rossouw et al., 2002; Shumaker et al., 2004). This work indicates that the effects of reproductive hormone modulation on the brain in postmenopausal women are complicated by their age, uterine/ovarian status, and duration since their last menstrual period. Thus, nuanced effects of hormonal status and endocrine therapy may modulate behavior in cancer patients and requires consistent reporting in clinical studies.
The majority of behavioral comorbidity studies in cancer patients are not designed to differentiate between chemotherapy with or without endocrine therapy. However, those that are suggest that cognitive problems are worse in patients receiving both therapies than one or the other (Castellon et al., 2004; Collins et al., 2009); but see (Buchanan et al., 2015). The various estrogen-modulating factors associated with breast cancer likely impact neurobiological mechanisms underlying these behaviors (Ahles and Saykin, 2007). Estrogen significantly modulates cognitive behavior (McEwen and Alves, 1999) potentially through observed neuroprotective and antioxidant actions (Unfer et al., 2006) and by helping to maintain telomere length (Lee et al., 2005). Estrogen is also anti-inflammatory, reducing proinflammatory cytokines in the brain (Brown et al., 2010; Duckles and Krause, 2011; Vegeto et al., 2008). As neuroinflammation is associated with cognitive decline, negative mood, and fatigue, natural or pharmacologically-induced reductions in estrogen in cancer patients may exacerbate neuroinflammation, and thus, behavioral consequences (Cribbs et al., 2012).
Indeed, numerous female rodent models of solid tumors or cancer treatments report increased inflammation in the brain and deficits in cognitive performance or elevations in affective-like behaviors (Lamkin et al., 2011; McGinnis et al., 2017; Pyter et al., 2009). However, very few cancer modelling studies have assessed the role of estrogen in these neurobehavioral results through ovariectomy, hormone replacement, or estrogen modulator treatments. One relevant study demonstrates that long-term olfactory recognition memory impairments in mice receiving cranial radiation therapy are dependent upon estrous stage (Perez et al., 2018). Cancer anorexia is also hypothesized to be influenced by sex-related hormones (Varma et al., 2001). Other studies not directly related to cancer modelling demonstrate that the SERM, raloxifene, combined with E2 treatment reduces anxiety- and depressive-like behavior in ovariectomized rats (Karahancer et al., 2008; Walf and Frye, 2010). Finally, cognitive performance improves with AI treatment in ovariectomized mice (Aydin et al., 2008; Meng et al., 2011), suggesting that cancer-typical estrogen modulation in much needed models of post-menopausal cancer may similarly improve behavioral impairments.
Results gleaned from healthy rodents used to assess the effects of endocrine therapies on neuroinflammation may also be relevant in the context of cancer. The anti-inflammatory mechanisms of SERMs in the brain have been reviewed elsewhere (Arevalo et al., 2011), but, briefly, SERMs influence various brain glial cells through modulation of ER signalling in their nuclei, their membranes or cytoplasm, or through ER-independent mechanisms. Indeed, ERα and ERβ in the brain are increased under several pathological inflammatory conditions (see (Arevalo et al., 2011)). Most relevant to tumors, microglia ERβ activity is responsible for the neural loss induced by an optic glioma tumor in mice (Toonen et al., 2017). Relevant to cancer treatment, tamoxifen decreases the microglia inflammatory response induced by cranial irradiation (Liu et al., 2010). SERMs also suppress in vitro LPS-induced microglial activation and neuronal cell death via an ER-dependent pathway (Ishihara et al., 2015). Long-term second-line (more specific) SERM treatment of aged ovariectomized mice successfully reduces the number of astrocytes and microglia in the hippocampus similar to E2 (Lei et al., 2003), suggesting that these more specific SERMs may confer the benefits of estrogen on the brain while inhibiting estrogen signalling in tumors outside the brain. Furthermore, some SERMs can mitigate neuroinflammation, neurotransmitter transport, and gliosis via their actions on astrocytes (Acaz-Fonseca et al., 2014). These astrocyte studies focus primarily on in vitro and in vivo models of traumatic brain injury (Johann and Beyer, 2013). Finally, nonnuclear ER stimulation reduces leukocyte infiltration and neuroinflammation in the brain after ischemic stroke in ovariectomized mice (Selvaraj et al., 2018). Of note, raloxifene has moderate pro-inflammatory effects on non-pathological brain tissue (Tapia-Gonzalez et al., 2008), suggesting potential negative inflammatory consequences of this SERM in patients asymptomatic for mental health issues. Thus, female-specific sex hormones particularly influence cancer development and the cognitive consequences that ensue, yet our understanding of the neuroimmune interactions that are important for this influence remains poor. There is an immediate need for improved basic and clinical research in this field to ensure we have optimal treatments to assist vulnerable females to move forward into healthy aging.
