115 results on '"Bilbo SD"'
Search Results
2. Microglial MyD88-dependent pathways are regulated in a sex-specific manner in the context of HMGB1-induced anxiety.
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Rawls A, Nyugen D, Dziabis J, Anbarci D, Clark M, Dzirasa K, and Bilbo SD
- Abstract
Chronic stress is a significant risk factor for the development and recurrence of anxiety disorders. Chronic stress impacts the immune system, causing microglial functional alterations in the medial prefrontal cortex (mPFC), a brain region involved in the pathogenesis of anxiety. High mobility group box 1 protein (HMGB1) is an established modulator of neuronal firing and a potent pro-inflammatory stimulus released from neuronal and non-neuronal cells following stress. HMGB1, in the context of stress, acts as a danger-associated molecular pattern (DAMP), instigating robust proinflammatory responses throughout the brain, so much so that localized drug delivery of HMGB1 alters behavior in the absence of any other forms of stress, i.e., social isolation, or behavioral stress models. Few studies have investigated the molecular mechanisms that underlie HMGB1-associated behavioral effects in a cell-specific manner. The aim of this study is to investigate cellular and molecular mechanisms underlying HMGB1-induced behavioral dysfunction with regard to cell-type specificity and potential sex differences. Here, we report that both male and female mice exhibited anxiety-like behavior following increased HMGB1 in the mPFC as well as changes in microglial morphology. Interestingly, our results demonstrate that HMGB1-induced anxiety may be mediated by distinct microglial MyD88-dependent mechanisms in females compared to males. This study supports the hypothesis that MyD88 signaling in microglia may be a crucial mediator of the stress response in adult female mice.
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- 2024
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3. Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity.
- Author
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Batorsky R, Ceasrine AM, Shook LL, Kislal S, Bordt EA, Devlin BA, Perlis RH, Slonim DK, Bilbo SD, and Edlow AG
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- Animals, Female, Pregnancy, Mice, Humans, Macrophages metabolism, Obesity, Maternal metabolism, Transcriptome genetics, Male, Placenta metabolism, Mice, Inbred C57BL, Diet, High-Fat adverse effects, Obesity pathology, Obesity metabolism, Microglia metabolism, Microglia pathology, Brain metabolism, Brain pathology, Fetus
- Abstract
Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide insights into fetal brain microglial programs and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders., Competing Interests: Declaration of interests A.G.E. serves as a consultant for Mirvie, Inc. outside of this work. A.G.E. receives research funding from Merck Pharmaceuticals outside of this work. R.H.P. is a founder and member of the scientific advisory board of Psy Therapeutics; a member of scientific advisory boards for Swan AI Studio, Belle Artificial Intelligence, Genomind, and Circular Genomics; and consults to Alkermes, Burrage Capital, and Vault Health. He serves as an associate editor for JAMA Network Open. All of these roles are outside the present work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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4. Neuron Derived Cytokine Interleukin-34 Controls Developmental Microglia Function.
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Devlin BA, Nguyen DM, Grullon G, Clark MJ, Ceasrine AM, Deja M, Shah A, Ati S, Finn A, Ribeiro D, Schaefer A, and Bilbo SD
- Abstract
Neuron-microglia interactions dictate the development of neuronal circuits in the brain. However, the factors that support and broadly regulate these processes across developmental stages are largely unknown. Here, we find that IL34, a neuron-derived cytokine, is upregulated in development and plays a critical role in supporting and maintaining neuroprotective, mature microglia in the anterior cingulate cortex (ACC) of mice. We show that IL34 mRNA and protein is upregulated in neurons in the second week of postnatal life and that this increase coincides with increases in microglia number and expression of mature, homeostatic markers, e.g., TMEM119. We also found that IL34 mRNA is higher in more active neurons, and higher in excitatory (compared to inhibitory) neurons. Genetic KO of IL34 prevents the functional maturation of microglia and results in an anxiolytic phenotype in these mice by adulthood. Acute, low dose blocking of IL34 at postnatal day (P)15 in mice decreased microglial TMEM119 expression and increased aberrant microglial phagocytosis of thalamocortical synapses within the ACC. In contrast, viral overexpression of IL34 early in life (P1-P8) caused early maturation of microglia and prevented microglial phagocytosis of thalamocortical synapses during the appropriate neurodevelopmental refinement window. Taken together, these findings establish IL34 as a key regulator of neuron-microglia crosstalk in postnatal brain development, controlling both microglial maturation and synapse engulfment.
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- 2024
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5. Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function.
- Author
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Bordt EA, Moya HA, Jo YC, Ravichandran CT, Bankowski IM, Ceasrine AM, McDougle CJ, Carlezon WA Jr, and Bilbo SD
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- Animals, Mice, Pregnancy, Female, Male, Brain metabolism, Gonadal Hormones metabolism, Mitochondria metabolism, Microglia metabolism, Autism Spectrum Disorder
- Abstract
There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2024
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6. Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity.
- Author
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Batorsky R, Ceasrine AM, Shook LL, Kislal S, Bordt EA, Devlin BA, Perlis RH, Slonim DK, Bilbo SD, and Edlow AG
- Abstract
Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide novel insights into fetal brain microglial programs, and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders in the setting of maternal exposures., Competing Interests: A.G.E. serves as a consultant for Mirvie, Inc. outside of this work. A.G.E. receives research funding from Merck Pharmaceuticals outside of this work. R.H.P. is a founder and member of the scientific advisory board of Psy Therapeutics; a member of scientific advisory boards for Swan AI Studio, Belle Artificial Intelligence, Genomind, and Circular Genomics; and consults to Alkermes, Burrage Capital, and Vault Health. He serves as an associate editor for JAMA Network Open. All of these roles are outside the present work.
- Published
- 2023
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7. Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system.
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Smith CJ, Rendina DN, Kingsbury MA, Malacon KE, Nguyen DM, Tran JJ, Devlin BA, Raju RM, Clark MJ, Burgett L, Zhang JH, Cetinbas M, Sadreyev RI, Chen K, Iyer MS, and Bilbo SD
- Subjects
- Pregnancy, Female, Mice, Male, Animals, Social Behavior, Vehicle Emissions, Dopaminergic Neurons, Microglia metabolism, Dopamine metabolism
- Abstract
Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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8. Protocol to measure endotoxin from opaque tissues in mice using an optimized kinetic limulus amebocyte lysate assay.
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Ceasrine AM, Green LA, and Bilbo SD
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- Animals, Mice, Limulus Test methods, Biological Assay, Kinetics, Endotoxins analysis, Horseshoe Crabs
- Abstract
Endotoxin accumulation has been widely noted in several pathologies ranging from metabolic dysregulation to bacterial infection. Using limulus amebocyte lysate (LAL) assays to detect endotoxin load has been the only reliable way to assess endotoxin accumulation, but assays optimized for detection in opaque tissues are still lacking. We optimized a sensitive Kinetic LAL assay for endotoxin detection from murine tissues. In this protocol, we describe tissue collection and homogenization, followed by the procedure to run the assay and data analysis. For complete details on the use and execution of this protocol, please refer to Ceasrine et al. (2022)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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9. β-Endorphin mediates radiation therapy fatigue.
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Hermann AL, Fell GL, Kemény LV, Fung CY, Held KD, Biggs PJ, Rivera PD, Bilbo SD, Igras V, Willers H, Kung J, Gheorghiu L, Hideghéty K, Mao J, Woolf CJ, and Fisher DE
- Abstract
Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin irradiation has been suggested. β-Endorphin, an endogenous opioid, is synthesized in skin following genotoxic ultraviolet irradiation and acts systemically, producing addiction. Exogenous opiates with the same receptor activity as β-endorphin can cause fatigue. Using rodent models of radiation therapy, exposing tails and sparing vital organs, we tested whether skin-derived β-endorphin contributes to radiation-induced fatigue. Over a 6-week radiation regimen, plasma β-endorphin increased in rats, paralleled by opiate phenotypes (elevated pain thresholds, Straub tail) and fatigue-like behavior, which was reversed in animals treated by the opiate antagonist naloxone. Mechanistically, all these phenotypes were blocked by opiate antagonist treatment and were undetected in either β-endorphin knockout mice or mice lacking keratinocyte p53 expression. These findings implicate skin-derived β-endorphin in systemic effects of radiation therapy. Opioid antagonism may warrant testing in humans as treatment or prevention of radiation-induced fatigue.
