Selected Grantee Publications
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- Nonhuman Primate Models
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- nia
Disruption of Myelin Structure and Oligodendrocyte Maturation in a Macaque Model of Congenital Zika Infection
Tisoncik-Go et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49524-2
Maternal infection during pregnancy can have severe consequences on fetal development and survival. Using a pigtail macaque model for Zika virus infection, researchers show that in utero exposure of a fetus to Zika virus due to maternal infection results in significantly decreased myelin formation around neurons. Myelin is a protective sheath that forms around neurons and is required for brain processing speed. This study suggests that reduced myelin resulting from Zika infection in utero is likely a contributing factor to severe deficits in brain development and microcephaly. Supported by ORIP (P51OD010425), NEI, and NIAID.
Genetic Diversity of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation and Identifies Disease Models
Wang et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49922-6
Nonhuman primates are ideal models for certain human diseases, including retinal and neurodevelopmental disorders. Using a reverse genetics approach, researchers profiled the genetic diversity of rhesus macaque populations across eight primate research centers in the United States and uncovered rhesus macaques carrying naturally occurring pathogenic mutations. They identified more than 47,000 single-nucleotide variants in 374 genes that had been previously linked with retinal and neurodevelopmental disorders in humans. These newly identified variants can be used to study human disease pathology and to test novel treatments. Supported by ORIP (P51OD011107, P51OD011106, P40OD012217, S10OD032189), NEI, NIAID, and NIMH.
Identification of Constrained Sequence Elements Across 239 Primate Genomes
Kuderna et al., Nature. 2024.
https://pubmed.ncbi.nlm.nih.gov/38030727/
Functional genomic elements that have acquired selective constraints specific to the primate order are prime candidates for understanding evolutionary changes in humans, but the selective constraints specific to the phylogenetic branch from which the human species ultimately emerged remain largely unidentified. Researchers constructed a genome-wide multiple sequence alignment of 239 primate species to better characterize constraint at noncoding regulatory sequences in the human genome. Their work reveals noncoding regulatory elements that are under selective constraint in primates but not in other placental mammals and are enriched for variants that affect human gene expression and complex traits in diseases. These findings highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals. Supported by ORIP (P40OD024628), NHGRI, NIA, and NICHD.
Effect of Hormone Replacement Therapy on Amyloid Beta (Aβ) Plaque Density in the Rhesus Macaque Amygdala
Appleman et al., Frontiers in Aging Neuroscience. 2024.
https://www.frontiersin.org/articles/10.3389/fnagi.2023.1326747/full
Amyloid beta plaque density is associated with Alzheimer’s disease. In this study, the authors examined its concentration in aged female nonhuman primates’ cerebrospinal fluid, as well as in the amygdala, an area of the brain involved with emotion and memory. They set out to test the hypothesis that estrogen hormone replacement therapy can beneficially affect amygdala Aβ plaque density in “surgically menopausal” females (i.e., aged rhesus macaques that had undergone ovariectomy). Female rhesus macaques that received estrogen replacement therapy showed fewer amyloid plaques than those that did not receive the hormone. This effect was observed regardless of the type of diet that the animals consumed. These findings suggest that hormone replacement might be a helpful treatment to consider for Alzheimer’s disease. Supported by ORIP (P51OD011092, R24OD011895, S10OD025002) and NIA.
Deep Analysis of CD4 T Cells in the Rhesus CNS During SIV Infection
Elizaldi et al., PLOS Pathogens. 2023.
https://pubmed.ncbi.nlm.nih.gov/38060615/
Systemic HIV infection results in chronic inflammation that causes lasting damage to the central nervous system (CNS), despite long-term antiretroviral therapy (ART). Researchers studied neurocognitive outcomes in male and female rhesus macaques infected with simian immunodeficiency virus (SIV) using an ART regimen simulating suboptimal adherence; one group received no ART, and the other received ART with periodic interruptions. Using single-cell transcriptomic profiling, the researchers also identified molecular programs induced in the brain upon infection. They found that acute infection led to marked imbalance in the CNS CD4/CD8 T‑cell ratio, which persisted into the chronic phase. The studies provide insight into the role of CD4 T cells in the CNS during HIV infection. Supported by ORIP (P51OD011107, K01OD023034), NIA, NIAID, and NCI.
