Biology subjects

Amaral, D. G.

Publications and source records attributed to Amaral, D. G..

6 recordsLinked to original sources

bioRxiv2025

Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice.

CHD8 mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. Chd8+/- mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nucleus transcriptomics (snRNA-seq), we found increased Chd8+/- cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive Chd8+/- and conditional Camk2a-Cre Chd8+/-mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found Chd8+/-mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, Chd8 haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.

genomics↗

bioRxiv2025

Cellular mechanisms of early brain overgrowth in autistic children: elevated levels of GPX4 and resistance to ferroptosis

Autistic individuals with disproportionate megalencephaly (ASD-DM), characterized by enlarged brains relative to body height, have higher rates of intellectual disability and face more severe cognitive challenges than autistic children with average brain sizes. The cellular and molecular mechanisms underlying this neurophenotype remain poorly understood. To investigate these mechanisms, we generated human induced pluripotent stem cells from non-autistic typically developing children and autistic children with and without disproportionate megalencephaly. We assessed these children longitudinally from ages two to twelve years using magnetic resonance imaging and comprehensive cognitive and medical evaluations. We show that neural progenitor cells (NPCs) derived from ASD-DM children exhibit increased rates of cell survival and suppressed cell death, accompanied by heightened oxidative stress and ferrous iron accumulation. Despite these stressors, ASD-DM NPCs actively suppress apoptosis and ferroptosis by regulating proteins such as caspase-3 (CASP3), poly(ADP-ribose) polymerase 1 (PARP1), and glutathione peroxidase 4 (GPX4). Cellular ferroptotic signatures are further supported by elevated expression of selenocysteine genes, including GPX4, in the blood of ASD-DM children and their mothers, suggesting potential hereditary or environmental influences. Furthermore, we show that peripheral expression of GPX4 and other selenocysteine genes correlate with cognitive outcomes (IQ). These findings underscore the role of ferroptosis in autism, pointing to potential diagnostic biomarkers and targets for intervention.

neuroscience↗

bioRxiv2024

Brain Charts for the Rhesus Macaque Lifespan

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

neuroscience↗

bioRxiv2021

Social Housing Status Impacts Rhesus Monkeys' Affective Responding in Classic Threat Processing Tasks

The established literature clearly demonstrates that whether or not monkeys are socially reared has long term consequences for their affective behavior. Yet, in the context of behavioral neuroscience and pharmacological studies, social context of adult animals is often ignored. When social context has been studied in adult monkeys, such studies have typically focused on welfare-related issues, as social isolation often leads to the development of abnormal behavior, rather than the impact on outcomes in behavioral neuroscience studies. Variation in social housing conditions for adult animals could have an impact on affective responding and may have significant implications for the interpretation of data from biopsychiatry and behavioral neuroscience studies. We evaluated the affective reactivity of rhesus monkeys (Macaca mulatta) maintained in one of four housing conditions (individually-housed, grate-paired, intermittently-paired, and continuously-paired) using two classic threat processing tasks--a test of responsivity to objects and the Human Intruder Test. Individually-housed monkeys exhibited consistently blunted sensitivity to ostensibly threatening stimuli as compared to socially-housed monkeys. Within the three socially-housed conditions, intermittently- and continuously-paired monkeys behaved similarly to each other and grate-paired monkeys exhibited relatively enhanced sensitivity to threatening stimuli. These findings suggest that the adult housing conditions of monkeys can robustly modulate affective responding in a way that may be consistent with behavioral phenotypes observed in human psychiatric conditions. Results are considered in the context of the broad behavioral and psychiatric neuroscience literatures, which have historically used individually-housed animals, pointing to the potential need to reconsider inferences drawn from those studies.

animal behavior and cognition↗

bioRxiv2021

Increased cortical volume without increased neuron number in heterozygous Chd8 mutant mouse cortex

De novo mutations in the chromatin-remodeling factor CHD8 (Chromodomain-Helicase DNA-binding protein 8) have emerged as a key genetic risk factor for Autism Spectrum Disorder (ASD) and, more generally, neurodevelopmental disorders. Individuals with heterozygous mutations in CHD8 typically present hallmarks of ASD with comorbid cognitive disability and macrocephaly. Knockdown or haploinsufficiency of Chd8 in animal models has recapitulated phenotypes observed in patients, including increased head circumference and brain size. Here, we aimed to determine whether increased neuron numbers or soma size drives increased cortical volume. We performed design-based stereological analyses of cortical structure in adult male and female heterozygous Chd8 mice and wild-type littermate controls. Chd8 haploinsufficient male mice displayed a ~8-12% increase in cortical volume, no differences in cortical neuron number and comparable neuronal soma size. Our study reproduced previous reports of increased brain size associated with CHD8 mutation in humans and mice and are consistent with reported sex-specific impacts of Chd8 mutations in mice and increased burden of CHD8 mutations in human males with ASD. These findings suggest that the nature of the cortical enlargement due to Chd8 haploinsufficiency is complex and appears to be due to a factor other than an increased neuron number or soma size. Lay SummaryWe measured the size and neuron number in the neocortex in mice with heterozygous Chd8 mutation, a model relevant to Autism Spectrum Disorder. We found an increased cortical volume in male mutants, which was not accompanied by increased neuron number or soma size. Our results indicate that the enlarged brain in Chd8 mutant mice is complex, more evident here in males, and is due to factors other than increased neuron number.

neuroscience↗

bioRxiv2020

Maternal immune activation during pregnancy alters early neurobehavioral development in nonhuman primate offspring

BackgroundHuman epidemiologic studies have implicated exposure to infectious or inflammatory insults during gestation in the etiology of neurodevelopmental disorders. Rodent models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant brain and behavior development in offspring. The nonhuman primate MIA model provides an opportunity to maximize the translational utility of this model in a species more closely related to humans. MethodsHere we evaluate the effects of MIA on brain and behavioral development in the rhesus monkey (Macaca mulatta). A modified form of the viral mimic, Polyinosinic-polycytidylic acid (PolyIC), was delivered to pregnant rhesus monkeys (n=14) in the late first trimester to stimulate a maternal immune response. Control dams received saline injections at the same gestational time points (n=10) or were untreated (n=4). ResultsMIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature and inflammatory cytokines. MIA-exposed offspring developed species typical milestones and demonstrate subtle changes in early in social development. However, magnetic resonance imaging demonstrated significant gray matter volume reductions in prefrontal and frontal cortices at 6, 12 and 24 months of age. ConclusionsThese findings provide new insights into the emergence of neuropathology in MIA-exposed primates and have implications for the pathophysiology of human psychiatric disorders associated with maternal gestational infection.

neuroscience↗