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Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (both p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.
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Maternal immune dysregulation is a prenatal risk factor for autism spectrum disorder (ASD). Importantly, a clinically relevant connection exists between inflammation and metabolic stress that can result in aberrant cytokine signaling and autoimmunity. In this study we examined the potential for maternal autoantibodies (aAbs) to disrupt metabolic signaling and induce neuroanatomical changes in the brains of exposed offspring. To accomplish this, we developed a model of maternal aAb exposure in rats based on the clinical phenomenon of maternal autoantibody-related ASD (MAR-ASD). Following confirmation of aAb production in rat dams and antigen-specific immunoglobulin G (IgG) transfer to offspring, we assessed offspring behavior and brain structure longitudinally. MAR-ASD rat offspring displayed a reduction in pup ultrasonic vocalizations and a pronounced deficit in social play behavior when allowed to freely interact with a novel partner. Additionally, longitudinal in vivo structural magnetic resonance imaging (sMRI) at postnatal day 30 (PND30) and PND70, conducted in a separate cohort of animals, revealed sex-specific differences in total and regional brain volume. Treatment-specific effects by region appeared to converge on midbrain and cerebellar structures in MAR-ASD offspring. Simultaneously, in vivo 1H magnetic resonance spectroscopy (1H-MRS) data were collected to examine brain metabolite levels in the medial prefrontal cortex. Results showed that MAR-ASD offspring displayed decreased levels of choline-containing compounds and glutathione, accompanied by increased taurine compared to control animals. Overall, we found that rats exposed to MAR-ASD aAbs present with alterations in behavior, brain structure, and neurometabolites; reminiscent of findings observed in clinical ASD.
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Transtorno do Espectro Autista , Transtorno Autístico , Efeitos Tardios da Exposição Pré-Natal , Humanos , Masculino , Gravidez , Feminino , Ratos , Animais , Transtorno Autístico/metabolismo , Transtorno do Espectro Autista/metabolismo , Autoanticorpos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Encéfalo/metabolismo , Exposição MaternaRESUMO
Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring's neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.
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Efeitos Tardios da Exposição Pré-Natal , Esquizofrenia , Feminino , Animais , Humanos , Masculino , Citocinas , Encéfalo , Modelos Animais de Doenças , Primatas , Comportamento Animal/fisiologiaRESUMO
Women who contract a viral or bacterial infection during pregnancy have an increased risk of giving birth to a child with a neurodevelopmental or psychiatric disorder. The effects of maternal infection are likely mediated by the maternal immune response, as preclinical animal models have confirmed that maternal immune activation (MIA) leads to long lasting changes in offspring brain and behavior development. The present study sought to determine the impact of MIA-exposure during the first or second trimester on neuronal morphology in dorsolateral prefrontal cortex (DLPFC) and hippocampus from brain tissue obtained from MIA-exposed and control male rhesus monkey (Macaca mulatta) during late adolescence. MIA-exposed offspring display increased neuronal dendritic branching in pyramidal cells in DLPFC infra- and supragranular layers relative to controls, with no significant differences observed between offspring exposed to maternal infection in the first and second trimester. In addition, the diameter of apical dendrites in DLPFC infragranular layer is significantly decreased in MIA-exposed offspring relative to controls, irrespective of trimester exposure. In contrast, alterations in hippocampal neuronal morphology of MIA-exposed offspring were not evident. These findings demonstrate that a maternal immune challenge during pregnancy has long-term consequences for primate offspring dendritic structure, selectively in a brain region vital for socioemotional and cognitive development.