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- 2022
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10. Maternal diet disrupts the placenta-brain axis in a sex-specific manner.
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Ceasrine AM, Devlin BA, Bolton JL, Green LA, Jo YC, Huynh C, Patrick B, Washington K, Sanchez CL, Joo F, Campos-Salazar AB, Lockshin ER, Kuhn C, Murphy SK, Simmons LA, and Bilbo SD
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- Pregnancy, Male, Female, Mice, Animals, Humans, Brain, Diet, High-Fat adverse effects, Dietary Fats, Placenta, Serotonin
- Abstract
High maternal weight is associated with detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression and communicative disorders. Despite widespread acknowledgement of sex biases in the development of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we show that a maternal high-fat diet causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation contributes to sex-specific behavioural outcomes in offspring. In male offspring exposed to a maternal high-fat diet, increased macrophage Toll-like receptor 4 signalling results in excess microglial phagocytosis of serotonin (5-HT) neurons in the developing dorsal raphe nucleus, decreasing 5-HT bioavailability in the fetal and adult brains. Bulk sequencing from a large cohort of matched first-trimester human samples reveals sex-specific transcriptome-wide changes in placental and brain tissue in response to maternal triglyceride accumulation (a proxy for dietary fat content). Further, fetal brain 5-HT levels decrease as placental triglycerides increase in male mice and male human samples. These findings uncover a microglia-dependent mechanism through which maternal diet can impact offspring susceptibility for neuropsychiatric disorder development in a sex-specific manner., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
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11. Prenatal opioid exposure inhibits microglial sculpting of the dopamine system selectively in adolescent male offspring.
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Smith CJ, Lintz T, Clark MJ, Malacon KE, Abiad A, Constantino NJ, Kim VJ, Jo YC, Alonso-Caraballo Y, Bilbo SD, and Chartoff EH
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- Animals, Dopamine pharmacology, Female, Humans, Male, Microglia metabolism, Nucleus Accumbens, Oxycodone pharmacology, Pregnancy, Rats, Receptors, Dopamine D1 metabolism, Reward, Analgesics, Opioid pharmacology, Prenatal Exposure Delayed Effects
- Abstract
The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. A number of social and cognitive abnormalities have been documented in these children as they reach young adulthood. However, little is known about the mechanisms underlying developmental effects of prenatal opioid exposure. Microglia, the resident immune cells of the brain, respond to acute opioid exposure in adulthood. Moreover, microglia are known to sculpt neural circuits during typical development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors (D1R) in the nucleus accumbens (NAc) is required for the natural developmental decline in NAc-D1R that occurs between adolescence and adulthood in rats. This microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. However, virtually nothing is known as to whether this developmental program is altered by prenatal exposure to opioids. Here, we show in rats that maternal oxycodone self-administration during pregnancy leads to reduced adolescent microglial phagocytosis of D1R and subsequently higher D1R density within the NAc in adult male, but not female, offspring. Finally, we show prenatal and adult behavioral deficits in opioid-exposed offspring, including impaired extinction of oxycodone-conditioned place preference in males. This work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to changes in neural systems and behavior., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)
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- 2022
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12. Prenatal environmental stressors impair postnatal microglia function and adult behavior in males.
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Block CL, Eroglu O, Mague SD, Smith CJ, Ceasrine AM, Sriworarat C, Blount C, Beben KA, Malacon KE, Ndubuizu N, Talbot A, Gallagher NM, Chan Jo Y, Nyangacha T, Carlson DE, Dzirasa K, Eroglu C, and Bilbo SD
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- Animals, Behavior, Animal physiology, Brain, Female, Humans, Male, Mice, Microglia, Pregnancy, Neurodevelopmental Disorders, Prenatal Exposure Delayed Effects
- Abstract
Gestational exposure to environmental toxins and socioeconomic stressors is epidemiologically linked to neurodevelopmental disorders with strong male bias, such as autism. We model these prenatal risk factors in mice by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly activates the maternal immune system. Only male offspring display long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions. Cellularly, prenatal stressors diminish microglial function within the anterior cingulate cortex, a central node of the social coding network, in males during early postnatal development. Precise inhibition of microglial phagocytosis within the anterior cingulate cortex (ACC) of wild-type (WT) mice during the same critical period mimics the impact of prenatal stressors on a male-specific behavior, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development., Competing Interests: Declaration of interest The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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13. Dietary fat: a potent microglial influencer.
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Ceasrine AM and Bilbo SD
- Subjects
- Female, Humans, Inflammation, Obesity, Overweight, Pregnancy, Dietary Fats pharmacology, Microglia
- Abstract
Poor nutrition, lack of exercise, and genetic predisposition all contribute to the growing epidemic of obesity. Overweight/obesity create an environment of chronic inflammation that leads to negative physiological and neurological outcomes, such as diabetes, cardiovascular disease, and anxiety/depression. While the whole body contributes to metabolic homeostasis, the neuroimmune system has recently emerged as a key regulator of metabolism. Microglia, the resident immune cells of the brain, respond both directly and indirectly to dietary fat, and the environment in which microglia develop contributes to their responsiveness later in life. Thus, high maternal weight during pregnancy may have consequences for microglial function in offspring. Here, we discuss the most recent findings on microglia signaling in overweight/obesity with a focus on perinatal programming., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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14. Microglia and Sensitive Periods in Brain Development.
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Dziabis JE and Bilbo SD
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- Brain physiology, Neuronal Plasticity, Neurons physiology, Microglia, Synapses physiology
- Abstract
From embryonic neuronal migration to adolescent circuit refinement, the immune system plays an essential role throughout central nervous system (CNS) development. Immune signaling molecules serve as a common language between the immune system and CNS, allowing them to work together to modulate brain function both in health and disease. As the resident CNS macrophage, microglia comprise the majority of immune cells in the brain. Much like their peripheral counterparts, microglia survey their environment for pathology, clean up debris, and propagate inflammatory responses when necessary. Beyond this, recent studies have highlighted that microglia perform a number of complex tasks during neural development, from directing neuronal and axonal positioning to pruning synapses, receptors, and even whole cells. In this chapter, we discuss this literature within the framework that immune activation during discrete windows of neural development can profoundly impact brain function long-term, and thus the risk of neurodevelopmental and neuropsychiatric disorders. In this chapter, we review three sensitive developmental periods - embryonic wiring, early postnatal synaptic pruning, and adolescent circuit refinement - in order to highlight the diversity of functions that microglia perform in building a brain. In reviewing this literature, it becomes obvious that timing matters, perhaps more so than the nature of the immune activation itself; largely conserved patterns of microglial response to diverse insults result in different functional impacts depending on the stage of brain maturation at the time of the challenge., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2022
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15. Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis.
