Selected Grantee Publications
Sociability in a Non-Captive Macaque Population Is Associated with Beneficial Gut Bacteria
Johnson et al., Frontiers in Microbiology. 2022.
https://www.doi.org/10.3389/fmicb.2022.1032495
Social connections are essential for good health and well-being in social animals, such as humans and other primates. Increasingly, evidence suggests that the gut microbiome—through the so-called “gut–brain axis”—plays a key role in physical and mental health and that bacteria can be transmitted socially (e.g., through touch). Here, the authors explore behavioral variation in non‑captive rhesus macaques of both sexes with respect to the abundance of specific bacterial genera. Their results indicate that microorganisms whose abundance varies with individual social behavior also have functional links to host immune status. Overall, these findings highlight the connections between social behavior, microbiome composition, and health in an animal population. Supported by ORIP (P40OD012217) and NIMH.
Cell-Specific Regulation of Gene Expression Using Splicing-Dependent Frameshifting
Ling et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33523-2
Precise and reliable cell-specific gene delivery remains technically challenging. Investigators report a splicing-based approach for controlling gene expression whereby separate translational reading frames are coupled to the inclusion or exclusion of mutated, frameshifting cell-specific alternative exons. Candidate exons are identified by analyzing thousands of publicly available RNA sequencing datasets and filtering by cell specificity, conservation, and local intron length. This method, which they denote as splicing-linked expression design (SLED), can be combined in a Boolean manner with such existing techniques as minipromoters and viral capsids. SLED can use strong constitutive promoters, without sacrificing precision, by decoupling the tradeoff between promoter strength and selectivity. AAV-packaged SLED vectors can selectively deliver fluorescent reporters and calcium indicators to various neuronal subtypes in vivo. The authors also demonstrate gene therapy utility by creating SLED vectors that can target PRPH2 and SF3B1 mutations. The flexibility of SLED technology enables creative avenues for basic and translational research. Supported by ORIP (T32OD011089, S10OD026859), NEI, and NIMH.
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.
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.
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.
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.
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.
Effects of Ex Vivo Blood Anticoagulation and Preanalytical Processing Time on the Proteome Content of Platelets
Yunga et al., Journal of Thrombosis and Haemostasis. 2022.
https://www.doi.org/10.1111/jth.15694
The investigators studied how various blood anticoagulation options and processing times affect platelet function and protein content ex vivo. Using platelet proteome quantification and triple quadrupole mass spectrometry, they found that anticoagulant-specific effects on platelet proteomes included increased complement system and decreased α-granule proteins in platelets from EDTA-anticoagulated blood. Heparinized blood had higher levels of histone and neutrophil-associated proteins, as well as formation of platelet–neutrophil extracellular trap interactions in whole blood ex vivo. The study indicates that different anticoagulants and preanalytical processing times affect platelet function and platelet protein content ex vivo, suggesting more rigorous phenotyping strategies for platelet omics studies. Supported by ORIP (S10OD012246), NHLBI, NCI and NEI.
Natural Disaster and Immunological Aging in a Nonhuman Primate
Watowich et al., PNAS. 2022.
https://www.pnas.org/content/119/8/e2121663119
Weather-related disasters can exacerbate existing morbidities and increase mortality risk. Researchers examined Hurricane Maria’s impact on immune cell gene expression in large, age-matched, cross-sectional samples from free-ranging rhesus macaques (Macaca mulatta) living on an isolated island. Hurricane Maria was significantly associated with differential expression of 4% of immune-cell-expressed genes and was correlated with age-associated alterations in gene expression, in addition to expression of key immune genes, dysregulated proteostasis networks, and greater expression of inflammatory immune cell-specific marker genes. These findings illuminate that natural disasters might become biologically embedded and contribute to earlier onset of disease and death. Supported by ORIP (P40OD012217), NIA, NIMH.