RESUMO
In addition to their traditional role as immune sentinels, recent discoveries over the last decade have shown that microglial functions now include regulation of neuronal/glial cell migration, differentiation and maturation, as well as neuronal network formation. It was thus proposed that disruption of these microglial roles, during critical periods of brain development, could lead to the pathological onset of several neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, schizophrenia, and major depressive disorder. The prevalence of these disorders exhibits a clear distinction along sex lines with very little known about the mechanisms underlying this difference. One of the fundamental discoveries that arose from recent research into the physiological roles of microglia in neurodevelopment is their sexual dimorphism, raising the intriguing possibility that sex differences in microglial colonization, maturation and/or function in the developing brain could underlie the emergence of various neurodevelopmental disorders. This review discusses the physiological roles of microglia across neurodevelopment, these roles in the two sexes, and the recent evidence that microglial sexually dimorphic nature may contribute, at least partially, to neurodevelopmental disorders.
Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Microglia/patologia , Microglia/fisiologia , Transtornos do Neurodesenvolvimento/patologia , Caracteres Sexuais , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Microglia/metabolismo , Transtornos do Neurodesenvolvimento/metabolismoRESUMO
Early life adversity remains a significant risk factor for the development of a host of negative behavioural and pathological outcomes in adulthood long after the stressor is over. Recent evidence indicates that these lasting effects of ELS may occur via alterations in the epigenetic landscape. Here, we review the main findings of the effects of early life adversity on DNA methylation, histone post-translational modification, and non-coding RNAs in the context of psychiatric disease in animal models and human cohorts. We specifically explore how early life adversity alters epigenetic patterns in both a global manner, and in specific candidate genes that play a role in relevant systems such as the hypothalamic-pituitary-adrenal axis, as well as neurotransmitter and neuroendocrine signalling. We also discuss how individual factors, such as genetics, sex, and age, as well as the type, and timing of early life adversity, can create differential susceptibility and significantly moderate outcomes. Although challenges remain in deciphering the complexity of how the early environment interacts with individual factors to determine epigenetic patterns, as well as how to translate these mechanistic findings into clinically relevant populations, the reviewed literature sheds light on the potential of the field to identify effective interventions for vulnerable individuals.
Assuntos
Epigênese Genética/genética , Transtornos Mentais/etiologia , Transtornos Mentais/genética , Resiliência Psicológica , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Fatores Etários , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Metilação de DNA/genética , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Camundongos , Sistema Hipófise-Suprarrenal/fisiologia , Processamento de Proteína Pós-Traducional/genética , Psicopatologia , RNA não Traduzido/genética , Ratos , Serotonina/metabolismo , Transdução de Sinais/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
Environmental challenges to the maternal immune system during pregnancy have been associated with an increase in the frequency of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) appearing in the offspring. Microglia, the brain's resident immune-cells, are now known to be critically involved in normal brain development, shaping connections between neurons by pruning superfluous synaptic spines. Our aim was to investigate whether maternal infection during critical stages of gestation compromises the role of microglia in sculpting neuronal circuits. Using a mouse model of maternal immune activation (MIA) induced by bacterial Lipopolysaccharide (LPS), we assayed the offspring's behavior during postnatal development. Additionally, we quantified spines within the offspring's brain and assessed alterations in some molecular signals involved in pruning. LPS-induced MIA led to behavioral changes relevant to ASD in the offspring in the absence of gross neurological problems. Prenatal LPS resulted in a significant increase in the number of spines in the granule cells of the dentate gyrus, as well as a reduction in hippocampal expression of the fractalkine microglial receptor (CX3CR1), involved in mediating the pruning process in the offspring. Interestingly, these changes were only noted in the male progeny of the LPS challenged dams. These results provide an early indicator that microglial function is altered in the brain of offspring from immune challenged mothers and that the effects in the brain appear to be specific along sex lines.
