Selected Grantee Publications
Profiling Development of Abdominal Organs in the Pig
Gabriel et al., Scientific Reports. 2022.
https://www.doi.org/10.1038/s41598-022-19960-5
The pig is a model system for studying human development and disease due to its similarities to human anatomy, physiology, size, and genome. Moreover, advances in CRISPR gene editing have made genetically engineered pigs a viable model for the study of human pathologies and congenital anomalies. However, a detailed atlas illustrating pig development is necessary for identifying and modeling developmental defects. Here, the authors describe normal development of the pig abdominal system (i.e., kidney, liver, pancreas, spleen, adrenal glands, bowel, gonads) and compare them with congenital defects that can arise in gene-edited SAP130 mutant pigs. This atlas and the methods described here can be used as tools for identifying developmental pathologies of the abdominal organs in the pig at different stages of development. Supported by ORIP (U42OD011140), NHLBI, NIAID, NIBIB, NICHD, and NINDS.
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.
X Chromosome Agents of Sexual Differentiation
Arnold et al., Nature Reviews Endocrinology. 2022.
https://www.doi.org/10.1038/s41574-022-00697-0
Many diseases affect one sex disproportionately. A major goal of biomedical research is to understand which sex-biasing factors influence disease severity and to develop therapeutic strategies to target these factors. Two groups of such agents are sex chromosome genes and gonadal hormones. Researchers use the “four core genotypes” model to enable comparisons among animals with different sex chromosomes but the same type of sex hormones, which allows investigators to distinguish disease mechanisms influenced by the sex chromosomes. Supported by ORIP (R01OD030496, R21OD026560), NICHD, NIDDK, and NHLBI.
A Molecularly Integrated Amygdalo-Fronto-Striatal Network Coordinates Flexible Learning and Memory
Li et al., Nature Neuroscience. 2022.
https://www.doi.org/10.1038/s41593-022-01148-9
Behavioral flexibility is critical for navigating dynamic environments and requires the durable encoding and retrieval of new memories to guide future choice. The orbitofrontal cortex (OFC) supports outcome-guided behaviors, but the coordinated neural circuitry and cellular mechanisms by which OFC connections sustain flexible learning and memory are not understood fully. Using a mouse model, researchers demonstrated that the OFC neuronal ensembles store a memory trace for newly learned information. They describe the directional transmission of information within an integrated amygdalo-fronto-striatal circuit across time. Supported by ORIP (P51OD011132), NIDA, NIMH, and NINDS.
Metabolic Transitions Define Spermatogonial Stem Cell Maturation
Voigt et al., Human Reproduction. 2022.
https://www.doi.org/10.1093/humrep/deac157
The spermatogonial stem cell (SSC) is the basis of male fertility. One potential option to preserve fertility in patients treated with anti-cancer therapy is isolation and laboratory culture of the juvenile SSC pool with subsequent transplantation to restore spermatogenesis. However, efficient culture of undifferentiated spermatogonia, including SSCs, in mammals other than rodents remains challenging. Investigators reported that the metabolic phenotype of prepubertal human spermatogonia is distinct from that of adult spermatogonia and that SSC development is characterized by specific metabolic transitions from oxidative phosphorylation to anaerobic metabolism. Supported by ORIP (R01OD016575) and NICHD.
Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth
Wang et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32554-z
About 150,000 children are infected postnatally with HIV each year. Early antiretroviral therapy (ART) in infants with HIV can reduce viral reservoir size, but ART-free virologic remission has not been achieved. The researchers hypothesized that proviral reservoir seeding in infants exposed to HIV might differ from that in adults. They characterized viral reservoirs in neonatal rhesus macaques of both sexes inoculated with simian immunodeficiency virus (SIV) at birth and given combination ART. The researchers reported that 9 months of treatment initiated at day 3 resulted in a sustained virologic remission, suggesting that early intervention with proper treatment regimens could be an effective strategy. Supported by ORIP (P51OD011104), NIAID, NICHD, and NIDCR.
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.
Neuroprotective Effects of Electrical Stimulation Following Ischemic Stroke in Non-Human Primates
Zhou et al., Institute of Electrical and Electronics Engineers. 2022.
https://www.doi.org/10.1109/EMBC48229.2022.9871335
Using rhesus macaques of both sexes, researchers identified a novel treatment for ischemic stroke, which occurs when brain cells die due to lack of oxygen. The treatment consisted of applying 60 minutes of electrical brain stimulation shortly after the stroke. The animals that received electrical stimulation had less brain damage, fewer cell deaths, and more protective neural activity patterns than the monkeys that did not receive electrical stimulation. Future work can determine whether this stimulation can be applied noninvasively, as well as how to improve the electrical stimulation patterns to optimize health outcomes for stroke patients. Supported by ORIP (P51OD010425) and NINDS.
Large Comparative Analyses of Primate Body Site Microbiomes Indicate That the Oral Microbiome Is Unique Among All Body Sites and Conserved Among Nonhuman Primates
Asangba et al., Microbiology Spectrum. 2022.
https://www.doi.org/10.1128/spectrum.01643-21
Microbiomes are critical to host health and disease, but large gaps remain in the understanding of the determinants, coevolution, and variation of microbiomes across body sites and host species. Thus, researchers conducted the largest comparative study of primate microbiomes to date by investigating microbiome community composition at eight distinct body sites in 17 host species. They found that the oral microbiome is unique in exhibiting notable similarity across primate species while being distinct from the microbiomes of all other body sites and host species. This finding suggests conserved oral microbial niche specialization, despite substantial dietary and phylogenetic differences among primates. Supported by ORIP (P51OD010425, P51OD011107, P40OD010965, R01OD010980), NIA, NIAID, and NICHD.
A Potent Myeloid Response Is Rapidly Activated in the Lungs of Premature Rhesus Macaques Exposed to Intra-Uterine Inflammation
Jackson et al., Mucosal Immunology. 2022.
https://www.doi.org/10.1038/s41385-022-00495-x
Up to 40% of preterm births are associated with histological chorioamnionitis (HCA), which can lead to neonatal mortality, sepsis, respiratory disease, and neurodevelopmental problem. Researchers used rhesus macaques to comprehensively describe HCA-induced fetal mucosal immune responses and delineate the individual roles of IL-1β and TNFα in HCA-induced fetal pathology. Their data indicate that the fetal innate immune system can mount a rapid, multifaceted pulmonary immune response to in utero exposure to inflammation. Taken together, this work provides mechanistic insights into the association between HCA and the postnatal lung morbidities of the premature infant and highlights the therapeutic potential of inflammatory blockade in the fetus. Supported by ORIP (P51OD011107), NIEHS, NIDDK, NHLBI, and NICHD.