Selected Grantee Publications
GluN2B Inhibition Confers Resilience against Long-Term Cocaine-Induced Neurocognitive Sequelae
Li et al., Neuropsychopharmacology. 2023.
https://www.nature.com/articles/s41386-022-01437-8
Cocaine self-administration can disrupt the capacity of humans and rodents to flexibly modify familiar behavioral routines, but effects on mechanistic factors—particularly those driving long-term behavioral changes—have not been characterized fully. Researchers used mice to examine the flexibility of decision-making behavior with oral cocaine self-administration. They found that GluN2B inhibition prevented cocaine-induced dysregulation of neuronal structure and function in the orbitofrontal cortex (OFC), preserving mature, mushroom-shaped dendritic spine densities on deep-layer pyramidal neurons. These findings suggest that cocaine potentiates GluN2B-dependent signaling, which triggers a series of durable adaptations that result in the dysregulation of post-synaptic neuronal structure in the OFC, ultimately weakening the capacity for flexible choice. Supported by ORIP (P51OD011132) and NINDS.
The Drosophila Chemokine-Like Orion Bridges Phosphatidylserine and Draper in Phagocytosis of Neurons
Ji et al., PNAS. 2023.
https://pubmed.ncbi.nlm.nih.gov/37276397/
Degenerating neurons can be cleared by phagocytosis triggered by “eat-me” signal phosphatidylserine (PS) and mediated by the engulfment receptor Draper (Drpr), yet the process is poorly understood. Investigators used several Drosophila models to study dendrite degeneration and demonstrated that the fly chemokine-like protein Orion binds to PS and mediates interactions between PS and Drpr to enable phagocytosis. This study identifies a link between immunomodulatory proteins and phagocytosis of neurons and reveals conserved mechanisms of clearing degenerating neurons. Supported by ORIP (R24OD031953, R21OD023824, S10OD018516) and NINDS.
Lymph-Node-Based CD3+ CD20+ Cells Emerge From Membrane Exchange Between T Follicular Helper Cells and B Cells and Increase Their Frequency Following Simian Immunodeficiency Virus Infection
Samer et al., Journal of Virology. 2023.
https://www.doi.org/10.1128/jvi.01760-22
CD4+ T follicular helper cells are known to persist during antiretroviral therapy (ART) and have been identified as key targets for viral replication and persistence. Researchers identified a lymphocyte population that expresses CD3 (i.e., T cell lineage marker) and CD20 (i.e., B cell lineage marker) on the cellular surface in lymphoid tissues from rhesus macaques of both sexes and humans of male and female sexes. In macaques, the cells increased following simian immunodeficiency virus infection, were reduced with ART, and increased in frequency after ART interruption. These cells represent a potential area for future therapeutic strategies. Supported by ORIP (P51OD011132, U42OD011023), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
CD8+ T Cells Promote HIV Latency by Remodeling CD4+ T Cell Metabolism to Enhance Their Survival, Quiescence, and Stemness
Mutascio et al., Immunity. 2023.
https://www.doi.org/10.1016/j.immuni.2023.03.010
An HIV reservoir persists following antiretroviral therapy, representing the main barrier to an HIV cure. Using a validated in vitro model, investigators explored the mechanism by which CD8+ T cells promote HIV latency and inhibit latency reversal in HIV-infected CD4+ T cells. They reported that CD8+ T cells favor the establishment of HIV latency by modulating metabolic, stemness, and survival pathways that correlate with the downregulation of HIV expression and promote HIV latency. In future studies, comparative analyses may provide insight into common molecular mechanisms in the silencing of HIV expression by CD8+ T cells and macrophages, which can be applied to new intervention strategies that target the HIV reservoir. Supported by ORIP (P51OD011132, S10OD026799), NIAID, NIDDK, NIDA, NHLBI, and NINDS.
In Vivo MRI Is Sensitive to Remyelination in a Nonhuman Primate Model of Multiple Sclerosis
Donadieu et al., eLife. 2023.
https://pubmed.ncbi.nlm.nih.gov/37083540/
Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a model for studying inflammatory demyelination in multiple sclerosis (MS). Researchers investigated the feasibility and sensitivity of magnetic resonance imaging (MRI) in characterizing remyelination, a crucial step to recover from MS. Investigators demonstrated that multisequence 7T MRI could detect spontaneous remyelination in marmoset EAE at high statistical sensitivity and specificity in vivo. This study suggests that in vivo MRI can be used for preclinical testing of therapeutic remyelinating agents for MS. Supported by ORIP (R21OD030163) and NINDS.
Longitudinal Characterization of Circulating Extracellular Vesicles and Small RNA During Simian Immunodeficiency Virus Infection and Antiretroviral Therapy
Huang et al., AIDS. 2023.
https://www.doi.org/10.1097/QAD.0000000000003487
Antiretroviral therapy is effective for controlling HIV infection but does not fully prevent early aging disorders or serious non-AIDS events among people with HIV. Using pigtail and rhesus macaques (sex not specified), researchers profiled extracellular vesicle small RNAs during different phases of simian immunodeficiency virus infection to explore the potential relationship between extracellular vesicle–associated small RNAs and the infection process. They reported that average particle counts correlated with infection, but the trend could not be explained fully by virions. These findings raise new questions about the distribution of extracellular vesicle RNAs in HIV latent infection. Supported by ORIP (U42OD013117), NIDA, NIMH, NIAID, NCI, and NINDS.
Mechanism of STMN2 Cryptic Splice-Polyadenylation and its Correction for TDP-43 Proteinopathies
Baughn et al., Science. 2023.
Loss of the RNA-binding protein TDP-43 from the nuclei of affected neurons is a hallmark of neurodegeneration in TDP-43 proteinopathies (e.g., amyotrophic lateral sclerosis, frontotemporal dementia). Loss of functional TDP-43 is accompanied by misprocessing of the stathmin-2 (STMN2) RNA precursor. Investigators determined the elements through which TDP‑43 regulates STMN2 pre‑mRNA processing and identified steric binding antisense oligonucleotides that are capable of restoring normal STMN2 protein and RNA levels. This approach is potentially applicable for human therapy. Supported by ORIP (U42OD010921), NIA, NCI, NIGMS, and NINDS.
Naturally Occurring Osteochondrosis Latens Lesions Identified by Quantitative and Morphological 10.5 T MRI in Pigs
Armstrong et al., Journal of Orthopaedic Research. 2023.
https://pubmed.ncbi.nlm.nih.gov/35716161/
Juvenile osteochondritis dissecans (JOCD) is a pediatric orthopedic disorder that is associated with pain and gait deficits. JOCD lesions form in the knee, elbow, and ankle joints and can progress to early-onset osteoarthritis. In this study, researchers used a noninvasive magnetic resonance imaging (MRI) method to identify naturally occurring lesions in intact knee and elbow joints of juvenile pigs. This work can be applied to noninvasive identification and monitoring of early JOCD lesions and determination of risk factors that contribute to their progression in children. Supported by ORIP (K01OD021293, T32OD010993), NIAMS, and NIBIB.
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.
PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS
Hung et al., Cell . 2023.
https://doi.org/10.1016/j.cell.2023.01.005
Investigators showed that pharmacological suppression of PIKFYVE activity reduces pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of amyotrophic lateral sclerosis (ALS). Upon PIKFYVE inhibition, exocytosis is activated to transport aggregation-prone proteins out of the cells, a process that does not require stimulating macroautophagy or the ubiquitin-proteosome system. These findings suggest therapeutic potential to manage multiple forms of ALS. Supported by ORIP (S10OD021553) and NINDS.