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Petrozziello T, Bordt EA, Mills AN, Kim SE, Sapp E, Devlin BA, Obeng-Marnu AA, Farhan SMK, Amaral AC, Dujardin S, Dooley PM, Henstridge C, Oakley DH, Neueder A, Hyman BT, Spires-Jones TL, Bilbo SD, Vakili K, Cudkowicz ME, Berry JD, DiFiglia M, Silva MC, Haggarty SJ, and Sadri-Vakili G
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- Aged, Aged, 80 and over, Cell Line, Tumor, Female, Humans, Male, Middle Aged, Phosphorylation, Synapses metabolism, Amyotrophic Lateral Sclerosis metabolism, Mitochondria metabolism, Neurons metabolism, Oxidative Stress physiology, tau Proteins metabolism
- Abstract
Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Previous studies have demonstrated that mitochondrial dysfunction is a key pathogenetic event in ALS. Interestingly, studies in Alzheimer's disease (AD) post-mortem brain and animal models link alterations in mitochondrial function to interactions between hyperphosphorylated tau and dynamin-related protein 1 (DRP1), the GTPase involved in mitochondrial fission. Recent evidence suggest that tau may be involved in ALS pathogenesis, therefore, we sought to determine whether hyperphosphorylated tau may lead to mitochondrial fragmentation and dysfunction in ALS and whether reducing tau may provide a novel therapeutic approach. Our findings demonstrated that pTau-S396 is mis-localized to synapses in post-mortem motor cortex (mCTX) across ALS subtypes. Additionally, the treatment with ALS synaptoneurosomes (SNs), enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity without affecting cell survival in vitro. Furthermore, pTau-S396 interacted with DRP1, and similar to pTau-S396, DRP1 accumulated in SNs across ALS subtypes, suggesting increases in mitochondrial fragmentation in ALS. As previously reported, electron microscopy revealed a significant decrease in mitochondria density and length in ALS mCTX. Lastly, reducing tau levels with QC-01-175, a selective tau degrader, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS. pTau-S396 mis-localizes to synapses in ALS. ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentation in vitro. pTau-S396 interacts with the pro-fission GTPase DRP1 in ALS. Reducing tau with a selective degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stress in vitro., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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16. Sickness and the Social Brain: How the Immune System Regulates Behavior across Species.
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Devlin BA, Smith CJ, and Bilbo SD
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- Animals, Brain, Immune System, Illness Behavior physiology, Social Behavior
- Abstract
Many instances of sickness critically involve the immune system. The immune system talks to the brain in a bidirectional loop. This discourse affords the immune system immense control, such that it can influence behavior and optimize recovery from illness. These behavioral responses to infection are called sickness behaviors and can manifest in many ways, including changes in mood, motivation, or energy. Fascinatingly, most of these changes are conserved across species, and most organisms demonstrate some form of sickness behaviors. One of the most interesting sickness behaviors, and not immediately obvious, is altered sociability. Here, we discuss how the immune system impacts social behavior, by examining the brain regions and immune mediators involved in this process. We first outline how social behavior changes in response to infection in various species. Next, we explore which brain regions control social behavior and their evolutionary origins. Finally, we describe which immune mediators establish the link between illness and social behavior, in the context of both normal development and infection. Overall, we hope to make clear the striking similarities between the mechanisms that facilitate changes in sociability in derived and ancestral vertebrate, as well as invertebrate, species., (© 2021 S. Karger AG, Basel.)
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- 2022
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17. Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses.
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Bordt EA, Shook LL, Atyeo C, Pullen KM, De Guzman RM, Meinsohn MC, Chauvin M, Fischinger S, Yockey LJ, James K, Lima R, Yonker LM, Fasano A, Brigida S, Bebell LM, Roberts DJ, Pépin D, Huh JR, Bilbo SD, Li JZ, Kaimal A, Schust DJ, Gray KJ, Lauffenburger D, Alter G, and Edlow AG
- Subjects
- Female, Humans, Immunity, Infectious Disease Transmission, Vertical, Placenta, Pregnancy, SARS-CoV-2, COVID-19, Pregnancy Complications, Infectious
- Abstract
There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.
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- 2021
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18. Morphine exposure alters Fos expression in a sex-, age-, and brain region-specific manner during adolescence.
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Figueroa C, Yang H, DiSpirito J, Bourgeois JR, Kalyanasundaram G, Doshi I, Bilbo SD, and Kopec AM
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- Animals, Brain, Female, Male, Prefrontal Cortex physiology, Reward, Morphine pharmacology, Nucleus Accumbens metabolism
- Abstract
Data in both humans and preclinical animal models clearly indicate drug exposure during adolescence, when the "reward" circuitry of the brain develops, increases the risk of substance use and other mental health disorders later in life. Human data indicate that different neural and behavioral sequelae can be observed in early versus late adolescence. However, most studies with rodent models examine a single adolescent age compared to a mature adult age, and often only in males. Herein, we sought to determine whether the acute response to the opioid morphine would also differ across adolescence, and by sex. By quantifying Fos positive cells, a proxy for neural activity, at different stages during adolescence (pre-, early, mid-, and late adolescence) and in multiple reward regions (prefrontal cortex, nucleus accumbens, caudate/putamen), we determined that the neural response to acute morphine is highly dependent on adolescent age, sex, and brain region. These data suggest that heterogeneity in the consequences of adolescent opioid exposure may be due to age- and sex-specific developmental profiles in individual reward processing regions. In future studies, it will be important to add age within adolescence as an independent variable for a holistic view of healthy or abnormal reward-related neural development., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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19. Primetime for microglia: When stress and infection collide.
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Ceasrine AM and Bilbo SD
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- Animals, Male, Mice, Neurons, Inflammation, Microglia
- Abstract
Inflammation during critical windows of development contributes to behavioral affect later in life. In this of Neuron, Cao et al. (2021) demonstrate a novel mechanism through which early life Tlr4-dependent inflammation in microglia permanently alters neuronal function and leaves male mice susceptible to stress-induced depressive-like behaviors., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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20. Associations between maternal obesity, gestational cytokine levels and child obesity in the NEST cohort.
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Maguire RL, House JS, Lloyd DT, Skinner HG, Allen TK, Raffi AM, Skaar DA, Park SS, McCullough LE, Kollins SH, Bilbo SD, Collier DN, Murphy SK, Fuemmeler BF, Gowdy KM, and Hoyo C
- Subjects
- Black or African American, Body Mass Index, Child, Child, Preschool, Cohort Studies, Female, Humans, Pregnancy, White People, Cytokines blood, Obesity, Maternal epidemiology, Pediatric Obesity epidemiology
- Abstract
Background: Although maternal systemic inflammation is hypothesized to link maternal pre-pregnancy obesity to offspring metabolic dysfunction, patient empirical data are limited., Objectives: In this study, we hypothesized that pre-pregnancy obesity alters systemic chemo/cytokines concentrations in pregnancy, and this alteration contributes to obesity in children., Methods: In a multi-ethnic cohort of 361 mother-child pairs, we measured prenatal concentrations of plasma TNF-α, IL-6, IL-8, IL-1β, IL-4, IFN-γ, IL-12 p70 subunit, and IL-17A using a multiplex ELISA and examined associations of pre-pregnancy obesity on maternal chemo/cytokine levels, and associations of these cytokine levels with offspring body mass index z score (BMI-z) at age 2-6 years using linear regression., Results: After adjusting for maternal smoking, ethnicity, age, and education, pre-pregnancy obesity was associated with increased concentrations of TNF-α (P = .026) and IFN-γ (P = .06). While we found no evidence for associations between TNF-α concentrations and offspring BMI-z, increased IFN-γ concentrations were associated with decreased BMI-z (P = .0002), primarily in Whites (P = .0011). In addition, increased maternal IL-17A concentrations were associated with increased BMI-z in offspring (P = .0005) with stronger associations in African Americans (P = .0042) than Whites (P = .24)., Conclusions: Data from this study are consistent with maternal obesity-related inflammation during pregnancy, increasing the risk of childhood obesity in an ethnic-specific manner., (© 2020 World Obesity Federation.)
- Published
- 2021
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21. Vitamin D deficiency exacerbates UV/endorphin and opioid addiction.