IL-21-IgFc Immunotherapy Alters Transcriptional Landscape of Lymph Node Cells Leading to Enhanced Flu Vaccine Response in Aging and SIV Infection
Pallikkuth et al., Aging Cell. 2023.
https://pubmed.ncbi.nlm.nih.gov/37712598/
Aging is associated with increased risk of seasonal flu disease burden and serious flu-related complications, particularly for people with HIV. In this study, investigators aimed to elucidate the immunomodulation following flu vaccination in aging male and female rhesus macaques infected with simian immunodeficiency virus (SIV). Their results suggest that IL-21 treatment at the time of flu vaccination modulates the inductive lymph node germinal center activity to reverse SIV-associated immune dysfunction. The authors identified IL-21 as a potential candidate molecule for immunotherapy to enhance flu vaccine responses in affected populations. Further studies could examine the overall benefit of IL-21 immunotherapy on mucosal lung immunity and protection against infection. Supported by ORIP (R24OD010947), NIA, and NIAID.
A Class of Anti-Inflammatory Lipids Decrease with Aging in the Central Nervous System
Tan et al., Nature Chemical Biology. 2023.
https://doi.org/10.1038/s41589-022-01165-6
Impaired lipid metabolism in the brain has been implicated in neurological disorders of aging, yet analyses of lipid pathway changes with age have been lacking. The researchers examined the brain lipidome of mice of both sexes across the lifespan using untargeted lipidomics. They found that 3-sulfogalactosyl diacylglycerols (SGDGs) are structural components of myelin and decline with age in the central nervous system. The researchers discovered that SGDGs also are present in male human and rhesus macaque brains, demonstrating their evolutionary conservation in mammals. The investigators showed that SGDGs possess anti-inflammatory activity, suggesting a potential role for this lipid class in age-related neurodegenerative diseases. Supported by ORIP (P51OD011092), NIA, NCI, NIDDK, and NINDS.
SARS-CoV-2 Infects Neurons and Induces Neuroinflammation in a Non-Human Primate Model of COVID-19
Beckman et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111573
SARS-CoV-2 causes brain fog and other neurological complications in some patients. It has been unclear whether SARS-CoV-2 infects the brain directly or whether central nervous system sequelae result from systemic inflammatory responses triggered in the periphery. Using a rhesus macaque model, researchers detected SARS-CoV-2 in the olfactory cortex and interconnected regions 7 days after infection, demonstrating that the virus enters the brain through the olfactory nerve. Neuroinflammation and neuronal damage were more severe in elderly monkeys with type 2 diabetes. The researchers found that in aged monkeys, SARS-CoV-2 traveled farther along nerve pathways to regions associated with Alzheimer's disease. Supported by ORIP (P51OD011107) and NIA.
Molecular and Cellular Evolution of the Primate Dorsolateral Prefrontal Cortex
Ma et al., Science. 2022.
https://www.doi.org/10.1126/science.abo7257
The dorsolateral prefrontal cortex (dlPFC) exists only in primates, lies at the center of high-order cognition, and is a locus of pathology underlying many neuropsychiatric diseases. The investigators generated single-nucleus transcriptome data profiling more than 600,000 nuclei from the dlPFC of adult humans, chimpanzees, rhesus macaques, and common marmosets of both sexes. Postmortem human samples were obtained from tissue donors. The investigators’ analyses delineated dlPFC cell-type homology and transcriptomic conservation across species and identified species divergence at the molecular and cellular levels, as well as potential epigenomic mechanisms underlying these differences. Expression patterns of more than 900 genes associated with brain disorders revealed a variety of conserved, divergent, and group-specific patterns. The resulting data resource will help to vertically integrate marmoset and macaque models with human-focused efforts to develop treatments for neuropsychiatric conditions. Supported by ORIP (P51OD011133), NIA, NICHD, NIDA, NIGMS, NHGRI, NIMH, and NINDS.
Parallel Processing, Hierarchical Transformations, and Sensorimotor Associations along the “Where” Pathway
Doudlah et al., eLife. 2022.
https://www.doi.org/10.7554/eLife.78712
Visually guided behaviors require the brain to transform ambiguous retinal images into object-level spatial representations and map those representations to motor responses. These capabilities are supported by the dorsal “where” pathway in the brain, but the specific contributions of areas along this pathway have remained elusive. Using a rhesus macaque model, researchers compared neuronal activity in two areas along the “where” pathway that bridge the parieto-occipital junction: intermediate visual area V3A and the caudal intraparietal (CIP) area. Neuronal activity was recorded while the animals made perceptual decisions based on judging the tilt of 3D visual patterns. The investigators found that CIP shows higher-order spatial representations and more choice-correlated responses, which support a V3A-to-CIP hierarchy. The researchers also discovered modulation of V3A activity by extraretinal factors, suggesting that V3A might be better characterized as contributing to higher-order behavioral functions rather than low-level visual feature processing. Supported by ORIP (P51OD011106), NEI, NICHD, and NINDS.