RESUMEN
Prenatal exposure to inflammation via maternal infection, allergy, or autoimmunity increases one's risk for developing neurodevelopmental and psychiatric disorders. Many of these disorders are associated with altered social behavior, yet the mechanisms underlying inflammation-induced social impairment remain unknown. We previously found that a rat model of acute allergic maternal immune activation (MIA) produced deficits like those found in MIA-linked disorders, including impairments in juvenile social play behavior. The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) regulate social behavior, including juvenile social play, across mammalian species. OT and AVP are also implicated in neuropsychiatric disorders characterized by social impairment, making them good candidate regulators of social deficits after MIA. We profiled how acute prenatal exposure to allergic MIA changed OT and AVP innervation in several brain regions important for social behavior in juvenile male and female rat offspring. We also assessed whether MIA altered additional behavioral phenotypes related to sociality and anxiety. We found that allergic MIA increased OT and AVP fiber immunoreactivity in the medial amygdala and had sex-specific effects in the nucleus accumbens, bed nucleus of the stria terminalis, and lateral hypothalamic area. We also found that MIA reduced ultrasonic vocalizations in neonates and increased the stereotypical nature of self-grooming behavior. Overall, these findings suggest that there may be sex-specific mechanisms underlying MIA-induced behavioral impairment and underscore OT and AVP as ideal candidates for future mechanistic studies.
Asunto(s)
Oxitocina , Efectos Tardíos de la Exposición Prenatal , Humanos , Ratas , Masculino , Femenino , Animales , Vasopresinas/metabolismo , Conducta Social , Encéfalo/metabolismo , Arginina Vasopresina/metabolismo , Receptores de Oxitocina/metabolismo , Mamíferos/metabolismoRESUMEN
The study of sex differences in the brain is a topic of neuroscientific study that has broad reaching implications for culture, society and biomedical science. Recent research in rodent models has led to dramatic shifts in our views of the mechanisms underlying the sexual differentiation of the brain. These include the surprising discoveries of a role for immune cells and inflammatory mediators in brain masculinization and a role for epigenetic suppression in brain feminization. How and to what degree these findings will translate to human brain development will be questions of central importance in future research in this field.
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Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Epigénesis Genética/fisiología , Sistema Inmunológico/fisiología , Mediadores de Inflamación/fisiología , Caracteres Sexuales , Diferenciación Sexual/fisiología , Animales , HumanosRESUMEN
Allergic inflammation during pregnancy increases risk for a diagnosis of neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) in the offspring. Previously, we found a model of such inflammation, allergy-induced maternal immune activation (MIA), produced symptoms analogous to those associated with neurodevelopmental disorders in rats, including reduced juvenile play behavior, hyperactivity, and cognitive inflexibility. These behaviors were preceded by perinatal changes in microglia colonization and phenotype in multiple relevant brain regions. Given the role that microglia play in synaptic patterning as well as evidence for altered synaptic architecture in neurodevelopmental disorders, we investigated whether allergic MIA altered the dynamics of dendritic spine patterning throughout key regions of the rat forebrain across neurodevelopment. Adult virgin female rats were sensitized to the allergen, ovalbumin, with alum adjuvant, bred, and allergically challenged on gestational day 15. Brain tissue was collected from male and female offspring on postnatal days (P) 5, 15, 30, and 100-120 and processed for Golgi-Cox staining. Mean dendritic spine density was calculated for neurons in brain regions associated with cognition and social behavior, including the medial prefrontal cortex (mPFC), basal ganglia, septum, nucleus accumbens (NAc), and amygdala. Allergic MIA reduced dendritic spine density in the neonatal (P5) and juvenile (P15) mPFC, but these mPFC spine deficits were normalized by P30. Allergic inflammation reduced spine density in the septum of juvenile (P30) rats, with an interaction suggesting increased density in males and reduced density in females. MIA-induced reductions in spine density were also found in the female basal ganglia at P15, as well as in the NAc at P30. Conversely, MIA-induced increases were found in the NAc in adulthood. While amygdala dendritic spine density was generally unaffected throughout development, MIA reduced density in both medial and basolateral subregions in adult offspring. Correlational analyses revealed disruption to amygdala-related networks in the neonatal animals and cortico-striatal related networks in juvenile and adult animals in a sex-specific manner. Collectively, these data suggest that communication within and between these cognitive and social brain regions may be altered dynamically throughout development after prenatal exposure to allergic inflammation. They also provide a basis for future intervention studies targeted at rescuing spine and behavior changes via immunomodulatory treatments.