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Kemény LV, Robinson KC, Hermann AL, Walker DM, Regan S, Yew YW, Lai YC, Theodosakis N, Rivera PD, Ding W, Yang L, Beyer T, Loh YE, Lo JA, van der Sande AAJ, Sarnie W, Kotler D, Hsiao JJ, Su MY, Kato S, Kotler J, Bilbo SD, Chopra V, Salomon MP, Shen S, Hoon DSB, Asgari MM, Wakeman SE, Nestler EJ, and Fisher DE
- Subjects
- Analgesics, Opioid pharmacology, Animals, Humans, Mice, Vitamin D pharmacology, Vitamins, Endorphins, Opioid-Related Disorders, Vitamin D Deficiency complications, Vitamin D Deficiency epidemiology
- Abstract
The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of VitD levels with self-reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)
- Published
- 2021
- Full Text
- View/download PDF
22. Sexually dimorphic placental responses to maternal SARS-CoV-2 infection.
- Author
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Bordt EA, Shook LL, Atyeo C, Pullen KM, De Guzman RM, Meinsohn MC, Chauvin M, Fischinger S, Yockey LJ, James K, Lima R, Yonker LM, Fasano A, Brigida S, Bebell LM, Roberts DJ, Pépin D, Huh JR, Bilbo SD, Li JZ, Kaimal A, Schust D, Gray KJ, Lauffenburger D, Alter G, and Edlow AG
- Abstract
There is a persistent male bias in the prevalence and severity of COVID-19 disease. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of disease in adults, and play a key role in the placental anti-viral response. Moreover, the interferon response has been shown to alter Fc-receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of viral-induced placental interferon responses, maternal-fetal antibody transfer, and fetal sex. Placental interferon stimulated genes (ISGs), Fc-receptor expression, and SARS-CoV-2 antibody transfer were interrogated in 68 pregnancies. Sexually dimorphic placental expression of ISGs, interleukin-10, and Fc receptors was observed following maternal SARS-CoV-2 infection, with upregulation in males. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were noted in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.
- Published
- 2021
- Full Text
- View/download PDF
23. Sickness and the Social Brain: Love in the Time of COVID.
- Author
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Smith CJ and Bilbo SD
- Abstract
As a highly social species, inclusion in social networks and the presence of strong social bonds are critical to our health and well-being. Indeed, impaired social functioning is a component of numerous neuropsychiatric disorders including depression, anxiety, and substance use disorder. During the current COVID-19 pandemic, our social networks are at risk of fracture and many are vulnerable to the negative consequences of social isolation. Importantly, infection itself leads to changes in social behavior as a component of "sickness behavior." Furthermore, as in the case of COVID-19, males and females often differ in their immunological response to infection, and, therefore, in their susceptibility to negative outcomes. In this review, we discuss the many ways in which infection changes social behavior-sometimes to the benefit of the host, and in some instances for the sake of the pathogen-in species ranging from eusocial insects to humans. We also explore the neuroimmune mechanisms by which these changes in social behavior occur. Finally, we touch upon the ways in which the social environment (group living, social isolation, etc.) shapes the immune system and its ability to respond to challenge. Throughout we emphasize how males and females differ in their response to immune activation, both behaviorally and physiologically., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Smith and Bilbo.)
- Published
- 2021
- Full Text
- View/download PDF
24. Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number.
- Author
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Smith CJ, Kingsbury MA, Dziabis JE, Hanamsagar R, Malacon KE, Tran JN, Norris HA, Gulino M, Bordt EA, and Bilbo SD
- Subjects
- Animals, Cell Count, Female, Lipopolysaccharides, Mice, Microglia, Pregnancy, Social Behavior, Somatostatin, Somatostatin-Secreting Cells
- Abstract
Decreases in social behavior are a hallmark aspect of acute "sickness behavior" in response to infection. However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits. Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females. Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC. Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNFα and IL-1β) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, largely independent of microglial inflammatory signaling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
25. Sex-dependent neurobiological features of prenatal immune activation via TLR7.
- Author
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Missig G, Robbins JO, Mokler EL, McCullough KM, Bilbo SD, McDougle CJ, and Carlezon WA Jr
- Subjects
- Animals, Cytokines, Female, Male, Mice, Mice, Inbred C57BL, Pregnancy, Prenatal Exposure Delayed Effects immunology, Fetus immunology, Immunity, Innate, Membrane Glycoproteins immunology, Sex Characteristics, Toll-Like Receptor 7 immunology
- Abstract
Immune activation during pregnancy via infection or autoimmune disease is a risk factor for neuropsychiatric illness. Mouse models of prenatal immune activation often involve maternal administration of agents that activate toll-like receptors (TLRs), a class of pattern recognition receptors that initiate innate immune responses. Such studies have focused primarily on activating the TLR3 or TLR4 subtypes, to mimic immune responses to viral or bacterial infections, respectively. Here, we characterize the effects of prenatal activation of TLR7, which is implicated in the pathogenesis of autoimmune disease. Prenatal TLR7 activation via administration of the selective agonist imiquimod (5.0 mg/kg) induces a phenotype in offspring characterized by reduced anxiety-like behavior, fragmented social behavior, and altered ultrasonic vocalization patterns at 6-12 weeks of age. The characteristics of this phenotype are readily distinguishable from-and in some ways opposite to-those seen following prenatal activation of TLR3 and/or TLR4. Prenatal TLR7-activated mice have normal baseline locomotor activity, but are hyperresponsive to stimuli including social partners, circadian cues, and gonadal hormone fluctuations. These alterations are accompanied by decreases in microglia density but increases in ramifications. RNA-sequencing of dorsal striatum, a region showing profound changes in microglial markers, indicates that prenatal TLR7 activation induces differential expression of hundreds of genes at 13 weeks of age, with virtually no overlap in differentially expressed genes between males and females. Our findings demonstrate that prenatal immune activation can promote a wide range of developmental trajectories, depending on the type and/or pattern of TLR activation and the sex of the offspring.
- Published
- 2020
- Full Text
- View/download PDF
26. Isolation of Microglia from Mouse or Human Tissue.
- Author
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Bordt EA, Block CL, Petrozziello T, Sadri-Vakili G, Smith CJ, Edlow AG, and Bilbo SD
- Subjects
- Animals, CD11b Antigen metabolism, Humans, Mice, Cell Separation methods, Microglia metabolism
- Abstract
Microglia are the innate immune cells of the central nervous system. Although numerous methods have been developed to isolate microglia from the brain, the method of dissociation and isolation can have a profound effect on the function of these highly dynamic cells. Here, we present an optimized protocol to isolate CD11b+ cells (microglia) from mouse or human brain tissue using magnetic bead columns. Isolated microglia can be used to model diseases with neuroinflammatory components for potential therapeutic discoveries. For complete details on the use and execution of this protocol, please refer to Hanamsagar et al. (2017), Rivera et al. (2019), and Edlow et al. (2019)., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
- Published
- 2020
- Full Text
- View/download PDF
27. Microglia and sexual differentiation of the developing brain: A focus on ontogeny and intrinsic factors.
- Author
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Bordt EA, Ceasrine AM, and Bilbo SD
- Subjects
- Animals, Humans, Male, Nervous System Diseases pathology, Neurons cytology, Brain cytology, Brain growth & development, Microglia physiology, Sex Characteristics, Sex Differentiation physiology
- Abstract
Sexual differentiation of the brain during early development likely underlies the strong sex biases prevalent in many neurological conditions. Mounting evidence indicates that microglia, the innate immune cells of the central nervous system, are intricately involved in these sex-specific processes of differentiation. In this review, we synthesize literature demonstrating sex differences in microglial number, morphology, transcriptional state, and functionality throughout spatiotemporal development as well as highlight current literature regarding ontogeny of microglia. Along with vanRyzin et al. in this issue, we explore the idea that differences in microglia imparted by chromosomal or ontogeny-related programming can influence microglial-driven sexual differentiation of the brain, as well as the idea that extrinsic differences in the male and female brain microenvironment may in turn impart sex differences in microglia., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2020
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28. Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease.