Assuntos
Transtorno do Espectro Autista/imunologia , Plasticidade Neuronal/fisiologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Transtorno do Espectro Autista/metabolismo , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia , Transtornos do Neurodesenvolvimento/imunologia , Plasticidade Neuronal/imunologia , Neurônios , Gravidez , Complicações Infecciosas na GravidezRESUMO
The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3 CR1 knockout mice), and Alzheimer's disease pathology (APP-PS1 mice). Even though these cells display ultrastructural features of microglia, they are strikingly distinct from the other phenotypes described so far at the ultrastructural level. They exhibit several signs of oxidative stress, including a condensed, electron-dense cytoplasm and nucleoplasm making them as "dark" as mitochondria, accompanied by a pronounced remodeling of their nuclear chromatin. Dark microglia appear to be much more active than the normal microglia, reaching for synaptic clefts, while extensively encircling axon terminals and dendritic spines with their highly ramified and thin processes. They stain for the myeloid cell markers IBA1 and GFP (in CX3 CR1-GFP mice), and strongly express CD11b and microglia-specific 4D4 in their processes encircling synaptic elements, and TREM2 when they associate with amyloid plaques. Overall, these findings suggest that dark microglia, a new phenotype that we identified based on their unique properties, could play a significant role in the pathological remodeling of neuronal circuits, especially at synapses.
Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Córtex Cerebral/patologia , Microglia/patologia , Estresse Psicológico/patologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Antígenos CD/metabolismo , Receptor 1 de Quimiocina CX3C , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH , Fenótipo , Presenilina-1/genética , Presenilina-1/metabolismo , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Estresse Psicológico/genéticaRESUMO
Recent evidence has demonstrated that consumption of high fat diets can trigger brain inflammation and subsequent injury in the absence of any peripheral inflammatory signaling. Here we sought to investigate whether a link exists between the concentration of highly saturated fats in the diet and the development of inflammation in the brain of rats and, whether the source of the saturated fat was an important factor in this process. Adult male rats had access to diets with a moderate level of total fat (32% of calories as fat) varying in level of saturated fat [low (20%) vs high (>60%)] and its source (butter or coconut oil). After 8 weeks of diet exposure peripheral and central tissues were collected for analysis of inflammatory signals. Neither blood nor white adipose tissue exhibited any changes in inflammatory mediators regardless of the saturated fat content or the source. In the brain however, we observed significant hypothalamic upregulation of the expression of markers of glial activation as well as of interleukin (IL)-1,6 and nuclear factor (NF)-IL-6, which were highest in the group fed the butter-based diets. The increase in these inflammatory mediators had no effect on basal body temperature or the temperature response to systemic lipopolysaccharide (LPS). The present results indicate that hypothalamic inflammation associated with consumption of diets high in fat is directly linked to the saturated fat content as well as the source of that fat. These effects are likely linked to other pathophysiological changes in the regulation of metabolism.
Assuntos
Gorduras na Dieta/toxicidade , Hipotálamo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Temperatura Corporal , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Sickness behaviors and fever during infection constitute an adaptive and tightly regulated mechanism designed to efficiently clear the invading pathogen from the body. Recent literature has demonstrated that changes in energy status can profoundly affect the fever response to an acute immune challenge. The purpose of the present study was to investigate whether the exacerbating effect of diet induced obesity (DIO) on the LPS-induced fever response demonstrated previously would generalize to other sickness behaviors and, further, whether incremental changes in body weight would influence these responses. Results showed that DIO male Wistar rats exhibited a higher number of sickness symptoms for a longer period after lipopolysaccharide (LPS) injection (100µg/kg) than lean rats. Similarly, they showed a more prolonged fever and a delayed recovery from LPS-induced suppression of social interaction. No difference in locomotor activity was observed between obese and lean groups. Comparisons among groups that varied in body weight showed that an 11% increase in body weight was sufficient to increase the number and duration of sickness symptoms displayed after an LPS-injection and that the severity of sickness symptoms increased with increasing body weight. Together these data suggest that DIO can have profound effects on multiple behavioral responses to an acute immune challenge placing obese organisms at higher risk of the consequences of prolonged inflammation.