Asunto(s)
Trastorno del Espectro Autista , Hipersensibilidad , Efectos Tardíos de la Exposición Prenatal , Animales , Animales Recién Nacidos , Encéfalo , Cognición , Espinas Dendríticas , Femenino , Inflamación , Masculino , Corteza Prefrontal , Embarazo , Ratas , Conducta SocialRESUMEN
Maternal systemic inflammation increases risk for neurodevelopmental disorders like autism, ADHD, and schizophrenia in offspring. Notably, these disorders are male-biased. Studies have implicated immune system dysfunction in the etiology of these disorders, and rodent models of maternal immune activation provide useful tools to examine mechanisms of sex-dependent effects on brain development, immunity, and behavior. Here, we employed an allergen-induced model of maternal inflammation in rats to characterize levels of mast cells and microglia in the perinatal period in male and female offspring, as well as social, emotional, and cognitive behaviors throughout the lifespan. Adult female rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally on gestational day 15 of pregnancy with OVA or saline. Allergic inflammation upregulated microglia in the fetal brain, increased mast cell number in the hippocampus on the day of birth, and conferred region-, time- and sex- specific changes in microglia measures. Additionally, offspring of OVA-exposed mothers subsequently exhibited abnormal social behavior, hyperlocomotion, and reduced cognitive flexibility. These data demonstrate the long-term effects of maternal allergic challenge on offspring development and provide a basis for understanding neurodevelopmental disorders linked to maternal systemic inflammation in humans.
Asunto(s)
Efectos Tardíos de la Exposición Prenatal , Animales , Cognición , Femenino , Sistema Inmunológico , Inflamación , Masculino , Ovalbúmina , Embarazo , Ratas , Conducta SocialRESUMEN
Many sex differences in brain and behavior are programmed during development by gonadal hormones, but the cellular mechanisms are incompletely understood. We found that immune-system-derived mast cells are a primary target for the masculinizing hormone estradiol and that mast cells are in turn primary mediators of brain sexual differentiation. Newborn male rats had greater numbers and more activated mast cells in the preoptic area (POA), a brain region essential for male copulatory behavior, than female littermates during the critical period for sexual differentiation. Inhibiting mast cells with a stabilizing agent blunted the masculinization of both POA neuronal and microglial morphology and adult sex behavior, whereas activating mast cells in females, even though fewer in number, induced masculinization. Treatment of newborn females with a masculinizing dose of estradiol increased mast cell number and induced mast cells to release histamine, which then stimulated microglia to release prostaglandins and thereby induced male-typical synaptic patterning. These findings identify a novel non-neuronal origin of brain sex differences and resulting motivated behaviors.SIGNIFICANCE STATEMENT We found that immune-system-derived mast cells are a primary target for the masculinizing hormone estradiol and that mast cells are in turn primary mediators of brain sexual differentiation. These findings identify a novel non-neuronal origin of brain sex differences and resulting motivated behaviors.