- Author
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Hollander JA, Cory-Slechta DA, Jacka FN, Szabo ST, Guilarte TR, Bilbo SD, Mattingly CJ, Moy SS, Haroon E, Hornig M, Levin ED, Pletnikov MV, Zehr JL, McAllister KA, Dzierlenga AL, Garton AE, Lawler CP, and Ladd-Acosta C
- Subjects
- Humans, Environmental Exposure adverse effects, Mental Disorders etiology
- Abstract
The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms-synaptic dysfunction, immune alterations, and gut-brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease.
- Published
- 2020
- Full Text
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29. Stressed-Out T Cells Fragment the Mind.
- Author
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Bordt EA and Bilbo SD
- Subjects
- Acetylation, Adenosine Triphosphate, Animals, Humans, Macrophages, Mice, Multienzyme Complexes, Oxo-Acid-Lyases, T-Lymphocytes, Toll-Like Receptors, ATP Citrate (pro-S)-Lyase, Histones
- Abstract
The immune system is increasingly recognized to play an integral role in regulating stress responses. In a recent article in Cell, Fan et al. demonstrate a novel mechanism through which stress drives mitochondrial fragmentation-induced xanthine accumulation in mouse CD4
+ T cells, subsequently acting on oligodendrocytes to induce anxiety-like behaviors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
30. The inflammatory event of birth: How oxytocin signaling may guide the development of the brain and gastrointestinal system.
- Author
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Kingsbury MA and Bilbo SD
- Subjects
- Humans, Infant, Newborn, Brain growth & development, Brain immunology, Brain metabolism, Fetal Development immunology, Gastrointestinal Microbiome, Inflammation immunology, Inflammation metabolism, Neurodevelopmental Disorders immunology, Neurodevelopmental Disorders metabolism, Oxytocin metabolism, Signal Transduction
- Abstract
The role of oxytocin (OT) as a neuropeptide that modulates social behavior has been extensively studied and reviewed, but beyond these functions, OT's adaptive functions at birth are quite numerous, as OT coordinates many physiological processes in the mother and fetus to ensure a successful delivery. In this review we explore in detail the potential adaptive roles of oxytocin as an anti-inflammatory, protective molecule at birth for the developing fetal brain and gastrointestinal system based on evidence that birth is a potent inflammatory/immune event. We discuss data with relevance for a number of neurodevelopmental disorders, as well as the emerging role of the gut-brain axis for health and disease. Finally, we discuss the potential relevance of sex differences in OT signaling present at birth in the increased male vulnerability to neurodevelopmental disabilities., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
31. Mitochondria, Oxytocin, and Vasopressin: Unfolding the Inflammatory Protein Response.
- Author
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Bordt EA, Smith CJ, Demarest TG, Bilbo SD, and Kingsbury MA
- Subjects
- Animals, Humans, Inflammation immunology, Inflammation metabolism, Macrophages immunology, Macrophages metabolism, Mitochondria immunology, Oxytocin immunology, Reactive Oxygen Species immunology, Reactive Oxygen Species metabolism, Vasopressins immunology, Immunity, Cellular physiology, Mitochondria metabolism, Oxytocin metabolism, Protein Folding, Vasopressins metabolism
- Abstract
Neuroendocrine and immune signaling pathways are activated following insults such as stress, injury, and infection, in a systemic response aimed at restoring homeostasis. Mitochondrial metabolism and function have been implicated in the control of immune responses. Commonly studied along with mitochondrial function, reactive oxygen species (ROS) are closely linked to cellular inflammatory responses. It is also accepted that cells experiencing mitochondrial or endoplasmic reticulum (ER) stress induce response pathways in order to cope with protein-folding dysregulation, in homeostatic responses referred to as the unfolded protein responses (UPRs). Recent reports indicate that the UPRs may play an important role in immune responses. Notably, the homeostasis-regulating hormones oxytocin (OXT) and vasopressin (AVP) are also associated with the regulation of inflammatory responses and immune function. Intriguingly, OXT and AVP have been linked with ER unfolded protein responses (UPR
ER ), and can impact ROS production and mitochondrial function. Here, we will review the evidence for interactions between these various factors and how these neuropeptides might influence mitochondrial processes.- Published
- 2019
- Full Text
- View/download PDF
32. A Protocol for Sedation Free MRI and PET Imaging in Adults with Autism Spectrum Disorder.
- Author
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Smith CJ, Bhanot A, Norman E, Mullett JE, Bilbo SD, McDougle CJ, Zürcher NR, and Hooker JM
- Subjects
- Adult, Humans, Male, Neuroimaging, Autism Spectrum Disorder diagnostic imaging, Magnetic Resonance Imaging methods, Positron-Emission Tomography methods
- Abstract
Imaging technologies such as positron emission tomography (PET) and magnetic resonance imaging (MRI) present unparalleled opportunities to investigate the neural basis of autism spectrum disorder (ASD). However, challenges such as deficits in social interaction, anxiety around new experiences, impaired language abilities, and hypersensitivity to sensory stimuli make participating in neuroimaging studies challenging for individuals with ASD. In this commentary, we describe the existent training protocols for preparing individuals with ASD for PET/MRI scans and our own experience developing a training protocol to facilitate the inclusion of low-functioning adults with ASD in PET-MRI studies. We hope to raise awareness of the need for more information exchange between research groups about lessons learned in this context in order to include the entire disease spectrum in neuroimaging studies.
- Published
- 2019
- Full Text
- View/download PDF
33. Neuro-Immune Mechanisms Regulating Social Behavior: Dopamine as Mediator?
- Author
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Kopec AM, Smith CJ, and Bilbo SD
- Subjects
- Animals, Brain immunology, Dopamine immunology, Humans, Immunity, Cellular physiology, Brain metabolism, Dopamine metabolism, Neuroimmunomodulation physiology, Reward, Social Behavior
- Abstract
Social interactions are fundamental to survival and overall health. The mechanisms underlying social behavior are complex, but we now know that immune signaling plays a fundamental role in the regulation of social interactions. Prolonged or exaggerated alterations in social behavior often accompany altered immune signaling and function in pathological states. Thus, unraveling the link between social behavior and immune signaling is a fundamental challenge, not only to advance our understanding of human health and development, but for the design of comprehensive therapeutic approaches for neural disorders. In this review, we synthesize literature demonstrating the bidirectional relationship between social behavior and immune signaling and highlight recent work linking social behavior, immune function, and dopaminergic signaling in adolescent neural and behavioral development., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
34. Microglia Sculpt Sex Differences in Social Behavior.
- Author
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Smith CJ and Bilbo SD
- Subjects
- Animals, Female, Male, Phagocytosis, Rats, Sex Characteristics, Social Behavior, Endocannabinoids, Microglia
- Abstract
Microglia are increasingly recognized as developmental sculptors of neural circuits. In this issue of Neuron, VanRyzin et al. (2019) demonstrate a novel mechanism by which endocannabinoids drive microglia to phagocytose newborn astrocytes in the medial amygdala of male rats, promoting sex differences in social play behavior., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
35. Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities.
- Author
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Liu X, Nemeth DP, McKim DB, Zhu L, DiSabato DJ, Berdysz O, Gorantla G, Oliver B, Witcher KG, Wang Y, Negray CE, Vegesna RS, Sheridan JF, Godbout JP, Robson MJ, Blakely RD, Popovich PG, Bilbo SD, and Quan N
- Published
- 2019
- Full Text
- View/download PDF
36. Removal of microglial-specific MyD88 signaling alters dentate gyrus doublecortin and enhances opioid addiction-like behaviors.
