Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model.

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.

Calorie restriction and pravastatin administration during pregnancy in obese rhesus macaques modulates maternal and infant metabolism and infant brain and behavioral development.

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.

Altered behavior, brain structure, and neurometabolites in a rat model of autism-specific maternal autoantibody exposure.

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.

Increased Striatal Presynaptic Dopamine in a Nonhuman Primate Model of Maternal Immune Activation: A Longitudinal Neurodevelopmental Positron Emission Tomography Study With Implications for Schizophrenia.

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.

Altered dendritic morphology in dorsolateral prefrontal cortex of nonhuman primates prenatally exposed to maternal immune activation.

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.

Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models.

Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain. The DMRs were enriched for neurodevelopmental functions, methylation-sensitive developmental transcription factor motifs, and human NDD DMRs identified from brain and placenta. Brain and cffDNA methylation levels from a large region overlapping mir-663 correlated with maternal obesity, metabolic and immune markers, and infant behavior. A DUX4 hippocampal co-methylation network correlated with maternal obesity, infant behavior, infant hippocampal lipidomic and metabolomic profiles, and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and metabolites. We conclude that in this model, maternal obesity was associated with changes in the infant brain and behavior, and these differences were detectable in pregnancy through integrative analyses of cffDNA methylation with immune and metabolic factors.

Global metabolic profiles in a non-human primate model of maternal immune activation: implications for neurodevelopmental disorders.

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.

Impact of Maternal Obesity on the Gestational Metabolome and Infant Metabolome, Brain, and Behavioral Development in Rhesus Macaques.

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.

Impact of Maternal Immune Activation on Nonhuman Primate Prefrontal Cortex Development: Insights for Schizophrenia.

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.

Primate Models as a Translational Tool for Understanding Prenatal Origins of Neurodevelopmental Disorders Associated With Maternal Infection.

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.

Reconsidering animal models used to study autism spectrum disorder: Current state and optimizing future.

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are pervasive, often lifelong disorders, lacking evidence-based interventions for core symptoms. With no established biological markers, diagnoses are defined by behavioral criteria. Thus, preclinical in vivo animal models of NDDs must be optimally utilized. For this reason, experts in the field of behavioral neuroscience convened a workshop with the goals of reviewing current behavioral studies, reports, and assessments in rodent models. Goals included: (a) identifying the maximal utility and limitations of behavior in animal models with construct validity; (b) providing recommendations for phenotyping animal models; and (c) guidelines on how in vivo models should be used and reported reliably and rigorously while acknowledging their limitations. We concluded by recommending minimal criteria for reporting in manuscripts going forward. The workshop elucidated a consensus of potential solutions to several problems, including revisiting claims made about animal model links to ASD (and related conditions). Specific conclusions included: mice (or other rodent or preclinical models) are models of the neurodevelopmental insult, not specifically any disorder (e.g., ASD); a model that perfectly recapitulates a disorder such as ASD is untenable; and greater attention needs be given to validation of behavioral testing methods, data analysis, and critical interpretation.

Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring.

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.

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates.

BACKGROUND: Maternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through which MIA imparts risk remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for studying underlying molecular correlates. METHODS: We performed RNA sequencing across psychiatrically relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus) and primary visual cortex for comparison from 3.5- to 4-year-old male MIA-exposed and control offspring-an age comparable to mid adolescence in humans. RESULTS: We identify 266 unique genes differentially expressed in at least one brain region, with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Although we observed temporal and regional differences, transcriptomic changes were shared across first- and second-trimester exposures, including for the top differentially expressed genes-PIWIL2 and MGARP. In addition to PIWIL2, several other regulators of retrotransposition and endogenous transposable elements were dysregulated following MIA, potentially connecting MIA to retrotransposition. CONCLUSIONS: Together, these results begin to elucidate the brain-level molecular processes through which MIA may impart risk for psychiatric disease.

Putative dendritic correlates of chronic traumatic encephalopathy: A preliminary quantitative Golgi exploration.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder that is associated with repetitive head impacts. Neuropathologically, it is defined by the presence of perivascular hyperphosphorylated tau aggregates in cortical tissue (McKee et al., 2016, Acta Neuropathologica, 131, 75-86). Although many pathological and assumed clinical correlates of CTE have been well characterized, its effects on cortical dendritic arbors are still unknown. Here, we quantified dendrites and dendritic spines of supragranular pyramidal neurons in tissue from human frontal and occipital lobes, in 11 cases with (Mage = 79 ± 7 years) and 5 cases without (Mage = 76 ± 11 years) CTE. Tissue was stained with a modified rapid Golgi technique. Dendritic systems of 20 neurons per region in each brain (N = 640 neurons) were quantified using computer-assisted morphometry. One key finding was that CTE neurons exhibited increased variability and distributional changes across six of the eight dendritic system measures, presumably due to ongoing degeneration and compensatory reorganization of dendritic systems. However, despite heightened variation among CTE neurons, CTE cases exhibited lower mean values than Control cases in seven of the eight dendritic system measures. These dendritic alterations may represent a new pathological marker of CTE, and further examination of dendritic changes could contribute to both mechanistic and functional understandings of the disease.

New approaches to quantify social development in rhesus macaques (Macaca mulatta): Integrating eye tracking with traditional assessments of social behavior.

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.

Baseline immunoreactivity before pregnancy and poly(I:C) dose combine to dictate susceptibility and resilience of offspring to maternal immune activation.

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.

Translational opportunities in the prenatal immune environment: Promises and limitations of the maternal immune activation model.

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.

Amygdala growth from youth to adulthood in the macaque monkey.

Emerging evidence suggests that the human amygdala undergoes extensive growth through adolescence, coinciding with the acquisition of complex socioemotional learning. Our objective was to longitudinally map volumetric growth of the nonhuman primate amygdala in a controlled, naturalistic social environment from birth to adulthood. Magnetic resonance images were collected at five time-points in 24 male and female rhesus macaques from 6 months to adulthood at 5 years. We then compared amygdala growth to other brain regions, including newly collected isocortical gray and white matter volumes, and previously published data on the same cohort. We found that amygdala volume increases by nearly 50% from age 6 months to 5 years. This dramatic growth is in contrast to overall brain and hippocampal volume, which peak near 3 years, white matter, which slows from 3 to 5 years, and isocortical gray, which has a net decrease. Similar to isocortical gray and hippocampal volumes, amygdala volume is ~8% larger in males than females. Rate of growth does not differ by sex. Although the underlying neurobiological substrate for protracted amygdala growth into adulthood is unclear, we propose it may be due in part to the unique cellular development of immature neurons in paralaminar nucleus that mature in size and connectivity with age. Prolonged amygdala maturation raises the possibility that environmental and genetic perturbations that disrupt this trajectory may contribute to the emergence of psychiatric disorders, such as anxiety, depression, schizophrenia, and autism; all in which the amygdala is strongly implicated.