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Transtornos Mentais , Efeitos Tardios da Exposição Pré-Natal , Humanos , Animais , Gravidez , Masculino , Feminino , Córtex Pré-Frontal Dorsolateral , Exposição Materna , Encéfalo , Modelos Animais de Doenças , Poli I-C/farmacologia , Comportamento Animal/fisiologia , Córtex Pré-FrontalRESUMO
Epidemiological evidence implicates severe maternal infections as risk factors for neurodevelopmental disorders, such as ASD and schizophrenia. Accordingly, animal models mimicking infection during pregnancy, including the maternal immune activation (MIA) model, result in offspring with neurobiological, behavioral, and metabolic phenotypes relevant to human neurodevelopmental disorders. Most of these studies have been performed in rodents. We sought to better understand the molecular signatures characterizing the MIA model in an organism more closely related to humans, rhesus monkeys (Macaca mulatta), by evaluating changes in global metabolic profiles in MIA-exposed offspring. Herein, we present the global metabolome in six peripheral tissues (plasma, cerebrospinal fluid, three regions of intestinal mucosa scrapings, and feces) from 13 MIA and 10 control offspring that were confirmed to display atypical neurodevelopment, elevated immune profiles, and neuropathology. Differences in lipid, amino acid, and nucleotide metabolism discriminated these MIA and control samples, with correlations of specific metabolites to behavior scores as well as to cytokine levels in plasma, intestinal, and brain tissues. We also observed modest changes in fecal and intestinal microbial profiles, and identify differential metabolomic profiles within males and females. These findings support a connection between maternal immune activation and the metabolism, microbiota, and behavioral traits of offspring, and may further the translational applications of the MIA model and the advancement of biomarkers for neurodevelopmental disorders such as ASD or schizophrenia.
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Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Masculino , Animais , Feminino , Humanos , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Primatas , MetabolomaRESUMO
Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are conducted in rodents, the nonhuman primate provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a nonhuman primate MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.
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Encéfalo/patologia , Modelos Animais de Doenças , Transtornos do Neurodesenvolvimento/etiologia , Complicações Infecciosas na Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Feminino , Indutores de Interferon/toxicidade , Macaca mulatta , Masculino , Transtornos do Neurodesenvolvimento/patologia , Neurogênese/fisiologia , Poli I-C/toxicidade , Gravidez , Complicações Infecciosas na Gravidez/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamenteRESUMO
Remarkably little is known about the postnatal cellular development of the human amygdala. It plays a central role in mediating emotional behavior and has an unusually protracted development well into adulthood, increasing in size by 40% from youth to adulthood. Variation from this typical neurodevelopmental trajectory could have profound implications on normal emotional development. We report the results of a stereological analysis of the number of neurons in amygdala nuclei of 52 human brains ranging from 2 to 48 years of age [24 neurotypical and 28 autism spectrum disorder (ASD)]. In neurotypical development, the number of mature neurons in the basal and accessory basal nuclei increases from childhood to adulthood, coinciding with a decrease of immature neurons within the paralaminar nucleus. Individuals with ASD, in contrast, show an initial excess of amygdala neurons during childhood, followed by a reduction in adulthood across nuclei. We propose that there is a long-term contribution of mature neurons from the paralaminar nucleus to other nuclei of the neurotypical human amygdala and that this growth trajectory may be altered in ASD, potentially underlying the volumetric changes detected in ASD and other neurodevelopmental or neuropsychiatric disorders.
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Tonsila do Cerebelo/fisiopatologia , Transtorno Autístico/patologia , Neurônios/citologia , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Neurônios/fisiologia , Adulto JovemRESUMO
The prenatal environment, and in particular, the maternal-fetal immune environment, has emerged as a targeted area of research for central nervous system (CNS) diseases with neurodevelopmental origins. Converging evidence from both clinical and preclinical research indicates that changes in the maternal gestational immune environment can alter fetal brain development and increase the risk for certain neurodevelopmental disorders. Here we focus on the translational potential of one prenatal animal model - the maternal immune activation (MIA) model. This model stems from the observation that a subset of pregnant women who are exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder, such as autism spectrum disorder (ASD) or schizophrenia (SZ). The preclinical MIA model provides a system in which to explore causal relationships, identify underlying neurobiological mechanisms, and, ultimately, develop novel therapeutic interventions and preventative strategies. In this review, we will highlight converging evidence from clinical and preclinical research that links changes in the maternal-fetal immune environment with lasting changes in offspring brain and behavioral development. We will then explore the promises and limitations of the MIA model as a translational tool to develop novel therapeutic interventions. As the translational potential of the MIA model has been the focus of several excellent review articles, here we will focus on what is perhaps the least well developed area of MIA model research - novel preventative strategies and therapeutic interventions.