- Author
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Rivera PD, Hanamsagar R, Kan MJ, Tran PK, Stewart D, Jo YC, Gunn M, and Bilbo SD
- Subjects
- Animals, Behavior, Addictive genetics, Conditioning, Classical drug effects, Conditioning, Operant drug effects, Dentate Gyrus drug effects, Doublecortin Domain Proteins, Doublecortin Protein, Hippocampus drug effects, Hippocampus metabolism, Male, Memory drug effects, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia drug effects, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism, Narcotics pharmacology, Neural Stem Cells drug effects, Neural Stem Cells metabolism, Neurogenesis drug effects, Neurons drug effects, Neurons metabolism, Opioid-Related Disorders genetics, Opioid-Related Disorders metabolism, Reward, Behavior, Addictive metabolism, Dentate Gyrus metabolism, Microglia metabolism, Microtubule-Associated Proteins metabolism, Morphine pharmacology, Myeloid Differentiation Factor 88 deficiency, Neuropeptides metabolism
- Abstract
Drugs of abuse promote a potent immune response in central nervous system (CNS) via the activation of microglia and astrocytes. However, the molecular mechanisms underlying microglial activation during addiction are not well known. We developed and functionally characterized a novel transgenic mouse (Cx3cr1-CreBT
tg/0 :MyD88f/f [Cretg/0 ]) wherein the immune signaling adaptor gene, MyD88, was specifically deleted in microglia. To test the downstream effects of loss of microglia-specific MyD88 signaling in morphine addiction, Cretg/0 and Cre0/0 mice were tested for reward learning, extinction, and reinstatement using a conditioned place preference (CPP) paradigm. There were no differences in drug acquisition, but Cretg/0 mice had prolonged extinction and enhanced reinstatement compared to Cre0/0 controls. Furthermore, morphine-treated Cretg/0 mice showed increased doublecortin (DCX) signal relative to Cre0/0 control mice in the hippocampus, indicative of increased number of immature neurons. Additionally, there was an increase in colocalization of microglial lysosomal marker CD68 with DCX+ cells in morphine-treated Cretg/0 mice but not in Cre0/0 or drug-naїve mice, suggesting a specific role for microglial MyD88 signaling in neuronal phagocytosis in the hippocampus. Our results show that MyD88 deletion in microglia may negatively impact maturing neurons within the adult hippocampus and thus reward memories, suggesting a novel protective role for microglia in opioid addiction., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
37. Maternal immune activation: reporting guidelines to improve the rigor, reproducibility, and transparency of the model.
- Author
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Kentner AC, Bilbo SD, Brown AS, Hsiao EY, McAllister AK, Meyer U, Pearce BD, Pletnikov MV, Yolken RH, and Bauman MD
- Subjects
- Animals, Consensus, Disease Models, Animal, Female, Pregnancy, Reproducibility of Results, Neurodevelopmental Disorders immunology, Prenatal Exposure Delayed Effects immunology, Research Design
- Abstract
The 2017 American College of Neuropychopharmacology (ACNP) conference hosted a Study Group on 4 December 2017, Establishing best practice guidelines to improve the rigor, reproducibility, and transparency of the maternal immune activation (MIA) animal model of neurodevelopmental abnormalities. The goals of this session were to (a) evaluate the current literature and establish a consensus on best practices to be implemented in MIA studies, (b) identify remaining research gaps warranting additional data collection and lend to the development of evidence-based best practice design, and (c) inform the MIA research community of these findings. During this session, there was a detailed discussion on the importance of validating immunogen doses and standardizing the general design (e.g., species, immunogenic compound used, housing) of our MIA models both within and across laboratories. The consensus of the study group was that data does not currently exist to support specific evidence-based model selection or methodological recommendations due to lack of consistency in reporting, and that this issue extends to other inflammatory models of neurodevelopmental abnormalities. This launched a call to establish a reporting checklist focusing on validation, implementation, and transparency modeled on the ARRIVE Guidelines and CONSORT (scientific reporting guidelines for animal and clinical research, respectively). Here we provide a summary of the discussions in addition to a suggested checklist of reporting guidelines needed to improve the rigor and reproducibility of this valuable translational model, which can be adapted and applied to other animal models as well.
- Published
- 2019
- Full Text
- View/download PDF
38. Microglial dopamine receptor elimination defines sex-specific nucleus accumbens development and social behavior in adolescent rats.
- Author
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Kopec AM, Smith CJ, Ayre NR, Sweat SC, and Bilbo SD
- Subjects
- Animals, Complement System Proteins immunology, Dopamine metabolism, Down-Regulation, Female, Male, Microglia immunology, Microglia metabolism, Models, Animal, Nucleus Accumbens immunology, Nucleus Accumbens metabolism, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D1 antagonists & inhibitors, Receptors, Dopamine D1 immunology, Sex Factors, Animal Communication, Microglia physiology, Nucleus Accumbens growth & development, Receptors, Dopamine D1 physiology, Reward
- Abstract
Adolescence is a developmental period in which the mesolimbic dopaminergic "reward" circuitry of the brain, including the nucleus accumbens (NAc), undergoes significant plasticity. Dopamine D1 receptors (D1rs) in the NAc are critical for social behavior, but how these receptors are regulated during adolescence is not well understood. In this report, we demonstrate that microglia and complement-mediated phagocytic activity shapes NAc development by eliminating D1rs in male, but not female rats, during adolescence. Moreover, immune-mediated elimination of D1rs is required for natural developmental changes in male social play behavior. These data demonstrate for the first time that microglia and complement-mediated immune signaling (i) participate in adolescent brain development in a sex-specific manner, and (ii) are causally implicated in developmental changes in behavior. These data have broad implications for understanding the adolescent critical period of development, the molecular mechanisms underlying social behavior, and sex differences in brain structure and function.
- Published
- 2018
- Full Text
- View/download PDF
39. Gut-immune-brain dysfunction in Autism: Importance of sex.
- Author
-
Kopec AM, Fiorentino MR, and Bilbo SD
- Subjects
- Female, Humans, Male, Autistic Disorder pathology, Brain physiopathology, Gastrointestinal Tract physiopathology, Immune System physiopathology, Sex Characteristics
- Abstract
Autism Spectrum Disorder (ASD) is characterized by social behavior deficits, stereotypies, cognitive rigidity, and in some cases severe intellectual impairment and developmental delay. Although ASD is most widely identified by its neurological deficits, gastrointestinal issues are common in ASD. An intimate and complex relationship exists between the gut, the immune system, and the brain, leading to the hypothesis that ASD may be a systems-level disease affecting the gut and immune systems, in addition to the brain. Despite significant advances in understanding the contribution of the gut and immune systems to the etiology of ASD, there is an intriguing commonality among patients that is not well understood: they are predominantly male. Virtually no attention has been given to the potential role of sex-specific regulation of gut, peripheral, and central immune function in ASD, despite the 4:1 male-to-female bias in this disorder. In this review, we discuss recent revelations regarding the impact of gut-immune-brain relationships on social behavior in rodent models and in ASD patients, placing them in the context of known or putative sex specific mechanisms., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
40. The diverse culinary habits of microglia.
- Author
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Bilbo SD
- Subjects
- Brain, Feeding Behavior, Habits, Epigenesis, Genetic, Microglia
- Published
- 2018
- Full Text
- View/download PDF
41. Associations between maternal cytokine levels during gestation and measures of child cognitive abilities and executive functioning.