Asunto(s)
Estradiol/farmacología , Mastocitos/fisiología , Área Preóptica/fisiología , Caracteres Sexuales , Diferenciación Sexual/fisiología , Conducta Sexual Animal/fisiología , Animales , Recuento de Células , Forma de la Célula/efectos de los fármacos , Forma de la Célula/fisiología , Femenino , Cetotifen/farmacología , Masculino , Mastocitos/citología , Mastocitos/efectos de los fármacos , Microglía/citología , Microglía/efectos de los fármacos , Microglía/fisiología , Área Preóptica/citología , Área Preóptica/efectos de los fármacos , Ratas , Diferenciación Sexual/efectos de los fármacos , Conducta Sexual Animal/efectos de los fármacosRESUMEN
Early life stress leads to long lasting effects on behavior. Neuroimmune cells have been implicated as key mediators of experience-induced changes in brain and behavioral development, in that they are highly responsive to stress. Mast cells are one such type of neuroimmune cell, but little is known about their role in brain development or following early life stress. Here, we assessed the impact of three different early life stress exposure paradigms on mast cell dynamics in the developing brain of male and female rats, focusing on the hippocampus and hypothalamus, where most mast cells reside. We found that exposure to two weeks of chronic variable stress during gestation led to increased mast cell number and activation in the female offspring hypothalamus on the day of birth. Acute exposure to maternal separation stress on postnatal day (PN) 2 led to significant decreases in mast cells within the hypothalamus and hippocampus of females, but not males. In contrast, one week of exposure to brief daily maternal separation stress (e.g., handling), increased mast cell numbers in the female, but not male, hippocampus. We found significant sex differences in mast cell number and activation, including males having more mast cells than females in the hippocampus on the day of birth and males having significantly more degranulated mast cells on PN11. Thus, mast cells may be an unappreciated mediator of sex-specific brain development in response to early life perturbations.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Mastocitos/patología , Privación Materna , Estrés Psicológico , Animales , Animales Recién Nacidos , Encéfalo/inmunología , Encéfalo/metabolismo , Recuento de Células , Femenino , Hipocampo/crecimiento & desarrollo , Hipocampo/inmunología , Hipocampo/patología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/inmunología , Hipotálamo/patología , Masculino , Neuroinmunomodulación/fisiología , Ratas , Ratas Sprague-Dawley , Caracteres Sexuales , Estrés Psicológico/inmunología , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
Sexual differentiation of the brain occurs early in life as a result of sex-typical hormone action and sex chromosome effects. Immunocompetent cells are being recognized as underappreciated regulators of sex differences in brain and behavioral development, including microglia, astrocytes, and possibly other less well studied cell types, including T cells and mast cells. Immunocompetent cells in the brain are responsive to steroid hormones, but their role in sex-specific brain development is an emerging field of interest. This Review presents a summary of what is currently known about sex differences in the number, morphology, and signaling profile of immune cells in the developing brain and their role in the early-life programming of sex differences in brain and behavior. We review what is currently known about sex differences in the response to early-life perturbations, including stress, inflammation, diet, and environmental pollutants. We also discuss how and why understanding sex differences in the developing neuroimmune environment may provide insight into understanding the etiology of several neurodevelopmental disorders. This Review also highlights what remains to be discovered in this emerging field of developmental neuroimmunology and underscores the importance of filling in these knowledge gaps. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Encéfalo/fisiología , Sistema Inmunológico/fisiología , Caracteres Sexuales , Diferenciación Sexual , Animales , Encéfalo/citología , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/crecimiento & desarrollo , Neuroglía/fisiologíaRESUMEN
Microglia regulate brain development through many processes, such as promoting neurogenesis, supporting cell survival, and phagocytizing progenitor, newly-born, and dying cells. Many of these same developmental processes show robust sex differences, yet very few studies have assessed sex differences in microglia function during development. Hormonally-induced sexual differentiation of the brain occurs during the perinatal period, thus we examined sex differences in microglial morphology, phagocytosis, and proliferation in the hippocampus during the early postnatal period. We found that the neonatal female hippocampus had significantly more microglia with phagocytic cups than the male hippocampus. We subsequently found that female microglia phagocytized more neural progenitor cells and healthy cells compared to males, but there were no sex differences in the number of newly-born or dying cells targeted by microglial phagocytosis. We found that the number of phagocytic microglia in females was reduced to male-typical levels by treatment with estradiol, the hormone responsible for masculinizing the rodent brain. Females also had higher expression of several phagocytic pathway genes in the hippocampus compared to males. In contrast to robust sex differences in phagocytic microglia, we found no sex differences in the number of microglia with amoeboid, transitioning, or ramified morphologies or differences in three-dimensional reconstructions of microglial morphology. While we did not find a baseline sex difference in microglial proliferation during or following the prenatal gonadal hormone surge in males, we found that estradiol treatment increased microglia proliferation in females. Overall, these data show that there are important sex differences in microglia function in the hippocampus during the early neonatal period.
