Hormonal contraceptives in adolescence impact the neuroimmune environment of the medial prefrontal cortex and hippocampus in female rats.

Adolescence is a period of protracted neurodevelopment, during which the prefrontal cortex (PFC) undergoes significant remodeling. Microglia are integral to neurodevelopment and are sensitive to gonadal hormones, which increase during adolescence. Microglia and gonadal hormones can interact to influence adolescent development of the PFC (or medial prefrontal cortex [mPFC] in rodents).

Peripartum buprenorphine and oxycodone exposure impair maternal behavior and increase neuroinflammation in new mother rats.

7 % of pregnant people use opioids. Opioid use during pregnancy can negatively impact maternal and offspring health. Medications for opioid use disorder (MOUD), commonly buprenorphine, are the recommended treatment for opioid use disorder during pregnancy to prevent cycles of withdrawal and relapse.

Developmental functions of microglia: Impact of psychosocial and physiological early life stress.

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.

Prenatal allergic inflammation in rats confers sex-specific alterations to oxytocin and vasopressin innervation in social brain regions.

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.

Sex Differences in Neurodevelopmental Disorders: A Key Role for the Immune System.

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.

Prenatal allergic inflammation in rats programs the developmental trajectory of dendritic spine patterning in brain regions associated with cognitive and social behavior.

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.

Immune System Alterations and Postpartum Mental Illness: Evidence From Basic and Clinical Research.

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.

Maternal allergic inflammation in rats impacts the offspring perinatal neuroimmune milieu and the development of social play, locomotor behavior, and cognitive flexibility.

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.

Microglia Regulate Cell Genesis in a Sex-dependent Manner in the Neonatal Hippocampus.

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.

Sex differences in the effects of early life stress exposure on mast cells in the developing rat brain.

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.

Prenatal Allergen Exposure Perturbs Sexual Differentiation and Programs Lifelong Changes in Adult Social and Sexual Behavior.

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.

Small cells with big implications: Microglia and sex differences in brain development, plasticity and behavioral health.

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.

Mast Cells in the Developing Brain Determine Adult Sexual Behavior.

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.

Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function.

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.

Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain.

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.

Sex differences in microglial phagocytosis in the neonatal hippocampus.

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.

The immune system as a novel regulator of sex differences in brain and behavioral development.

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.

Microglia depletion in early life programs persistent changes in social, mood-related, and locomotor behavior in male and female rats.

Microglia, the innate immune cells of the central nervous system, regulate brain development by promoting cell genesis, pruning synapses, and removing dying, newly-born or progenitor cells. However, the role of microglia in the early life programming of behavior under normal conditions is not well characterized. We used central infusion of liposomal clodronate to selectively deplete microglia from the neonatal rat brain and subsequently assessed the impact of microglial depletion on programming of juvenile and adult motivated behaviors.

Brain feminization requires active repression of masculinization via DNA methylation.

The developing mammalian brain is destined for a female phenotype unless exposed to gonadal hormones during a perinatal sensitive period. It has been assumed that the undifferentiated brain is masculinized by direct induction of transcription by ligand-activated nuclear steroid receptors. We found that a primary effect of gonadal steroids in the highly sexually dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression.

A starring role for microglia in brain sex differences.

Microglia, the resident innate immune cells in the brain, have long been understood to be crucial to maintenance in the nervous system, by clearing debris, monitoring for infiltration of infectious agents, and mediating the brain's inflammatory and repair response to traumatic injury, stroke, or neurodegeneration. A wave of new research has shown that microglia are also active players in many basic processes in the healthy brain, including cell proliferation, synaptic connectivity, and physiology. Microglia, both in their capacity as phagocytic cells and via secretion of many neuroactive molecules, including cytokines and growth factors, play a central role in early brain development, including sexual differentiation of the brain.

Microglia are essential to masculinization of brain and behavior.

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.

Sexual differentiation of the rodent brain: dogma and beyond.

Steroid hormones of gonadal origin act on the neonatal brain to produce sex differences that underlie adult reproductive physiology and behavior. Neuronal sex differences occur on a variety of levels, including differences in regional volume and/or cell number, morphology, physiology, molecular signaling, and gene expression. In the rodent, many of these sex differences are determined by steroid hormones, particularly estradiol, and are established by diverse downstream effects.