- Author
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Dozmorov MG, Bilbo SD, Kollins SH, Zucker N, Do EK, Schechter JC, Zhang JJ, Murphy SK, Hoyo C, and Fuemmeler BF
- Subjects
- Adult, Birth Weight, Body Mass Index, Chemokines analysis, Chemokines blood, Child, Child, Preschool, Cognition drug effects, Cohort Studies, Cytokines analysis, Cytokines blood, Cytokines metabolism, Executive Function drug effects, Female, Fetal Development immunology, Fetal Development physiology, Humans, Infant, Newborn, Male, Mothers, Pregnancy, Prospective Studies, Cognition physiology, Executive Function physiology, Prenatal Exposure Delayed Effects physiopathology
- Abstract
Preclinical studies demonstrate that environmentally-induced alterations in inflammatory cytokines generated by the maternal and fetal immune system can significantly impact fetal brain development. Yet, the relationship between maternal cytokines during gestation and later cognitive ability and executive function remains understudied. Children (n = 246) were born of mothers enrolled in the Newborn Epigenetic Study - a prospective pre-birth cohort in the Southeastern US. We characterized seven cytokines [IL-1β, IL-4,IL-6, IL-12p70, IL-17A, tumor necrosis factor-α (TNFα), and interferon-γ (IFNγ)] and one chemokine (IL-8) from maternal plasma collected during pregnancy. We assessed children's cognitive abilities and executive functioning at a mean age of 4.5 (SD = 1.1) years. Children's DAS-II and NIH toolbox scores were regressed on cytokines and the chemokine, controlling for maternal age, race, education, body mass index, IQ, parity, smoking status, delivery type, gestational weeks, and child birth weight and sex. Higher IL-12p70 (β
IL-12p70 = 4.26, p = 0.023) and IL-17A (βIL-17A = 3.70, p = 0.042) levels were related to higher DAS-II GCA score, whereas higher IL-1β (βIL-1B = -6.07, p = 0.003) was related to lower GCA score. Higher IL-12p70 was related to higher performance on NIH toolbox measures of executive functions related to inhibitory control and attention (βIL-12p70 = 5.20, p = 0.046) and cognitive flexibility (βIL-12p70 = 5.10, p = 0.047). Results suggest that dysregulation in gestational immune activity are associated with child cognitive ability and executive functioning., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
42. Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity.
- Author
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Hanamsagar R, Alter MD, Block CS, Sullivan H, Bolton JL, and Bilbo SD
- Published
- 2018
- Full Text
- View/download PDF
43. Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders.
- Author
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Bilbo SD, Block CL, Bolton JL, Hanamsagar R, and Tran PK
- Subjects
- Animals, Autism Spectrum Disorder pathology, Autism Spectrum Disorder psychology, Female, Humans, Immune System physiopathology, Microglia immunology, Pregnancy, Autism Spectrum Disorder etiology, Autism Spectrum Disorder immunology, Environment, Microglia pathology
- Abstract
Immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy, e.g. in response to infection, may disrupt the normal expression of immune molecules during critical stages of neural development and thereby contribute to the risk for neurodevelopmental disorders such as autism spectrum disorder (ASD). This hypothesis has in large part been shepherded by the work of Dr. Paul Patterson and colleagues, which has elegantly demonstrated that a single viral infection or injection of a viral mimetic to pregnant mice significantly and persistently impacts offspring immune and nervous system function, changes that underlie ASD-like behavioral dysfunction including social and communication deficits. Subsequent studies by many labs - in humans and in non-human animal models - have supported the hypothesis that ongoing disrupted immune molecule expression and/or neuroinflammation contributes to at least a significant subset of ASD. The heterogeneous clinical and biological phenotypes observed in ASD strongly suggest that in genetically susceptible individuals, environmental risk factors combine or synergize to create a tipping or threshold point for dysfunction. Importantly, animal studies showing a link between maternal immune activation (MIA) and ASD-like outcomes in offspring involve different species and diverse environmental factors associated with ASD in humans, beyond infection, including toxin exposures, maternal stress, and maternal obesity, all of which impact inflammatory or immune pathways. The goal of this review is to highlight the broader implications of Dr. Patterson's work for the field of autism, with a focus on the impact that MIA by diverse environmental factors has on fetal brain development, immune system development, and the pathophysiology of ASD., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
44. Environment matters: microglia function and dysfunction in a changing world.
- Author
-
Hanamsagar R and Bilbo SD
- Subjects
- Animals, Female, Humans, Pregnancy, Prenatal Exposure Delayed Effects immunology, Brain immunology, Environmental Exposure adverse effects, Microglia immunology, Pregnancy Complications
- Abstract
The immune system is our interface with the environment, and immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy or the early postnatal period, for example, in response to infection, may disrupt the normal developmental trajectory of microglia and consequently their interactions with neurons, thereby contributing to the risk for neurological disorders. The current article outlines recent findings on the impact of diverse, pervasive environmental challenges, beyond infection, including air pollution and maternal stress; and their impact on microglial development and its broad implications for neural pathologies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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45. Opioid Self-Administration is Attenuated by Early-Life Experience and Gene Therapy for Anti-Inflammatory IL-10 in the Nucleus Accumbens of Male Rats.
- Author
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Lacagnina MJ, Kopec AM, Cox SS, Hanamsagar R, Wells C, Slade S, Grace PM, Watkins LR, Levin ED, and Bilbo SD
- Subjects
- Animals, Animals, Newborn, Conditioning, Operant, Cytokines metabolism, Disease Models, Animal, Female, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Handling, Psychological, Interleukin-10 metabolism, Male, Mannose therapeutic use, Nucleus Accumbens drug effects, Opioid-Related Disorders psychology, Pregnancy, Rats, Rats, Sprague-Dawley, Reinforcement Schedule, Remifentanil, Signal Transduction drug effects, Signal Transduction physiology, Analgesics, Opioid administration & dosage, Genetic Therapy, Interleukin-10 genetics, Nucleus Accumbens metabolism, Opioid-Related Disorders therapy, Piperidines administration & dosage
- Abstract
Early-life conditions can contribute to the propensity for developing neuropsychiatric disease, including substance abuse disorders. However, the long-lasting mechanisms that shape risk or resilience for drug addiction remain unclear. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuates morphine conditioning, reduces morphine-induced glial activation, and increases microglial expression of the anti-inflammatory cytokine interleukin-10 (IL-10). We thus hypothesized that anti-inflammatory signaling may underlie the effects of early-life experience on later-life opioid drug-taking. Here we demonstrate that neonatal handling attenuates intravenous self-administration of the opioid remifentanil in a drug-concentration-dependent manner. Transcriptional profiling of the nucleus accumbens (NAc) from handled rats following repeated exposure to remifentanil reveals a suppression of pro-inflammatory cytokine and chemokine gene expression, consistent with an anti-inflammatory phenotype. To determine if anti-inflammatory signaling alters drug-taking behavior, we administered intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) into the NAc of non-handled rats. We discovered that pDNA-IL-10 treatment reduces remifentanil self-administration in a drug-concentration-dependent manner, similar to the effect of handling. In contrast, neither handling nor pDNA-IL-10 treatment alters self-administration of food or sucrose rewards. These collective observations suggest that neuroimmune signaling mechanisms in the NAc are shaped by early-life experience and may modify motivated behaviors for opioid drugs. Moreover, manipulation of the IL-10 signaling pathway represents a novel approach for influencing opioid reinforcement.
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- 2017
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46. Perinatal western-type diet and associated gestational weight gain alter postpartum maternal mood.