Asunto(s)
Hipocampo/fisiología , Microglía/fisiología , Fagocitosis , Caracteres Sexuales , Animales , Animales Recién Nacidos , Proliferación Celular , Femenino , Expresión Génica , Hipocampo/citología , Hipocampo/metabolismo , Masculino , Microglía/citología , Microglía/metabolismo , Ratas Sprague-DawleyRESUMEN
During pregnancy and the postpartum period, the adult female brain is remarkably plastic exhibiting modifications of neurons, astrocytes and oligodendrocytes. However, little is known about how microglia, the brain's innate immune cells, are altered during this time. In the current studies, microglial density, number and morphological phenotype were analyzed within multiple regions of the maternal brain that are known to show neural plasticity during the peripartum period and/or regulate peripartum behavioral changes. Our results show a significant reduction in microglial density during late pregnancy and the early-mid postpartum period in the basolateral amygdala, medial prefrontal cortex, nucleus accumbens shell and dorsal hippocampus. In addition, microglia numbers were reduced postpartum in all four brain regions, and these reductions occurred primarily in microglia with a thin, ramified morphology. Across the various measures, microglia in the motor cortex were unaffected by reproductive status. The peripartum decrease in microglia may be a consequence of reduced proliferation as there were fewer numbers of proliferating microglia, and no changes in apoptotic microglia, in the postpartum hippocampus. Finally, hippocampal concentrations of the cytokines interleukin (IL)-6 and IL-10 were increased postpartum. Together, these data point to a shift in the maternal neuroimmune environment during the peripartum period that could contribute to neural and behavioral plasticity occurring during the transition to motherhood.
Asunto(s)
Periodo Posparto/inmunología , Preñez/inmunología , Animales , Apoptosis , Encéfalo/citología , Encéfalo/inmunología , Química Encefálica , Proteínas de Unión al Calcio/biosíntesis , Proteínas de Unión al Calcio/genética , Recuento de Células , Proliferación Celular , Citocinas/metabolismo , Femenino , Inmunohistoquímica , Interleucina-10/biosíntesis , Interleucina-10/genética , Interleucina-6/biosíntesis , Interleucina-6/genética , Proteínas de Microfilamentos/biosíntesis , Proteínas de Microfilamentos/genética , Microglía/inmunología , Embarazo , Psiconeuroinmunología , Ratas , Ratas Sprague-DawleyRESUMEN
Brain sexual differentiation in rodents results from the perinatal testicular androgen surge. In the preoptic area (POA), estradiol aromatized from testosterone upregulates the production of the proinflammatory molecule, prostaglandin E(2) (PGE(2)) to produce sex-specific brain development. PGE(2) produces a two-fold greater density of dendritic spines in males than in females and masculinizes adult copulatory behavior. One neonatal dose of PGE(2) masculinizes the POA and behavior, and simultaneous treatment with an inhibitor of additional prostaglandin synthesis prevents this masculinization, indicating a positive feedforward process that leads to sustained increases in PGE(2). The mechanisms underlying this feedforward process were unknown. Microglia, the primary immunocompetent cells in the brain, are active neonatally, contribute to normal brain development, and both produce and respond to prostaglandins. We investigated whether there are sex differences in microglia in the POA