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Encéfalo/crescimento & desenvolvimento , Modelos Animais de Doenças , Transtornos do Neurodesenvolvimento/imunologia , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Encéfalo/imunologia , Feminino , Humanos , Transtornos do Neurodesenvolvimento/etiologia , Gravidez , Pesquisa Translacional BiomédicaRESUMO
Despite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, current approaches using these models ignore two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal viral infection and (ii) susceptible pregnancies can lead to different combinations of phenotypes in offspring. Here, we report two new sources of variability-the baseline immunoreactivity (BIR) of isogenic females prior to pregnancy and differences in immune responses in C57BL/6 dams across vendors-that contribute to resilience and susceptibility to distinct combinations of behavioral and biological outcomes in offspring. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all pregnancies and a combination of poly(I:C) dose and BIR predicts susceptibility and resilience of pregnancies to aberrant repetitive behaviors and alterations in striatal protein levels in offspring. Even more surprising is that the intermediate levels of BIR and poly(I:C) dose are most detrimental to offspring, with higher BIR and poly(I:C) doses conferring resilience to measured phenotypes in offspring. Importantly, we identify the BIR of female mice as a biomarker before pregnancy that predicts which dams will be most at risk as well as biomarkers in the brains of newborn offspring that correlate with changes in repetitive behaviors. Together, our results highlight considerations for optimizing MIA protocols to enhance rigor and reproducibility and reveal new factors that drive susceptibility of some pregnancies and resilience of others to MIA-induced abnormalities in offspring.
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Efeitos Tardios da Exposição Pré-Natal , Animais , Comportamento Animal , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C , Gravidez , Reprodutibilidade dos TestesRESUMO
The nonhuman primate provides a sophisticated animal model system both to explore neurobiological mechanisms underlying complex behaviors and to facilitate preclinical research for neurodevelopmental and neuropsychiatric disease. A better understanding of evolutionarily conserved behaviors and brain processes between humans and nonhuman primates will be needed to successfully apply recently released NIMH guidelines (NOT-MH-19-053) for conducting rigorous nonhuman primate neurobehavioral research. Here, we explore the relationship between two measures of social behavior that can be used in both humans and nonhuman primates-traditional observations of social interactions with conspecifics and eye gaze detection in response to social stimuli. Infant male rhesus macaques (Macaca mulatta) serving as controls (N = 14) for an ongoing study were observed in their social rearing groups and participated in a noninvasive, longitudinal eye-tracking study. We found significant positive relationships between time spent viewing eyes of faces in an eye tracker and number of initiations made for social interactions with peers that is consistent with similar observations in human populations. Although future studies are needed to determine if this relationship represents species-typical social developmental processes, these preliminary results provide a novel framework to explore the relationship between social interactions and social attention in nonhuman primate models for neurobehavioral development.
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Animais Recém-Nascidos/psicologia , Medições dos Movimentos Oculares/veterinária , Macaca mulatta/psicologia , Comportamento Social , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Movimentos Oculares , Macaca mulatta/crescimento & desenvolvimento , MasculinoRESUMO
Nonhuman primates provide a human-relevant experimental model system to explore the mechanisms by which oxytocin (OT) regulates social processing and inform its clinical applications. Here, we highlight contributions of the nonhuman primate model to our understanding of OT treatment and address unique challenges in administering OT to awake behaving primates. Prior preclinical research utilizing macaque monkeys has demonstrated that OT can modulate perception of other individuals and their expressions, attention to others, imitation, vigilance to social threats, and prosocial decisions. We further describe ongoing efforts to develop an OT delivery system for use in experimentally naïve juvenile macaque monkeys compatible with naturalistic social behavior outcomes. Finally, we discuss future directions to further develop the rhesus monkey as a preclinical test bed to evaluate the effects of OT exposure and advance efforts to translate basic science OT research into safe and effective OT therapies.