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Bolton JL, Wiley MG, Ryan B, Truong S, Strait M, Baker DC, Yang NY, Ilkayeva O, O'Connell TM, Wroth SW, Sánchez CL, Swamy G, Newgard C, Kuhn C, Bilbo SD, and Simmons LA
- Subjects
- Adult, Animals, Female, Histidine blood, Humans, Mice, Pregnancy, Psychiatric Status Rating Scales, Statistics as Topic, Tyrosine blood, Anxiety blood, Anxiety diagnosis, Anxiety etiology, Depression blood, Depression diagnosis, Depression etiology, Diet, Western psychology, Postpartum Period blood, Postpartum Period psychology, Puerperal Disorders diagnosis, Puerperal Disorders etiology, Puerperal Disorders prevention & control, Weight Gain physiology
- Abstract
Introduction: The role of perinatal diet in postpartum maternal mood disorders, including depression and anxiety, remains unclear. We investigated whether perinatal consumption of a Western-type diet (high in fat and branched-chain amino acids [BCAA]) and associated gestational weight gain (GWG) cause serotonin dysregulation in the central nervous system (CNS), resulting in postpartum depression and anxiety (PPD/A)., Methods: Mouse dams were fed one of four diets (high-fat/high BCAA, low-fat/high BCAA, high-fat, and low-fat) prior to mating and throughout gestation and lactation. Postpartum behavioral assessments were conducted, and plasma and brain tissues assayed. To evaluate potential clinical utility, we conducted preliminary human studies using data from an extant sample of 17 primiparous women with high GWG, comparing across self-reported postpartum mood symptoms using the Edinburgh Postnatal Depression Scale (EPDS) for percent GWG and plasma amino acid levels., Results: Mouse dams fed the high-fat/high BCAA diet gained more weight per kcal consumed, and BCAA-supplemented dams lost weight more slowly postpartum. Dams on BCAA-supplemented diets exhibited increased PPD/A-like behavior, decreased dopaminergic function, and decreased plasma tyrosine and histidine levels when assessed on postnatal day (P)8. Preliminary human data showed that GWG accounted for 29% of the variance in EPDS scores. Histidine was also lower in women with higher EPDS scores., Conclusions: These findings highlight the role of perinatal diet and excess GWG in the development of postpartum mood disorders.
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- 2017
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47. Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity.
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Hanamsagar R, Alter MD, Block CS, Sullivan H, Bolton JL, and Bilbo SD
- Subjects
- Animals, Cells, Cultured, Escherichia coli, Estrous Cycle physiology, Female, Hippocampus cytology, Humans, Lipopolysaccharides, Male, Mice, Mice, Inbred C57BL, Microglia cytology, Neuroimmunomodulation physiology, Gene Expression Profiling methods, Gene Expression Regulation, Developmental physiology, Hippocampus growth & development, Hippocampus immunology, Microglia metabolism, Sex Characteristics
- Abstract
Evidence suggests many neurological disorders emerge when normal neurodevelopmental trajectories are disrupted, i.e., when circuits or cells do not reach their fully mature state. Microglia play a critical role in normal neurodevelopment and are hypothesized to contribute to brain disease. We used whole transcriptome profiling with Next Generation sequencing of purified developing microglia to identify a microglial developmental gene expression program involving thousands of genes whose expression levels change monotonically (up or down) across development. Importantly, the gene expression program was delayed in males relative to females and exposure of adult male mice to LPS, a potent immune activator, accelerated microglial development in males. Next, a microglial developmental index (MDI) generated from gene expression patterns obtained from purified mouse microglia, was applied to human brain transcriptome datasets to test the hypothesis that variability in microglial development is associated with human diseases such as Alzheimer's and autism where microglia have been suggested to play a role. MDI was significantly increased in both Alzheimer's Disease and in autism, suggesting that accelerated microglial development may contribute to neuropathology. In conclusion, we identified a microglia-specific gene expression program in mice that was used to create a microglia developmental index, which was applied to human datasets containing heterogeneous cell types to reveal differences between healthy and diseased brain samples, and between males and females. This powerful tool has wide ranging applicability to examine microglial development within the context of disease and in response to other variables such as stress and pharmacological treatments., (© 2017 Wiley Periodicals, Inc.)
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- 2017
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48. Sex differences in microglial appetites during development: Inferences and implications.
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Bilbo SD
- Subjects
- Female, Hippocampus, Humans, Male, Microglia, Phagocytosis, Appetite, Sex Characteristics
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- 2017
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49. Gestational Exposure to Air Pollution Alters Cortical Volume, Microglial Morphology, and Microglia-Neuron Interactions in a Sex-Specific Manner.
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Bolton JL, Marinero S, Hassanzadeh T, Natesan D, Le D, Belliveau C, Mason SN, Auten RL, and Bilbo SD
- Abstract
Microglia are the resident immune cells of the brain, important for normal neural development in addition to host defense in response to inflammatory stimuli. Air pollution is one of the most pervasive and harmful environmental toxicants in the modern world, and several large scale epidemiological studies have recently linked prenatal air pollution exposure with an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Diesel exhaust particles (DEP) are a primary toxic component of air pollution, and markedly activate microglia in vitro and in vivo in adult rodents. We have demonstrated that prenatal exposure to DEP in mice, i.e., to the pregnant dams throughout gestation, results in a persistent vulnerability to behavioral deficits in adult offspring, especially in males, which is intriguing given the greater incidence of ASD in males to females (∼4:1). Moreover, there is a striking upregulation of toll-like receptor (TLR) 4 gene expression within the brains of the same mice, and this expression is primarily in microglia. Here we explored the impact of gestational exposure to DEP or vehicle on microglial morphology in the developing brains of male and female mice. DEP exposure increased inflammatory cytokine protein and altered the morphology of microglia, consistent with activation or a delay in maturation, only within the embryonic brains of male mice; and these effects were dependent on TLR4. DEP exposure also increased cortical volume at embryonic day (E)18, which switched to decreased volume by post-natal day (P)30 in males, suggesting an impact on the developing neural stem cell niche. Consistent with this hypothesis, we found increased microglial-neuronal interactions in male offspring that received DEP compared to all other groups. Taken together, these data suggest a mechanism by which prenatal exposure to environmental toxins may affect microglial development and long-term function, and thereby contribute to the risk of neurodevelopmental disorders.
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- 2017
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50. Optimized solubilization of TRIzol-precipitated protein permits Western blotting analysis to maximize data available from brain tissue.
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Kopec AM, Rivera PD, Lacagnina MJ, Hanamsagar R, and Bilbo SD
- Subjects
- Animals, Brain cytology, Brain metabolism, Chemical Precipitation, Edetic Acid chemistry, Electrophoresis, Polyacrylamide Gel, Female, Guanidines chemistry, Male, Mice, Inbred C57BL, Microglia metabolism, Neurons cytology, Neurons metabolism, Phenols chemistry, Proteins chemistry, Proteins metabolism, Rats, Sprague-Dawley, Sodium Chloride chemistry, Sodium Dodecyl Sulfate chemistry, Solubility, Temperature, Time Factors, Blotting, Western methods, Brain Chemistry, Proteins analysis
- Abstract
Background: Techniques simultaneously assessing multiple levels of molecular processing are appealing because molecular signaling underlying complex neural phenomena occurs at complementary levels. The TRIzol method isolates RNA and DNA, but protein retrieval is difficult due to inefficient solubilization of precipitated protein pellets., New Method: We optimized a buffer for the efficient solubilization of protein from TRIzol-precipitated brain tissue for Western blotting analysis, which was also more effective at directly homogenizing brain tissue than RIPA buffer., Results: Protein yield during solubilization, in addition to protein yield via direct homogenization, is increased by optimizing concentrations of chemicals in a standard lysis buffer. Effective incubation parameters for both total protein yield and the analysis of post-translational modifications is remarkably flexible. Importantly, different neural cell types and protein classes are represented in solubilized protein samples. Moreover, we used dissociated mouse brain tissue to isolate microglia from other cell types and successfully resolved cell type-specific proteins from these small and difficult to attain samples., Comparison With Existing Method(s): Solubilization buffers to date have been comprised primarily of SDS or urea; the data herein demonstrate that components common to lysis buffers can also enhance protein solubilization both after direct homogenization and after precipitation., Conclusions: This method is suitable for assessing gene and protein expression from a single brain sample, allowing for a more comprehensive evaluation of neural phenomena while minimizing the number of subjects., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
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