and whether they influence developmental masculinization. Neonatal males had twice as many ameboid microglia as females and a more activated morphological profile, and both estradiol and PGE(2) masculinized microglial number and morphology in females. Microglial inhibition during the critical period for sexual differentiation prevented sex differences in microglia, estradiol-induced masculinization of dendritic spine density, and adult copulatory behavior. Microglial inhibition also prevented the estradiol-induced upregulation of PGE(2), indicating that microglia are essential to the feedforward process through which estradiol upregulates prostaglandin production. These studies demonstrate that immune cells in the brain interact with the nervous and endocrine systems during development, and are crucial for sexual differentiation of brain and behavior.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/citología , Encéfalo/fisiología , Microglía/fisiología , Diferenciación Sexual/fisiología , Animales , Western Blotting , Química Encefálica/fisiología , Recuento de Células , Células Cultivadas , Espinas Dendríticas/fisiología , Dinoprostona/metabolismo , Dinoprostona/fisiología , Estradiol/farmacología , Estradiol/fisiología , Femenino , Técnica del Anticuerpo Fluorescente , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Masculino , Minociclina/farmacología , Proteínas del Tejido Nervioso/biosíntesis , Área Preóptica/crecimiento & desarrollo , Área Preóptica/metabolismo , Área Preóptica/fisiología , Ratas , Conducta Sexual Animal/fisiología , Maduración SexualRESUMEN
Microglia play numerous important roles in brain development. From early embryonic stages through adolescence, these immune cells influence neuronal genesis and maturation, guide connectivity, and shape brain circuits. They also interact with other glial cells and structures, influencing the brain's supportive microenvironment. While this central role makes microglia essential, it means that early life perturbations to microglia can have widespread effects on brain development, potentially resulting in long-lasting behavioral impairments. Here, we will focus on the effects of early life psychosocial versus physiological stressors in rodent models. Psychosocial stress refers to perceived threats that lead to stress axes activation, including prenatal stress, or chronic postnatal stress, including maternal separation and resource scarcity. Physiological stress refers to physical threats, including maternal immune activation, postnatal infection, and traumatic brain injury. Differing sources of early life stress have varied impacts on microglia, and these effects are moderated by factors such as developmental age, brain region, and sex. Overall, these stressors appear to either 1) upregulate basal microglia numbers and activity throughout the lifespan, while possibly blunting their responsivity to subsequent stressors, or 2) shift the developmental curve of microglia, resulting in differential timing and function, impacting the critical periods they govern. Either could contribute to behavioral dysfunctions that occur after the resolution of early life stress. Exploring how different stressors impact microglia, as well as how multiple stressors interact to alter microglia's developmental functions, could deepen our understanding of how early life stress changes the brain's developmental trajectory. This article is part of the Special Issue on "Microglia".