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Administração Intranasal/métodos , Macaca mulatta , Ocitocina/administração & dosagem , Ocitocina/farmacocinética , Administração Intranasal/instrumentação , Animais , Feminino , Masculino , Comportamento SocialRESUMO
Infection during pregnancy can lead to activation of the maternal immune system and has been associated with an increased risk of having an offspring later diagnosed with a neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) or schizophrenia (SZ). Most maternal immune activation (MIA) studies to date have been in rodents and usually involve the use of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). However, since NDD are based on behavioral changes, a model of MIA in non-human primates could potentially provide data that helps illuminate complex behavioral and immune outputs in human NDD. In this study twenty-one pregnant rhesus macaques were either given three injections over 72 hours of poly I:C-LC, a double stranded RNA analog (viral mimic), or saline as a control. Injections were given near the end of the first trimester or near the end of the second trimester to determine if there were differences in immune output due to the timing of MIA.An additional three non-treated animals were used as controls. The offspring were followed until 4 years of age, with blood collected at the end of their first (year 1) and fourth (year 4) years to assess dynamic cellular immune function. Induced responses from peripheral immune cells were measured using multiplex assays.At one year of age, MIA exposed offspring displayed elevated production of innate inflammatory cytokines including: interleukin (IL)-1ß, IL-6, IL-12p40, and tumor necrosis factor (TNF)α at baseline and following stimulation. At four years of age, the MIA exposed offspring continued to display elevated IL-1ß, and there was also a pattern of an increased production of T-cell helper type (TH)-2 cytokines, IL-4 and IL-13. Throughout this time period, the offspring of MIA treated dams exhibited altered behavioral phenotypes including increased stereotyped behaviors. During the first two years, stereotyped behaviors were associated with innate cytokine production. Self-directed behaviors were associated with TH2 cytokine production at year 4. Data from this study suggests long-term behavioral and immune activation was present in offspring following MIA. This novel non-human primate model of MIA may provide a relevant clinically translational model to help further elucidate the role between immune dysfunction and complex behavioral outputs following MIA.
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Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Comportamento Animal/fisiologia , Citocinas , Modelos Animais de Doenças , Feminino , Sistema Imunitário/efeitos dos fármacos , Interleucina-13/imunologia , Interleucina-4/imunologia , Macaca mulatta , Atividade Motora/efeitos dos fármacos , Poli I-C/farmacologia , Gravidez , Complicações Infecciosas na Gravidez , Comportamento Estereotipado , Células Th2/imunologiaRESUMO
Maternal infection during pregnancy increases the risk for neurodevelopmental disorders in offspring. Rodent models have played a critical role in establishing maternal immune activation (MIA) as a causal factor for altered brain and behavioral development in offspring. We recently extended these findings to a species more closely related to humans by demonstrating that rhesus monkeys (Macaca mulatta) prenatally exposed to MIA also develop abnormal behaviors. Here, for the first time, we present initial evidence of underlying brain pathology in this novel nonhuman primate MIA model. Pregnant rhesus monkeys were injected with a modified form of the viral mimic polyI:C (poly ICLC) or saline at the end of the first trimester. Brain tissue was collected from the offspring at 3.5 years and blocks of dorsolateral prefrontal cortex (BA46) were used to analyze neuronal dendritic morphology and spine density using the Golgi-Cox impregnation method. For each case, 10 layer III pyramidal cells were traced in their entirety, including all apical, oblique and basal dendrites, and their spines. We further analyzed somal size and apical dendrite trunk morphology in 30 cells per case over a 30 µm section located 100±10 µm from the soma. Compared to controls, apical dendrites of MIA-treated offspring were smaller in diameter and exhibited a greater number of oblique dendrites. These data provide the first evidence that prenatal exposure to MIA alters dendritic morphology in a nonhuman primate MIA model, which may have profound implications for revealing the underlying neuropathology of neurodevelopmental disorders related to maternal infection.