Assuntos
Comportamento de Doença/fisiologia , Obesidade/imunologia , Obesidade/fisiopatologia , Comportamento Social , Animais , Dieta Hiperlipídica/efeitos adversos , Comportamento de Doença/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Locomoção/imunologia , Masculino , Ratos , Ratos WistarRESUMO
Leptin is an important modulator of both inflammation and energy homeostasis, making it a key interface between the inflammatory response to pathogenic stimuli and the energy status of the host. In previous studies we demonstrated that sickness responses to systemic immune challenge, including fever, are significantly exacerbated in diet induced obese animals. To investigate whether this exacerbation is functionally linked to the obesity associated increase in circulating levels of leptin, a species-specific leptin antiserum (LAS) was used to neutralize endogenous leptin in diet-induced obese adult male Wistar rats treated with a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) (100µg/kg). LAS significantly reduced the magnitude of the later phases of the fever response, and attenuated the circulating levels of IL-6, IL-1ra and bioactivity of leptin in the obese animals. In addition, the antiserum significantly attenuated the hypothalamic expression of IL-1ß, IκBα, COX2, SOCS3 and IL-6 in both lean and obese rats 10h after the LPS injection and NF-IL6 in the hypothalamus of obese rats only. The relatively late rise in brain IL-6 suggested a role in mediating the extended fever response in obese animals and we tested this by neutralizing brain IL-6 using an IL6-AS injected intracerebroventricularly (4µl, icv). The IL6-AS significantly but transiently (between 9h and 12h post LPS) reduced the late fever response of obese rats. These results demonstrate that leptin plays an important part in modulating the late portion of the fever response to LPS, likely through the induction of hypothalamic IL-6 in obese animals.
Assuntos
Febre/metabolismo , Hipotálamo/metabolismo , Interleucina-6/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Animais , Ciclo-Oxigenase 2/metabolismo , Dieta Hiperlipídica , Febre/sangue , Febre/induzido quimicamente , Interleucina-1beta/metabolismo , Interleucina-6/sangue , Lipopolissacarídeos , Masculino , Obesidade/sangue , Obesidade/etiologia , Ratos , Ratos Wistar , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
Obesity contributes to a state of subclinical peripheral and central inflammation and is often associated with aging. Here we investigated the source and contribution of adipose tissue derived cytokines and the cytokine-like hormone leptin to age-related changes in lipopolysaccharide (LPS)-induced brain-controlled sickness-responses. Old (24 months) and young (2 months) rats were challenged with LPS or saline alone or in combination with a neutralizing leptin antiserum (LAS) or control serum. Changes in the sickness-response were monitored by biotelemetry. Additionally, ex vivo fat-explants from young and old rats were stimulated with LPS or saline and culture medium collected and analyzed by cytokine-specific bioassays/ELISAs. We found enhanced duration/degree of the sickness-symptoms, including delayed but prolonged fever in old rats. This response was accompanied by increased plasma-levels of interleukin (IL)-6 and IL-1ra and exaggerated expression of inflammatory markers in brain and liver analyzed by RT-PCR including inhibitor κBα, microsomal prostaglandin synthase and cyclooxygenase 2 (brain). Moreover, for the first time, we were able to show prolonged elevated plasma leptin-levels in LPS-treated old animals. Treatment with LAS in young rats tended to attenuate the early- and in old rats the prolonged febrile response. Fat-explants exhibited unchanged IL-6 but reduced IL-1ra and tumor necrosis factor (TNF)-α release from adipose tissue of aged compared to young animals. In addition, we found increased expression of the endogenous immune regulator microRNA146a in aged animals suggesting a role for these mediators in counteracting brain inflammation. Overall, our results indicate a role of adipose tissue and leptin in "aging-related-inflammation" and age-dependent modifications of febrile-responses.
Assuntos
Envelhecimento/metabolismo , Citocinas/sangue , Inflamação/metabolismo , Leptina/fisiologia , Tecido Adiposo/metabolismo , Animais , Ciclo-Oxigenase 2/metabolismo , Hipotálamo/metabolismo , Inflamação/sangue , Lipopolissacarídeos/toxicidade , Fígado/metabolismo , Masculino , MicroRNAs/metabolismo , Estresse Oxidativo , Ratos , Ratos WistarRESUMO
The intra-uterine environment provides the first regulatory connection for the developing fetus and shapes its physiological responses in preparation for postnatal life. Psychological stress acts as a programming determinant by setting functional parameters to abnormal levels, thus inducing postnatal maladaptation. The effects of prenatal maternal stress (PNMS) on the developing immune system have been documented mostly through animal studies, but inconsistent results and methodological differences have hampered the complete understanding of these findings. As the immune system follows a similar ontogenic pattern in all mammals, a translational framework based on the developmental windows of vulnerability proposed by immunotoxicology studies was created to integrate these findings. The objective of this review is to examine the available literature on PNMS and immune function in the offspring through the above framework and gain a better understanding of these results by elucidating the moderating influence of the stressor type, timing and duration, and the offspring species, sex and age at assessment. The evaluation of the literature through this framework showed that the effects of PNMS are parameter specific: the moderating effects of timing in gestation were relevant for lymphocyte population numbers, Natural Killer cell function and mitogen-induced proliferation. The presence of an important and directional sexual dimorphism was evident and the influence of the type or duration of PNMS paralleled that of stress in non-pregnant animals. In conclusion, PNMS is a relevant factor in the programming of immune function. Its consequences may be related to disorders with an important immune component such as allergies.