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Encéfalo , Microglía , Estrés Fisiológico , Estrés Psicológico , Animales , Estrés Fisiológico/fisiología , Humanos , Encéfalo/crecimiento & desarrollo , Femenino , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatologíaRESUMEN
Sex differences are prominent defining features of neurodevelopmental disorders. Understanding the sex biases in these disorders can shed light on mechanisms leading to relative risk and resilience for the disorders, as well as more broadly advance our understanding of how sex differences may relate to brain development. The prevalence of neurodevelopmental disorders is increasing, and the two most common neurodevelopmental disorders, Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) exhibit male-biases in prevalence rates and sex differences in symptomology. While the causes of neurodevelopmental disorders and their sex differences remain to be fully understood, increasing evidence suggests that the immune system plays a critical role in shaping development. In this chapter we discuss sex differences in prevalence and symptomology of ASD and ADHD, review sexual differentiation and immune regulation of neurodevelopment, and discuss findings from human and rodent studies of immune dysregulation and perinatal immune perturbation as they relate to potential mechanisms underlying neurodevelopmental disorders. This chapter will give an overview of how understanding sex differences in neuroimmune function in the context of neurodevelopmental disorders could lend insight into their etiologies and better treatment strategies.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastornos del Neurodesarrollo , Embarazo , Masculino , Humanos , Femenino , Caracteres Sexuales , Trastornos del Neurodesarrollo/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Sistema InmunológicoRESUMEN
The peripartum period is accompanied by peripheral immune alterations to promote a successful pregnancy. We and others have also demonstrated significant neuroimmune changes that emerge during late pregnancy and persist postpartum, most prominently decreased microglia numbers within limbic brain regions. Here we hypothesized that microglial downregulation is important for the onset and display of maternal behavior. To test this, we recapitulated the peripartum neuroimmune profile by depleting microglia in non-mother (i.e., nulliparous) female rats who are typically not maternal but can be induced to behave maternally towards foster pups after repeated exposure, a process called maternal sensitization. BLZ945, a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, was administered systemically to nulliparous rats, which led to ~75% decrease in microglia number. BLZ- and vehicle-treated females then underwent maternal sensitization and tissue was stained for ∆fosB to examine activation across maternally relevant brain regions. We found BLZ-treated females with microglial depletion met criteria for displaying maternal behavior significantly sooner than vehicle-treated females and displayed increased pup-directed behaviors. Microglia depletion also reduced threat appraisal behavior in an open field test. Notably, nulliparous females with microglial depletion had decreased numbers of ∆fosB+ cells in the medial amygdala and periaqueductal gray, and increased numbers in the prefrontal cortex and somatosensory cortex, compared to vehicle. Our results demonstrate that microglia regulate maternal behavior in adult females, possibly by shifting patterns of activity in the maternal brain network.
Asunto(s)
Encéfalo , Microglía , Ratas , Animales , Embarazo , Femenino , Humanos , Ratas Sprague-Dawley , Corteza Prefrontal , Conducta Materna/fisiologíaRESUMEN
The postpartum period is a time associated with high rates of depression and anxiety as well as greater risk for psychosis in some women. A growing number of studies point to aberrations in immune system function as contributing to postpartum mental illness. Here we review evidence from both clinical and animal models suggesting an immune component to postpartum depression, postpartum anxiety, and postpartum psychosis. Thus far, clinical data primarily highlights changes in peripheral cytokine signaling in disease etiology, while animal models have begun to provide insight into the immune environment of the maternal brain and how central inflammation may also be contributing to postpartum mental illnesses. Further research investigating peripheral and central immune function, along with neural and endocrine interactions, will be important in successfully developing novel prevention and treatment strategies for these serious disorders that impact a large portion of new mothers.
RESUMEN
Microglia, the innate immune cells of the brain, regulate brain development through many processes such as synaptic pruning, supporting cell genesis and phagocytosing living and dying cells. There are sex differences in these same developmental processes throughout the brain, thus microglia may contribute to brain sex differences. We examined whether microglia support a known sex difference in neonatal hippocampal neurogenesis and whether juvenile hippocampal neurogenesis was impacted by the loss of neonatal microglia. We used central infusion of liposomal clodronate to selectively deplete microglia and found decreased cell genesis in the male, but not female, dentate gyrus and hippocampus. We found that loss of microglia decreased cell genesis in the cortex and amygdala of both males and females. We assessed the expression of several cytokines and growth factors that have previously been shown to support cell genesis. We found that expression of Il1b and Tnf were decreased in the hippocampus due to microglia depletion however, there were no sex differences in the expression of any immune genes. In adolescence, there was an increase in the number of mitotic cells in the subgranular zone of the dentate gyrus of previously microglia depleted rats however, the number of newly-born neurons was unchanged in the adolescent animals. We also sought to determine whether there was a sex difference in the number of progenitor cells in the dentate gyrus in the neonatal period. We found no sex differences in the number of progenitor cells. Overall, these studies show that microglia are important for regulating region-specific sex differences in cell genesis in the developing brain.