6. The aging female brain: the neuroimmune phenotype and its role in cognitive function
By the year 2050 approximately 1/5th of the world’s population will be over the age of 65, a dramatic doubling of today’s aging populace (He et al., 2016). This is alarming because advanced age is the single strongest risk factor for developing Alzheimer’s disease, Parkinson’s dementia, and other persistent cognitive impairments precipitated by surgery, stroke, viral or bacterial infection, and other immune insults (Alzheimer’s Association, 2016; Inouye et al., 2014; Moller et al., 1998; Mozaffarian et al., 2015; Nguyen et al., 2014; Reeve et al., 2014; Wofford et al., 1996). Current treatments for many of these conditions are ineffective. Fortunately, in the last ten years numerous clinical and basic research studies have strongly implicated a critical role played by heightened neuroinflammation, owed to a sensitized microglial or altered astrocytic phenotype, in the pathogenesis of these conditions, thus providing a therapeutic target on which to focus (Barrientos et al., 2012; Cao et al., 2010; Chisholm and Sohrabji, 2016; Edison and Brooks, 2018; Ferreira et al., 2014; Frank et al., 2010; Jones et al., 2018; McKenzie et al., 2017; Rajendran and Paolicelli, 2018; Ransohoff, 2016; Rollins et al., 2018; Spencer et al., 2018; Spencer et al., 2017; Tucsek et al., 2014).
Despite the fact that over half of the aging population is comprised of females, the vast majority of basic research conducted on matters of aging, neuroinflammation, and cognitive decline has been conducted using only male subjects. This disproportionate focus on the male brain is unjustified and troubling because women exhibit increased susceptibility to cognitive impairments following an immune insult as early as middle age (Phillips Bute et al., 2003). Furthermore, aged women are reportedly twice as likely as men to exhibit long-lasting post-operative cognitive dysfunction (Kotekar et al., 2014), have poorer outcomes following stroke than men (Choleris et al., 2018), are more likely to suffer from Alzheimer’s disease and other dementias (Bachman et al., 1992; Borenstein et al., 2014; Hebert et al., 2013; Launer et al., 1999; Sun et al., 2014), and women with mild cognitive impairments show deteriorating cognitive functions at a rate twice as fast as men (Lin et al., 2015). The mechanisms underlying these sex differences are not fully understood and are under-studied, but there is growing evidence that this vulnerability is markedly influenced by changes in sex steroid hormone levels associated with advanced age (Choleris et al., 2018; Driscoll et al., 2005; Dubal and Rogine, 2017).
Menopause is associated with a precipitous decline in female sex hormones, including E2. Relevant to this discussion, it has been reported that normal E2-ER interactions in astrocytes and microglia of young adult rodents decrease NF-κB transcriptional activity and inhibit the release of proinflammatory compounds in response to inflammatory stimuli, while dysregulation of either ligand or receptor results in the opposite (Cerciat et al., 2010; Ghisletti et al., 2005; Spence and Voskuhl, 2012; Spence et al., 2013; Vegeto et al., 2006). Menopause-associated reductions in estrogen are strongly associated with significant declines in cognition (Abu-Taha et al., 2009; Dubal and Wise, 2002). Thus, there is reason to believe that menopause may be an important factor further driving neuroinflammation and cognitive decline in older women.
The use of a naturally menopausal aged rodent model is not possible because aging female rodents enter a state of persistent estrus (also termed estropause), producing constant intermediate estrogen levels (Berkley et al., 2007; Chakraborty and Gore, 2004; Huang and Meites, 1975; Meites and Lu, 1994), which does not resemble the ovarian function of aged women. Therefore, surgical removal of the ovaries is necessary in rodent models to achieve true estrogen depletion. In studies modeling various aging-related diseases this way, many have reported greater inflammatory risk and disease progression in ovariectomized rodents compared to those with intact ovaries (Berchtold et al., 2001; Burnham et al., 2016; Chen et al., 2016; Crain et al., 2013; da Palma et al., 2016; De Melo et al., 2016). Importantly, these studies were all performed on young adult, not aged, female rodents. Rendering rodents menopausal in the absence of advanced age disregards the robust aging-related alterations to the glial phenotype that have been widely reported (Barrientos et al., 2015; Costello et al., 2016; Niraula et al., 2017), and therefore likely underestimates the inflammatory response to a challenge and cognitive impairments that would result when both aging and menopause are combined.