Assuntos
Sistema Imunitário/embriologia , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Estresse Psicológico/fisiopatologia , Imunidade Adaptativa , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Sistema Endócrino/embriologia , Sistema Endócrino/imunologia , Feminino , Idade Gestacional , Hematopoese Extramedular , Humanos , Hipersensibilidade/embriologia , Hipersensibilidade/imunologia , Imunidade Inata , Imunocompetência , Síndromes de Imunodeficiência/embriologia , Síndromes de Imunodeficiência/imunologia , Intestinos/microbiologia , Subpopulações de Linfócitos/imunologia , Masculino , Microbiota , Gravidez , Psiconeuroimunologia , Caracteres Sexuais , Especificidade da EspécieRESUMO
BACKGROUND: Whereas the role played by interleukin (IL)-10 in modulating fever and sickness behavior has been linked to it targeting the production of pro-inflammatory cytokines in the circulation, liver and spleen, it is not known whether it could directly target the local production of pro-inflammatory cytokines within the sensory circumventricular organs (CVOs) situated within the brain, but outside the blood-brain barrier. Using inactivation of IL-10, we, therefore, investigated whether IL-10 could modulate the synthesis of pro-inflammatory cytokines within the sensory CVOs, in particular the organum vasculosum laminae terminalis (OVLT) and area postrema (AP). FINDINGS: Primary OVLT and AP microcultures were established from topographically excised rat pup brain tissue. The microcultures were pretreated with either IL-10 antibodies (AB) (10 µl/350 µl medium) or phosphate-buffered saline (PBS) (10 µl/350 µl medium) before being incubated with lipopolysaccharide (LPS) (100 µg/ml) or PBS in complete medium for 6 h. Supernatants were removed from the microcultures after 6 h of incubation with LPS and used for the determination of IL-6 and tumor necrosis factor (TNF)-α. Pre-treating the OVLT and AP microcultures with IL-10 antibodies significantly enhanced the LPS-induced increase in TNF-α and IL-6 in the supernatant obtained from the microcultures. CONCLUSIONS: Our results show for the first time that the LPS-induced release of pro-inflammatory cytokines in cells cultured from the AP and OVLT can be modulated in the presence of IL-10 antibodies. Thus, we have identified that the sensory CVOs may have a key role to play in both the initiation and modulation of neuroinflammation.
Assuntos
Área Postrema/metabolismo , Febre/metabolismo , Hipotálamo/metabolismo , Comportamento de Doença/fisiologia , Mediadores da Inflamação/metabolismo , Interleucina-10/fisiologia , Animais , Animais Recém-Nascidos , Barreira Hematoencefálica/metabolismo , Células Cultivadas , Feminino , Masculino , Projetos Piloto , Ratos , Ratos WistarRESUMO
A decrease in leptin levels with the onset of starvation triggers a myriad of physiological responses including immunosuppression and hypometabolism/hypothermia, both of which can counteract the fever response to pathogens. Here we examined the role of leptin in LPS-induced fever in rats that were fasted for 48 h prior to inflammation with or without leptin replacement (12 µg/day). The preinflammation fasting alone caused a progressive hypothermia that was almost completely reversed by leptin replacement. The LPS (100 µg/kg)-induced elevation in core body temperature (T(core)) was attenuated in the fasted animals at 2-6 h after the injection, an effect that was not reversed by leptin replacement. Increasing the LPS dose to 1,000 µg/kg caused a long-lasting fever that remained unabated for up to 36 h after the injection in the fed rats. This sustained response was strongly attenuated in the fasted rats whose T(core) started to decrease by 18 h after the injection. Leptin replacement almost completely restored the prolonged fever. The attenuation of the prolonged fever in the fasted animals was accompanied by the diminution of proinflammatory PGE(2) in the cerebrospinal fluid and mRNA of proopiomelanocortin (POMC) in the hypothalamus. Leptin replacement prevented the fasting-induced reduction of POMC but not PGE(2). Moreover, the leptin-dependent fever maintenance correlated closely with hypothalamic POMC levels (r = 0.77, P < 0.001). These results suggest that reduced leptin levels during starvation attenuate the sustained fever response by lowering hypothalamic POMC tone but not PGE(2) synthesis.