Asunto(s)
Hipocampo , Microglía , Animales , Giro Dentado , Femenino , Masculino , Neurogénesis , Neuronas , Ratas , Caracteres SexualesRESUMEN
Steroid hormones of gonadal origin act on the neonatal brain, particularly the hypothalamus, to produce sex differences that underlie copulatory behavior. Neuroanatomical sex differences include regional volume, cell number, connectivity, morphology, physiology, neurotransmitter phenotype and molecular signaling, all of which are determined by the action of steroid hormones, particularly by estradiol in males, and are established by diverse downstream effects. Sex differences in distinct hypothalamic regions can be organized by the same steroid hormone, but the direction of a sex difference is often specific to one region or cell type, illustrating the wide range of effects that steroid hormones have on the developing brain. Substantial progress has been made in elucidating the downstream mechanisms through which gonadal hormones sexually differentiate the brain, but gaps remain in establishing the precise relationship between changes in neuronal morphology and behavior. A complete understanding of sexual differentiation will require integrating the diverse mechanisms across multiple brain regions into a functional network that regulates behavioral output.
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Hormonas Esteroides Gonadales/metabolismo , Hipotálamo/crecimiento & desarrollo , Conducta Sexual Animal/fisiología , Animales , Encéfalo/anatomía & histología , Encéfalo/fisiología , Femenino , Hormonas Esteroides Gonadales/química , Hipotálamo/metabolismo , Masculino , Caracteres Sexuales , Diferenciación Sexual/fisiologíaRESUMEN
Maternal licking in rats affects the development of the spinal nucleus of the bulbocavernosus (SNB), a sexually dimorphic motor nucleus that controls penile reflexes involved with copulation. Reduced maternal licking results in decreased motoneuron number, size, and dendritic length in the adult SNB, as well as deficits in adult male copulatory behavior. Our previous findings that licking-like tactile stimulation influences SNB dendritic development and upregulates Fos expression in the lumbosacral spinal cord suggest that afferent signaling is changed by differences in maternal stimulation. Oxytocin afferents from the hypothalamus are a possible candidate, given previous research that has shown oxytocin is released following sensory stimulation, oxytocin modulates excitability in the spinal cord, and is a pro-erectile modulator of male sex behavior. In this experiment, we used immunofluorescence and immediate early gene analysis to assess whether licking-like tactile stimulation of the perineum activated parvocellular oxytocinergic neurons in the hypothalamus in neonates. We also used enzyme immunoassay to determine whether this same stroking stimulation produced an increase in spinal oxytocin levels. We found that stroking increased Fos immunolabeling in small oxytocin-positive cells in the paraventricular nucleus of the hypothalamus, in comparison to unstroked or handled control pups. In addition, 60s of licking-like perineal stimulation produced a transient 89% increase in oxytocin levels in the lumbosacral spinal cord. Together, these results suggest that oxytocin afferent activity may contribute to the effects of early maternal care on the masculinization of the SNB and resultant male copulatory behavior.
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Conducta Materna/fisiología , Neuronas Motoras/fisiología , Oxitocina/fisiología , Caracteres Sexuales , Desarrollo Sexual/fisiología , Médula Espinal/metabolismo , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Copulación/fisiología , Femenino , Masculino , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/metabolismo , Proteínas Oncogénicas v-fos/metabolismo , Oxitocina/análisis , Oxitocina/metabolismo , Oxitocina/farmacología , Ratas , Ratas Sprague-Dawley , Conducta Sexual Animal/efectos de los fármacos , Conducta Sexual Animal/fisiología , Desarrollo Sexual/efectos de los fármacos , Médula Espinal/fisiologíaRESUMEN
Brain sex differences are programmed largely by sex hormone secretions and direct sex chromosome effects in early life, and are subsequently modulated by early life experiences. The brain's resident immune cells, called microglia, actively contribute to brain development. Recent research has shown that microglia are sexually dimorphic, especially during early life, and may participate in sex-specific organization of the brain and behavior. Likewise, sex differences in immune cells and their signaling in the adult brain have been found, although in most cases their function remains unclear. Additionally, immune cells and their signaling have been implicated in many disorders in which brain development or plasticity is altered, including autism, schizophrenia, pain disorders, major depression, and postpartum depression. This review summarizes what is currently known about sex differences in neuroimmune function in development and during other major phases of brain plasticity, as well as the current state of knowledge regarding sex-specific neuroimmune function in psychiatric disorders.