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Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Neurônios/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Carboximetilcelulose Sódica/análogos & derivados , Carboximetilcelulose Sódica/farmacologia , Forma Celular/efeitos dos fármacos , Feminino , Macaca mulatta , Masculino , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Poli I-C/farmacologia , Polilisina/análogos & derivados , Polilisina/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologiaRESUMO
Nonhuman primates are widely used models to investigate the neural substrates of human behavior, including the development of higher cognitive and affective function. Due to their neuroanatomical and behavioral homologies with humans, the rhesus macaque monkey (Macaca mulatta) provides an excellent animal model in which to characterize the maturation of brain structures from birth through adulthood and into senescence. To evaluate hippocampal development in rhesus macaques, structural magnetic resonance imaging scans were obtained longitudinally at 9 time points between 1 week and 260 weeks (5 years) of age on 24 rhesus macaque monkeys (12 males, 12 females). In our sample, the hippocampus reaches 50% of its adult volume by 13 weeks of age and reaches an adult volume by 52 weeks in both males and females. The hippocampus appears to be slightly larger at 3 years than at 5 years of age. Male rhesus macaques have larger hippocampi than females from 8 weeks onward by approximately 5%. Interestingly, there was increased variability in hemispheric asymmetry for hippocampus volumes at younger ages than at later ages. These data provide a comprehensive evaluation of the longitudinal development of male and female rhesus macaque hippocampus across development from 1 week to 5 years of age.
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Hipocampo/crescimento & desenvolvimento , Macaca mulatta/crescimento & desenvolvimento , Imageamento por Ressonância Magnética , Neuroimagem , Animais , Feminino , Masculino , Tamanho do Órgão , Caracteres SexuaisRESUMO
The present experiments continue a longitudinal study of rhesus macaque social behavior following bilateral neonatal ibotenic acid lesions of the amygdala or hippocampus, or sham operations. Juvenile animals (approximately 1.5-2.5 years) were tested in four different social contexts--alone, while interacting with one familiar peer, while interacting with one unfamiliar peer, and in their permanent social groups. During infancy, the amygdala-lesioned animals displayed more interest in conspecifics (indexed by increased affiliative signaling) and paradoxically demonstrated more submission or fear (Bauman, Lavenex, Mason, Capitanio, & Amaral, 2004a, this journal). When these animals were assessed as juveniles, differences were less striking. Amygdala-lesioned animals generated fewer aggressive and affiliative signals (e.g., vocalizations, facial displays) and spent less time in social interactions with familiar peers. When animals were observed alone or with an unfamiliar peer, amygdala-lesioned animals, compared with other subjects, spent more time being inactive and physically explored the environment less. Despite the subtle, lesion-based differences in the frequency and duration of specific social behaviors, there were lesion-based differences in the organization of behavior such that lesion groups could be identified based on the patterning of social behaviors in a discriminant function analysis. The findings indicate that, although overall frequencies of many of the observed behaviors do not differ between groups, the general patterning of social behavior may distinguish the amygdala-lesioned animals.
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Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/patologia , Comportamento Exploratório/fisiologia , Comportamento Social , Fatores Etários , Animais , Feminino , Estudos Longitudinais , Macaca mulatta , MasculinoRESUMO
Background: Maternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development. Methods: A total of 19 obese mothers were assigned to either one of the two intervention groups (n = 5 for calorie restriction; n = 7 for pravastatin) or an obese control group (n = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers (n = 6) using metabolomics methods. Results: Gestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test. Conclusions: Although the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.
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BACKGROUND: Epidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring. METHODS: In this unique prospective longitudinal study, we used [18F]fluoro-l-m-tyrosine positron emission tomography to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n = 13) injected with a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid [poly(I:C)], in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine from these animals was compared with that of control offspring born to dams that received saline (n = 10) or no injection (n = 4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work with this cohort found decreased prefrontal gray matter volume in MIA offspring versus controls between 6 and 45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized that there would be a delayed (relative to the gray matter decrease) increase in striatal fluoro-l-m-tyrosine signal in the MIA group versus controls. RESULTS: [18F]fluoro-l-m-tyrosine signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months. CONCLUSIONS: These findings are highly relevant to the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.