Recent work has made several advances in this regard. In a series of informative papers, the Liposits laboratory found that ovariectomizing middle-aged rats provokes an upregulation of microglial activation markers (Iba1, CD68, and CD80, CD11b, and CD18), and recognition receptor molecules (TLR3, TLR9) in the hippocampus compared to ovary-intact middle-aged controls (young adult controls were not examined). E2 replacement ten days following ovariectomy attenuated the expression of many these markers, and increased expression of CD200R, indicating a shift towards a protective microglial phenotype (Sarvari et al., 2014). Response to an inflammatory stimulus was not examined. Follow-up studies demonstrated that the hippocampal transcriptome is extensively altered with ovariectomy (Sarvari et al., 2017), and that long-term treatment with the ERβ-specific agonist, diarylpropinontrile (DPN), contributes to processes involved in the regulation of transcription, translation, neurogenesis, neuromodulation, and neuroprotection in the hippocampus, suggesting that selective activation of ERβ may be an effective therapeutic approach to mitigate the neuroinflammatory phenotype caused by estrogen depletion in menopause (Sarvari et al., 2016). In another important study (Kireev et al., 2014), basal expression of various inflammatory markers in the dentate gyrus of the hippocampus was measured in female rats that were either intact (non-cycling), ovariectomized, or ovariectomized and supplemented with E2 at middle age (12 months) and allowed to age to 24 months. Findings revealed that, compared to intact young adult females, non-cycling intact aged rats exhibited increased expression of IL-1β, TNFα, and IL-6, GFAP, iNOS, and NFκB1. Twelve-month long estrogen depletion exacerbated these responses, while estrogen treatment (administered to mimic normal cycling levels) robustly attenuated them to levels indistinguishable from those of young adult controls. These findings further support the anti-neuroinflammatory role of estrogen, and underscore the importance of cycling estrogen levels for the health of the aging brain.
In another informative study, researchers ovariectomized mice at 5 months of age and allowed them to age to 12 or 22 months (Benedusi et al., 2012). Results revealed that ovariectomy dramatically increased ERα and ERβ mRNA expression in the hippocampus at the 22-month time point. In addition, expression of the proinflammatory cytokines and chemokines TNFα, IL-1β, and MIP2 was also significantly increased in the 22-month-old ovariectomized mice. Furthermore, the morphology of astrocytes and microglia took on a more reactive phenotype with ovariectomy. This study further demonstrated that the inflammatory response to an LPS challenge in middle-aged mice that had been surgically-induced menopausal for 7 months was robustly exacerbated compared to mice that had been menopausal for only 1 month (Benedusi et al., 2012). Taken together, these results suggest that the duration of estrogen depletion, in combination with advanced age, significantly alters the neuroinflammatory phenotype. These findings lend support for studies that claim that hormone replacement therapy only exerts beneficial effects when initiated near the onset of menopause (Henderson and Rocca, 2012; Rocca et al., 2011). Whether an ERβ-specific hormonal replacement therapeutic approach confers protection against developing Alzheimer’s disease (or other inflammatory-mediated cognitive impairments) in aged menopausal women, without also conferring detrimental side effects, remains to be examined.
As mentioned previously, fever is an important, beneficial, and adaptive physiological response to immune challenges and stressors, with important implications for mortality and cognition. Early work (Wachulec et al., 1997) showed that a peripheral LPS injection produced a significant increase in core body temperature in both male and female young adult rats. This response was significantly blunted in aged rats, with no sex differences evident in either age group. It should be noted that body temperatures were measured for only 8 hr, and estrogen levels were not depleted in the females to mimic aging-associated menopause (Wachulec et al., 1997). Follow-up studies demonstrated that central administration of prostaglandin or IL-1β produced comparable increases in core body temperatures in young and old rats, suggesting that the brain’s ability to generate fever is not impaired, but perhaps peripheral fever-causing signals to the brain are weakened (Plata-Salaman et al., 1998; Satinoff et al., 1999). A more recent study, with an extended measurement window, demonstrated a similar pattern of results during the first 24 hr following an E. coli infection (i.e., a hyperthermic response in young adults, and a hypothermic response in aged). Body temperature measurements extending beyond the first day however, revealed a striking hyperthermic response in aged rats that was both higher in magnitude and much longer in duration than that of young adult rats (Barrientos et al., 2009). Unfortunately, this study was conducted only in males, so these extended responses remain to be examined in aged females. Given that fever is mediated by activated microglia, and estrogen-depleted aged females show greater basal glial-activation markers and a greater proinflammatory response in the brain, it would not be too surprising to find that the fever response was also exaggerated in aged females.
