Selected Grantee Publications
Effect of Single Housing on Innate Immune Activation in Immunodeficiency Virus–Infected Pigtail Macaques (Macaca nemestrina) as a Model of Psychosocial Stress in Acute HIV Infection
Castell et al., Psychosomatic Medicine. 2022.
https://www.doi.org/10.1097/PSY.0000000000001132
Psychosocial stress is associated with immune system dysregulation and worsened clinical outcomes in people with HIV. Investigators performed a retrospective analysis of acute simian immunodeficiency virus (SIV) infection of male pigtail macaques to compare the innate immune responses of social and single housing. The singly housed macaques showed reduced expansion of classical and intermediate monocytes, prolonged thrombocytopenia, and suppression of platelet activation during the first 2 weeks after inoculation. These findings indicate that psychosocial stress might induce clinically significant immunomodulatory effects in the innate immune system during acute SIV infection. Supported by ORIP (P40OD013117, K01OD018244, T32OD011089, U42OD013117), NIAID, NIMH, and NINDS.
Orthotopic Transplantation of the Full-Length Porcine Intestine After Normothermic Machine Perfusion
Abraham et al., Transplantation Direct. 2022.
https://www.doi.org/10.1097/TXD.0000000000001390
Successful intestinal transplantation currently is hindered by graft injury that occurs during procurement and storage, which contributes to postoperative sepsis and allograft rejection. Improved graft preservation could expand transplantable graft numbers and enhance post-transplant outcomes. Superior transplant outcomes recently have been demonstrated in clinical trials using machine perfusion to preserve the liver. The investigators report the development and optimization of machine perfusion preservation of small intestine and successful transplantation of intestinal allografts in a porcine model. Supported by ORIP (K01OD019911), NIAID, and NIDDK.
Rapid Joule Heating Improves Vitrification Based Cryopreservation
Zhan et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33546-9
Cryopreservation by vitrification is an effective approach for long-term preservation of biosystems, but effective vitrification often requires high concentrations of cryoprotective agent (CPA), which can be toxic. The investigators described a joule heating–based platform technology for rapid rewarming of biosystems, which allows the use of low concentrations of CPA. They demonstrated the success of this platform in cryopreservation of three model systems: adherent cells, Drosophila melanogaster embryos, and rat kidney slices with low CPA concentrations. This work provides a general solution to cryopreserve a broad spectrum of cells, tissues, organs, and organisms. Supported by ORIP (R21OD028758), NIDDK, NHLBI, and NIGMS.
Reduced Alcohol Preference and Intake after Fecal Transplant in Patients with Alcohol Use Disorder Is Transmissible to Germ-Free Mice
Wolstenholme et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-34054-6
Alcohol use disorder is a major cause of reduced life expectancy worldwide, and this misuse has increased exponentially during the COVID-19 pandemic. Fecal microbiota transplant has been shown previously to reduce alcohol craving in humans with cirrhosis. Here, the investigators report that the reduction in craving and alcohol preference is transmissible to male germ-free mice only when live bacteria—and not germ-free supernatants—are used for colonization. This differential colonization was associated with alterations in the gut immune–inflammatory response through short-chain fatty acids. Supported by ORIP (P40OD010995), NIAAA, NIDDK, and NIMH.
Maternal Western-Style Diet Reduces Social Engagement and Increases Idiosyncratic Behavior in Japanese Macaque Offspring
Mitchell et al., Brain, Behavior, and Immunity. 2022.
https://www.doi.org/10.1016/j.bbi.2022.07.004
Evidence points to an association between maternal obesity and risk of early-emerging neurodevelopmental disorders in offspring, yet few preclinical studies have tested for associations between maternal Western-style diet (mWSD) and offspring behavior. Using Japanese macaques, researchers found that mWSD offspring exhibited less proximity to peers and initiated fewer affiliative social behaviors. These outcomes appear to be mediated by increased maternal interleukin-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin. These findings suggest specific prevention and intervention targets for early-emerging neurodevelopmental disorder in humans. Supported by ORIP (P51OD011092), NIMH, and NICHD.
Promoting Validation and Cross-Phylogenetic Integration in Model Organism Research
Cheng et al., Disease Models & Mechanisms. 2022.
https://www.doi.org/10.1242/dmm.049600
Model organisms are essential for biomedical research and therapeutic development, but translation of such research to the clinic is low. The authors summarized discussions from an NIH virtual workshop series, titled “Validation of Animal Models and Tools for Biomedical Research,” held from 2020 to 2021. They described challenges and opportunities for developing and integrating tools and resources and provided suggestions for improving the rigor, validation, reproducibility, and translatability of model organism research. Supported by ORIP (R01OD011116, R24OD031447, R03OD030597, R24OD018559, R24OD017870, R24OD026591, R24OD022005, U42OD026645, U42OD012210, U54OD030165, UM1OD023221, P51OD011107), NIAMS, NIDDK, NIGMS, NHGRI, 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.
Distinct Metabolic States Guide Maturation of Inflammatory and Tolerogenic Dendritic Cells
Adamik et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32849-1
The investigators mapped single-cell metabolic states and immune profiles of inflammatory and tolerogenic monocytic dendritic cells using recently developed multiparametric approaches. Activation scores revealed simultaneous engagement of multiple metabolic pathways in distinct monocytic dendritic cell differentiation stages (e.g., rapid reprogramming of glycolytic monocytes and transient co-activation of mitochondrial pathways followed by maturation of dendritic cells). This data set provides insights into metabolic pathways that affect the immune profiles of human dendritic cells. Supported by ORIP (S10OD026940) and NIDDK.