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Efeitos Tardios da Exposição Pré-Natal , Esquizofrenia , Gravidez , Animais , Feminino , Humanos , Masculino , Esquizofrenia/diagnóstico por imagem , Dopamina , Estudos Transversais , Estudos Longitudinais , Estudos Prospectivos , Tomografia por Emissão de Pósitrons , PrimatasRESUMO
Pregnant women represent a uniquely vulnerable population during an infectious disease outbreak, such as the COVID-19 pandemic. Although we are at the early stages of understanding the specific impact of SARS-CoV-2 exposure during pregnancy, mounting epidemiological evidence strongly supports a link between exposure to a variety of maternal infections and an increased risk for offspring neurodevelopmental disorders. Inflammatory biomarkers identified from archived or prospectively collected maternal biospecimens suggest that the maternal immune response is the critical link between infection during pregnancy and altered offspring neurodevelopment. This maternal immune activation (MIA) hypothesis has been tested in animal models by artificially activating the immune system during pregnancy and evaluating the neurodevelopmental consequences in MIA-exposed offspring. Although the vast majority of MIA model research is carried out in rodents, the nonhuman primate model has emerged in recent years as an important translational tool. In this review, we briefly summarize human epidemiological studies that have prompted the development of translationally relevant MIA models. We then highlight notable similarities between humans and nonhuman primates, including placental structure, pregnancy physiology, gestational timelines, and offspring neurodevelopmental stages, that provide an opportunity to explore the MIA hypothesis in species more closely related to humans. Finally, we provide a comprehensive review of neurodevelopmental alterations reported in current nonhuman primate models of maternal infection and discuss future directions for this promising area of research.
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COVID-19 , Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Animais , Modelos Animais de Doenças , Feminino , Humanos , Macaca mulatta , Transtornos do Neurodesenvolvimento/etiologia , Pandemias , Placenta , Gravidez , SARS-CoV-2RESUMO
Late adolescence is a period of dynamic change in the brain as humans learn to navigate increasingly complex environments. In particular, prefrontal cortical (PFC) regions undergo extensive remodeling as the brain is fine-tuned to orchestrate cognitive control over attention, reasoning, and emotions. Late adolescence also presents a uniquely vulnerable period as neurodevelopmental illnesses, such as schizophrenia, become evident and worsen into young adulthood. Challenges in early development, including prenatal exposure to infection, may set the stage for a cascade of maladaptive events that ultimately result in aberrant PFC connectivity and function before symptoms emerge. A growing body of research suggests that activation of the mother's immune system during pregnancy may act as a disease primer, in combination with other environmental and genetic factors, contributing to an increased risk of neurodevelopmental disorders, including schizophrenia. Animal models provide an invaluable opportunity to examine the course of brain and behavioral changes in offspring exposed to maternal immune activation (MIA). Although the vast majority of MIA research has been carried out in rodents, here we highlight the translational utility of the nonhuman primate (NHP) as a model species more closely related to humans in PFC structure and function. In this review, we consider the protracted period of brain and behavioral maturation in the NHP, describe emerging findings from MIA NHP offspring in the context of rodent preclinical models, and lastly explore the translational relevance of the NHP MIA model to expand understanding of the etiology and developmental course of PFC pathology in schizophrenia.
Assuntos
Efeitos Tardios da Exposição Pré-Natal , Esquizofrenia , Adulto , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Feminino , Humanos , Poli I-C , Córtex Pré-Frontal/patologia , Gravidez , Primatas , Adulto JovemRESUMO
Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of both pregnant mothers and their offspring, as well as on metabolic, brain, and behavioral development of offspring by utilizing metabolomics, protein, and behavioral assays in a non-human primate model. We found that maternal obesity was associated with elevated inflammation and significant alterations in metabolites of energy metabolism and one-carbon metabolism in maternal plasma and urine, as well as in the placenta. Infants that were born to obese mothers were significantly larger at birth compared to those that were born to lean mothers. Additionally, they exhibited significantly reduced novelty preference and significant alterations in their emotional response to stress situations. These changes coincided with differences in the phosphorylation of enzymes in the brain mTOR signaling pathway between infants that were born to obese and lean mothers and correlated with the concentration of maternal plasma betaine during pregnancy. In summary, gestational obesity significantly impacted the infant systemic and brain metabolome and adaptive behaviors.