In summary, despite the fact that for decades aging women have exhibited a greater susceptibility to cognitive impairments than men, our understanding of the neurobiological underpinnings of this disparity has been inadequate. Recent, albeit limited, preclinical research has demonstrated that the combination of advanced age and depletion of circulating estrogen levels plays a prominent role in exacerbating the neuroinflammatory milieu in the female brain. This research has advanced our understanding of important factors that contribute to this phenotype (e.g., age at time of menopause onset, time since menopause onset, and rhythmicity of estrogen). An exacerbated neuroinflammatory phenotype presumably drives cognitive decline, as has been shown in males, but whether this occurs in a similar manner to that seen in males remains to be investigated. Female-specific aging research is necessary to determine if the neuroinflammatory phenotype is restricted to the hippocampus, or if it is more widespread thus impacting other types of cognitive function (e.g., executive function). Furthermore, the magnitude, duration, and rate of cognitive decline also need to be fully characterized in these models.
1.7. Conclusions
Of the approximately 7.6 billion humans alive in the world at the time of writing, around 3.8 billion (give or take a few million) are female (Orzack et al., 2015). In addition, most of the world’s adult mammalian livestock and all of our egg-producing livestock are female. Yet female-only studies accounted for 20% or fewer of the papers published in 2009 in all life-sciences-related fields except reproduction (Beery and Zucker, 2011). This blinkered approach to research has resulted in a fundamental limitation in our understanding of the female brain with problematic health and economic consequences. Of a sample of 10 drugs withdrawn from the US pharmaceutical market between 1997 and 2001, 8 had greater adverse health effects in females due to pharmacodynamic or usage differences between males and females (Liu and Mager, 2016).
Specific female-centered research is essential now for answering several important challenges such as we have discussed here. Female-specific resilience and vulnerability to early life immune challenges means that it is now important to identify the meaning of quantitative and qualitative changes in gene expression after such challenges. This understanding could lead to new tools to mimic mechanisms by which females are sometimes relatively protected. Focused study on the importance of sex hormones in neuroimmune function is now needed for personalised pharmaceutical treatments, potentially advancing our capacity to tailor drug doses and delivery systems to accommodate sex hormone fluctuations. Moreover, females often spend decades taking hormonal contraception, and the impact of such chronic pharmaceutical hormone exposure could dramatically impact neuroimmune function in ways that have not been carefully considered in the context of individual differences in risk and resilience or the response to other pharmaceutical treatments or subsequent life events. Further understanding of a woman’s adaptive neuroimmune responses to pregnancy is needed for the prevention of pre-term birth by strategically enhancing these. Likewise, enhancing our understanding of the impact of neuroimmunological adaptations in pregnancy and post-partum on mood is important for strategies to prevent and treat pregnancy-related mood disorders. In the study of female-specific cancer effects on the brain, attention and systematic modelling of a more clinically-relevant physiological environment is imperative. For example, most breast cancer patients are post-menopausal and middle aged, whereas most neurobiological work in this field is performed in young adult rodents with functioning ovaries (i.e., higher circulating estrogens). In addition, basic research to address the strong potential for exposure to estrogen modulator treatments, which are commonly administered for 5-10+ years to estrogen-responsive cancer patients, to impact cognition and mood is long overdue. Much can also be gained regarding how estrogen modulates behavioral comorbidities in this context by reporting menopausal status, or better yet, circulating estrogen concentrations in the clinical research in this field. Aged females are at greatest risk for developing Alzheimer’s disease and other dementias. Neuroinflammation is widely regarded as playing a role in these diseases and, as we have reviewed, estrogen depletion in the context of aging exacerbates neuroinflammatory responses. A critical question in the aging literature that remains unanswered is whether early neuroinflammation triggers important neural changes that initiate neurodegenerative disease, or if other early disease modifications cause neuroinflammation, which in turn accelerate disease progression. Understanding prodromal modifications in the aged female brain will undoubtedly lead to exciting discoveries and more effective targets for treatments of Alzheimer’s disease.
Studying the female brain may pose some additional challenges; those associated with hormonal cycles and behavioral variability, yet to a scientific community capable of developing such magnificent technological leaps as the human genome project, Brainbow, and optogenetics, these challenges should not be insurmountable. Understanding something as dynamic, vulnerable, and resilient as the female brain presents one of the next great frontiers for future scientific endeavors.
Highlights.
Female brains are highly dynamic, remodelling throughout the normal ovarian cycle
They also demonstrate unique changes across various life stages
Females uniquely respond to early life challenges, pregnancy, disease and old-age
The female brain is under-researched but the field is, encouragingly, growing.
Acknowledgements:
This work was supported by grants from the National Institute on Aging, USA (RO1AG028271 and R21AG058109) to RMB; the Biotechnology and Biological Sciences Research Council, UK to PJB; the National Institute of Mental Health (R21MH105826) and NARSAD Young Investigator, USA Award to KML; the National Institute of Cancer, USA (R01CA216290 and R21AG058109) to LMP; and a National Health and Medical Research Count Career Development Fellowship II, Australia (APP1128646) to SJS. Graphic illustration funded by The Ohio State University Neurological Research Institute.
Footnotes
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