Asunto(s)
Encéfalo/inmunología , Microglía , Neuroinmunomodulación/inmunología , Caracteres Sexuales , Animales , Encéfalo/crecimiento & desarrollo , Femenino , Humanos , Masculino , Trastornos Mentales/inmunología , Plasticidad NeuronalRESUMEN
Sexual differentiation is the early life process by which the brain is prepared for male or female typical behaviors, and is directed by sex chromosomes, hormones and early life experiences. We have recently found that innate immune cells residing in the brain, including microglia and mast cells, are more numerous in the male than female rat brain. Neuroimmune cells are also key participants in the sexual differentiation process, specifically organizing the synaptic development of the preoptic area and leading to male-typical sexual behavior in adulthood. Mast cells are known for their roles in allergic responses, thus in this study we sought to determine if exposure to an allergic response of the pregnant female in utero would alter the sexual differentiation of the preoptic area of offspring and resulting sociosexual behavior in later life. Pregnant rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally with OVA on gestational day 15, which produced robust allergic inflammation, as measured by elevated immunoglobulin E. Offspring of these challenged mother rats were assessed relative to control rats in the early neonatal period for mast cell and microglia activation within their brains, downstream dendritic spine patterning on POA neurons, or grown to adulthood to assess behavior and dendritic spines. In utero exposure to allergic inflammation increased mast cell and microglia activation in the neonatal brain, and led to masculinization of dendritic spine density in the female POA. In adulthood, OVA-exposed females showed an increase in male-typical mounting behavior relative to control females. In contrast, OVA-exposed males showed evidence of dysmasculinization, including reduced microglia activation, reduced neonatal dendritic spine density, decreased male-typical copulatory behavior, and decreased olfactory preference for female-typical cues. Together these studies show that early life allergic events may contribute to natural variations in both male and female sexual behavior, potentially via underlying effects on brain-resident mast cells.
Asunto(s)
Alérgenos/inmunología , Neuroinmunomodulación/fisiología , Efectos Tardíos de la Exposición Prenatal/inmunología , Diferenciación Sexual/inmunología , Conducta Sexual Animal/fisiología , Animales , Técnicas de Observación Conductual , Señales (Psicología) , Espinas Dendríticas/inmunología , Espinas Dendríticas/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunidad Innata , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Masculino , Mastocitos/inmunología , Exposición Materna/efectos adversos , Microglía/inmunología , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/psicología , Área Preóptica/citología , Área Preóptica/inmunología , Área Preóptica/patología , Área Preóptica/fisiopatología , Ratas , Conducta SocialRESUMEN
Innate immune cells play a well-documented role in the etiology and disease course of many brain-based conditions, including multiple sclerosis, Alzheimer's disease, traumatic brain and spinal cord injury, and brain cancers. In contrast, it is only recently becoming clear that innate immune cells, primarily brain resident macrophages called microglia, are also key regulators of brain development. This review summarizes the current state of knowledge regarding microglia in brain development, with particular emphasis on how microglia during development are distinct from microglia later in life. We also summarize the effects of early life perturbations on microglia function in the developing brain, the role that biological sex plays in microglia function, and the potential role that microglia may play in developmental brain disorders. Finally, given how new the field of developmental neuroimmunology is, we highlight what has yet to be learned about how innate immune cells shape the development of brain and behavior.