Assuntos
Temperatura Corporal/efeitos dos fármacos , Febre/induzido quimicamente , Febre/metabolismo , Privação de Alimentos/fisiologia , Leptina/metabolismo , Análise de Variância , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Leptina/farmacologia , Lipopolissacarídeos/farmacologia , Prostaglandinas/líquido cefalorraquidiano , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TelemetriaRESUMO
The appetite suppressing hormone, leptin is now established as an important component of the immune response to pathogens partly via the induction of brain IL-1beta. We have previously demonstrated that this hormone acts on microglia to induce the release of IL-1beta through actions on its functional receptors. In the present study, we extended these findings by demonstrating that leptin's action on microglia is that of a modulator rather than a direct trigger of inflammation. Using primary microglia cultures prepared from rat brain we show that pre-incubation of these cells with leptin for 24h prior to treatment with LPS increased the IL-1beta output 2-fold. This effect was not limited to IL-1beta but was also true for another cytokine, TNF-alpha and chemokines such as CINC-1 and MIP-2. The role of leptin in potentiating the microglial response to LPS appeared to be linked to morphological changes rendering the microglia more reactive. These results suggest that leptin has an important role in microglial function in inflammation and given that its circulating levels fluctuate across a number of conditions, these findings can have important implications for an individual's ability to mount an efficient and complete response to invading pathogens.
Assuntos
Citocinas/metabolismo , Leptina/farmacologia , Microglia/metabolismo , Microglia/ultraestrutura , Animais , Encéfalo/citologia , Química Encefálica/efeitos dos fármacos , Química Encefálica/fisiologia , Células Cultivadas , Quimiocinas/metabolismo , Relação Dose-Resposta a Droga , Imunoensaio , Imuno-Histoquímica , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-1beta/biossíntese , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/biossínteseRESUMO
The main cause of hypoxic/ischemic brain damage in term human neonates is intrauterine asphyxia, in which the whole body is subjected to hypoxia. Inflammatory cytokines are thought to play an important role in modulating hypoxic/ischemic damage in immature brain. Evidence for this from animal models is based mainly on studies that used a model of carotid artery ligation with hypoxia in postnatal rats. However, little is known about the role of cytokines in brain injury after whole-body hypoxia at the time of birth. This study used a well-established rat model of global birth hypoxia to assess mRNA and protein expression of three key proinflammatory cytokines, interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha, (TNF-alpha) in the brain, liver, and kidney of neonates. We observed decreased IL-1beta and TNF-alpha protein, and decreased IL-6 mRNA in brains of neonates in the 2 hr after birth hypoxia but increased IL-6 and IL-1beta in liver compared with vaginally born controls. Increasing the severity of the insult by increasing the period of anoxic exposure further decreased brain IL-1beta, whereas delivering anoxia under hypothermic conditions, known to be neuroprotective, attenuated the decrease in brain IL-1beta. These data suggest that decreased brain levels of inflammatory cytokines may modulate central nervous system responses to global birth hypoxia in rats. Our findings of decreased brain cytokine expression after global birth hypoxia contrast with reports of increased brain cytokines after carotid artery ligation with hypoxia in postnatal rats; possible reasons for these differences are discussed.
