Publications

Background Opioid discontinuation generates a withdrawal syndrome marked by increased negative affect. Increased symptoms of anxiety and dysphoria during opioid discontinuation are a significant barrier to achieving long-term abstinence in opioid-dependent individuals. While adaptations in the nucleus accumbens are implicated in the opioid abstinence syndrome, the precise neural mechanisms are poorly understood. Additionally, our current knowledge is limited to changes following natural and semi-synthetic opioids, despite recent increases in synthetic opioid use and overdose.

MicroRNA miR-29 promotes endothelial function in human arterioles in part by targeting LYPLA1 and increasing nitric oxide production. In addition, miR-29 is a master inhibitor of extracellular matrix gene expression, which may attenuate fibrosis but could also weaken tissue structure. The goal of this study was to test whether miR-29 could be developed as an effective, broad-acting, and safe therapeutic.

Quiescent, differentiated adult vascular smooth muscle cells (VSMCs) can be induced to proliferate and switch phenotype. Such plasticity underlies blood vessel homeostasis and contributes to vascular disease development. Oligoclonal VSMC contribution is a hallmark of end-stage vascular disease. Here we aim to understand cellular mechanisms underpinning generation of this VSMC oligoclonality.We investigate the dynamics of VSMC clone formation using confocal microscopy and single cell transcriptomics in VSMC-lineage-traced animal models.

Intra-tumoral heterogeneity and cellular plasticity have emerged as hallmarks of cancer, including pancreatic ductal adenocarcinoma (PDAC). As PDAC portends a dire prognosis, a better understanding of the mechanisms underpinning cellular diversity in PDAC is crucial. Here, we investigated the cellular heterogeneity of PDAC cancer cells across a range of in vitro and in vivo growth conditions using single-cell genomics. Heterogeneity contracted significantly in 2D and 3D cell culture models but was restored upon orthotopic transplantation.

Cell ablation is a key method in the research fields of developmental biology, tissue regeneration, and tissue homeostasis. Eliminating specific cell populations allows for characterizing interactions that control cell differentiation, death, behavior, and spatial organization of cells. Current methodologies for inducing cell death suffer from relatively slow kinetics, making them unsuitable for analyzing rapid events and following primary and immediate consequences of the ablation.

Cells with latent stem ability can contribute to mammalian tissue regeneration after damage. Whether the central nervous system (CNS) harbors such cells remains controversial. Here, we report that DNGR-1 lineage tracing in mice identifies an ependymal cell subset, wherein resides latent regenerative potential. We demonstrate that DNGR-1-lineage-traced ependymal cells arise early in embryogenesis (E11.5) and subsequently spread across the lining of cerebrospinal fluid (CSF)-filled compartments to form a contiguous sheet from the brain to the end of the spinal cord.

Feeding behavior is regulated by both the homeostatic needs of the body and hedonic values of the food. Easy access to palatable energy-dense foods and the consequent obesity epidemic stress the urgent need for a better understanding of neural circuits that regulate hedonic feeding. Here, we report that neurotensin-positive neurons in the lateral septum (LSNts) play a crucial role in regulating hedonic feeding. Silencing LSNts specifically promotes feeding of palatable food, whereas activation of LSNts suppresses overall feeding.

Whole-exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group-binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate-4S (CS-4S) and regulates GAG content of the brain extracellular matrix (ECM).

Neuroinflammation leads to neuronal stress responses that contribute to neuronal dysfunction and loss. However, treatments that stabilize neurons and prevent their destruction are still lacking. Here, we identify the histone methyltransferase G9a as a druggable epigenetic regulator of neuronal vulnerability to inflammation. In murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS), we found that the G9a-catalyzed repressive epigenetic mark H3K9me2 was robustly induced by neuroinflammation.

The striatum plays a critical role in regulating addiction-related behaviors. The conventional dichotomy model suggests that striatal D1/D2 medium spiny neurons (MSNs) positively/negatively regulate addiction-related behaviors. However, this model does not account for the neuronal heterogeneity and functional diversity of the striatum, and whether MSN subtypes beyond the pan-D1/D2 populations play distinct roles in drug addiction remains unknown.