Assuntos
Hipóxia Fetal/fisiopatologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Animais , Animais Recém-Nascidos , Temperatura Corporal , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Gravidez , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Epidemiological studies revealed that environmental factors comprising prenatal infection are strongly linked to risk for later development of neuropsychiatric disorders such as schizophrenia. Considering strong sex differences in schizophrenia and its increased prevalence in males, we designed a methodological approach to investigate possible sex differences in pathophysiological mechanisms. Prenatal immune challenge was modeled by systemic administration of the viral mimic polyinosinic-polycytidylic acid (Poly I:C) to C57BL/6 mice at embryonic day 9.5. The consequences on behavior, gene expression, and microglia-brain immune cells that are critical for normal development-were characterized in male vs. female offspring at adulthood. The cerebral cortex, hippocampus, and cerebellum, regions where structural and functional alterations were mainly described in schizophrenia patients, were selected for cellular and molecular analyses. Confocal and electron microscopy revealed most pronounced differences in microglial distribution, arborization, cellular stress, and synaptic interactions in the hippocampus of male vs. female offspring exposed to Poly I:C. Sex differences in microglia were also measured under both steady-state and Poly I:C conditions. These microglial alterations were accompanied by behavioral impairment, affecting for instance sensorimotor gating, in males. Consistent with these results, increased expression of genes related to inflammation was measured in cerebral cortex and hippocampus of males challenged with Poly I:C. Overall, these findings suggest that schizophrenia's higher incidence in males might be associated, among other mechanisms, with an increased microglial reactivity to prenatal immune challenges, hence determining disease outcomes into adulthood.
RESUMO
Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2-/-), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety- and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons. In Eif4e ki/ki mice, brain IκBα, was decreased, while the NF-κB target, TNFα was elevated. TNFα inhibition in Eif4e ki/ki mice rescued, whereas TNFα administration to wild-type mice mimicked the depression-like behaviors and 5-HT synaptic deficits. We conclude that eIF4E phosphorylation modulates depression-like behavior through regulation of inflammatory responses.
Assuntos
Ansiedade/patologia , Depressão/patologia , Fator de Iniciação 4E em Eucariotos/metabolismo , Biossíntese de Proteínas/fisiologia , Proteínas Serina-Treonina Quinases/genética , Animais , Antidepressivos/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/genética , Comportamento Animal/fisiologia , Benzofuranos/farmacologia , Citalopram/farmacologia , Depressão/induzido quimicamente , Depressão/genética , Transtorno Depressivo Maior/patologia , Feminino , Fluoxetina/farmacologia , Inflamação/patologia , Ketamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidor de NF-kappaB alfa/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Transmissão Sináptica/fisiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Maternal infection during pregnancy is a risk factor for some psychiatric illnesses of neurodevelopmental origin such as schizophrenia and autism. In experimental animals, behavioral and neuropathological outcomes relevant to schizophrenia have been observed in offspring of infected dams. However, the type of infectious agent used and gestational age at time of administration have varied. The objective of the present study was to compare the effects of prenatal challenge with different immune agents given at different time windows during gestation on behavioral outcomes in offspring. For this, pregnant rats were administered bacterial endotoxin (lipopolysaccharide, LPS), the viral mimic polyinosinic: polycytidylic acid (poly I:C), or turpentine, an inducer of local inflammation, at doses known to produce fever, at three different stages in pregnancy: embryonic day (E)10-11, E15-16 and E18-19. Prepulse inhibition of acoustic startle (PPI) was later measured in male adult offspring. PPI was significantly decreased in offspring after prenatal LPS treatment at E15-16 and E18-19. Intramuscular injection of pregnant dams with turpentine at E15-16 also decreased PPI in adult offspring. Maternal poly I:C administration had no significant effect on PPI in offspring. In contrast to prenatal LPS exposure, acute LPS administration to naive adult males had no effect on PPI. Thus, prenatal exposure both to a systemic immunogen and to local inflammation at brief periods during later pregnancy produced lasting deficits in PPI in rat offspring. These findings support the idea that maternal infection during critical windows of pregnancy could contribute to sensorimotor gating deficits in schizophrenia.
Assuntos
Encéfalo/imunologia , Período Crítico Psicológico , Inibição Neural/imunologia , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Estimulação Acústica , Análise de Variância , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Cognição/fisiologia , Feminino , Idade Gestacional , Inflamação/induzido quimicamente , Inflamação/imunologia , Lipopolissacarídeos/imunologia , Masculino , Poli I-C/imunologia , Gravidez , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/imunologia , TerebintinaRESUMO
The cytokine interleukin-1beta (IL-1beta) contributes to ischemic, excitotoxic, and traumatic brain injury. IL-1beta actions depend on interaction with a single receptor (IL-1RI), which associates with an accessory protein (IL-1RAcP), and is blocked by IL-1 receptor antagonist (IL-1ra). Here we show that in normal mice [wild-type (WT)], intracerebroventricular injection of IL-1ra markedly reduces (-50%; p < 0.01) ischemic brain damage caused by reversible occlusion of the middle cerebral artery, whereas injection of IL-1beta exacerbates damage (+45%; p < 0.05). Mice lacking IL-1RI [IL-1RI knock-out (KO)] exhibited ischemic brain damage that is almost identical to that of the WT (infarct volume 43.7 +/- 6.1 and 46.2 +/- 6.2 mm3, respectively), but failed to respond to injection of IL-1ra. However, injection of IL-1beta (intracerebroventricularly) exacerbated ischemic brain damage in IL-1RI KO (+61%; p < 0.001) and in WT mice (+45%). This effect of IL-1beta was abolished by heat denaturation in all animals, and was reversed by IL-1ra in WT, but not IL-1RI KO mice. In contrast, IL-1RI KO mice were completely resistant to effects of IL-1beta on food intake or body weight. IL-1RAcP mRNA was increased by stroke in WT, but reduced in IL-1RI KO mice compared with sham-operated mice. Type II IL-1 receptor mRNA was significantly increased 4 hr after ischemia in WT and IL-1RI KO (+20%) animals. These data show that IL-1beta can exacerbate ischemic brain damage independently of IL-1RI and suggest the existence of additional signaling receptor or receptors for IL-1 in the brain.
Assuntos
Isquemia Encefálica/metabolismo , Interleucina-1/metabolismo , Receptores de Interleucina-1/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Cruzamentos Genéticos , Ingestão de Alimentos/efeitos dos fármacos , Injeções Intraventriculares , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1/administração & dosagem , Interleucina-1/farmacologia , Proteína Acessória do Receptor de Interleucina-1 , Masculino , Camundongos , Camundongos Knockout , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Receptores de Interleucina-1/deficiência , Receptores de Interleucina-1/genética , Receptores Tipo I de Interleucina-1 , Receptores Tipo II de Interleucina-1 , Sialoglicoproteínas/administração & dosagemRESUMO
Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients.
RESUMO
The relationship between psychological stress and immunity is well established, but it is not clear if prenatal maternal stress (PNMS) affects the development of the immune system in humans. Our objective was to determine the extent of this influence in a sample of teenagers whose mothers were pregnant during the 1998 Quebec ice storm. As part of a longitudinal study of PNMS, we measured the objective stress exposure and subjective distress of the women soon after the disaster. We obtained blood samples from 37 of their children when they were 13years old to measure cell population percentages and mitogen-induced cytokine production. We found that the mothers' objective degree of PNMS exposure significantly predicted reductions in total and CD4+ lymphocyte proportions, increases in TNF-α, IL-1ß, and IL-6 levels, and an enhancement of the Th2 cytokines IL-4 and IL-13. Sex and timing of PNMS exposure during gestation were also associated with some outcomes. These results show that PNMS is a programming factor that can produce long-lasting consequences on immunity, potentially explaining non-genetic variability in immune-related disorders. This information contributes to the understanding of the mechanisms underlying the influence of PNMS on immune-mediated disorders in humans.
Assuntos
Linfócitos T CD4-Positivos/patologia , Citocinas/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico/etiologia , Estresse Psicológico/patologia , Células Th2/patologia , Adolescente , Estudos de Coortes , Feminino , Citometria de Fluxo , Humanos , Modelos Lineares , Masculino , Valor Preditivo dos Testes , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estatísticas não Paramétricas , Células-Tronco/patologiaRESUMO
Global levels of obesity are reaching epidemic proportions, leading to a dramatic increase in incidence of secondary diseases and the significant economic burden associated with their treatment. These comorbidities include diabetes, cardiovascular disease, and some psychopathologies, which have been linked to a low-grade inflammatory state. Obese individuals exhibit an increase in circulating inflammatory mediators implicated as the underlying cause of these comorbidities. A number of these molecules are also manufactured and released by white adipose tissue (WAT), in direct proportion to tissue mass and are collectively known as adipokines. In the current review we focused on the role of two of the better-studied members of this family namely, leptin and adiponectin, with particular emphasis on their role in neuro-immune interactions, neuroinflammation and subsequent brain diseases. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.