Biology subjects

Bernstein, A. M.

Publications and source records attributed to Bernstein, A. M..

4 recordsLinked to original sources

bioRxiv2024

Oral cannabidiol administration in mice during pregnancy and lactation affects early postnatal body weight, fasting glucose, ingestive behavior, anxiety- and obsessive compulsive-like behaviors, and long-term object-memory in adult offspring in a sex-dependent manner

RationaleThe consequences of perinatal cannabidiol (CBD) exposure are severely understudied, but are important, given its widespread use and believed safety as a natural supplement. ObjectiveThe objective of this study was to test the health, metabolic, and behavioral consequences of perinatal CBD exposure on dams and their offspring raised to adult. MethodsPrimiparous female C57BL/6J mice were orally administered 100 mg/kg CBD in strawberry jam to expose offspring during gestation, lactation, or both using a cross-fostering design. Adult offspring were metabolically profiled using indirect calorimetry and intraperitoneal glucose tolerance testing. Adults were behaviorally phenotyped, video recorded, and mouse position tracked using DeepLabCut. ResultsCBD was detected in maternal plasma using LC-MS 10-min post consumption (34.2 {+/-} 1.7 ng/ul) and peaked within 30 min (371.0 {+/-} 34.0 ng/ul). Fetal exposure to CBD significantly decreased survival of the pups, and decreased male postnatal development, but did not alter litter size, maternal body weight or pup birth weight. We observed many sex-dependent effects of perinatal CBD exposure. Exposure to CBD during gestation and lactation increased meal size, caloric intake, and respiratory exchange ratio for adult male offspring, while exposure during lactation decreased fasting glucose, but had no effect on clearance. Adult female offspring exposed to CBD during lactation showed increased drink size. Perinatal CBD exposure increased obsessive compulsive- and decreased anxiety-like behaviors (marble burying, light-dark box, elevated-plus maze) in female mice, decreased long-term object memory in male mice, and had no effect on attention tasks for either sex. ConclusionsWe conclude that orally-administered CBD during pregnancy affects behavior and metabolism in a sex-dependent manner, and mice are differentially sensitive to exposure during gestation vs. lactation, or both. Because long-term changes are observed following perinatal exposure to the drug, and exposure significantly decreases survival to weaning, more research during development is warranted. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/602955v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1a9341dorg.highwire.dtl.DTLVardef@19c7356org.highwire.dtl.DTLVardef@5833baorg.highwire.dtl.DTLVardef@ac153c_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIMice can be trained to orally consume CBD using strawberry jam as the vehicle. C_LIO_LICBD administration to pregnant dams decreases pup survival to weaning age without significantly affecting maternal behavior. C_LIO_LIPerinatal CBD exposure decreases developmental body weight in males. C_LIO_LIGestational or lactational CBD increases the respiratory exchange ratio (RER), increases mean meal and drink size, and reduces fasting glucose in a sex-dependent manner. C_LIO_LICBD increases obsessive-compulsive like behavior in adult offspring, which could be eliminated in females by cross-fostering to a drug-free dam. C_LIO_LIPerinatal CBD selectively decreases anxiety-like behavior in females and decreases long-term object memory in males. C_LI

neuroscience↗

bioRxiv2022

Daam1 negatively regulates USP10 activity

The differentiation of fibroblasts into pathological myofibroblasts during wound healing is in part characterized by increased cell surface expression of v-integrins. Our previous studies found that the deubiquitinase (DUB) USP10 removes ubiquitin from v-integrins, leading to cell surface integrin accumulation, subsequent TGF{beta}1 activation, and myofibroblast differentiation. In this study, a yeast-two hybrid screen elucidated a novel binding partner for USP10, the formin, Daam1. The USP10/Daam1 interaction was also supported by proximity ligation assay (PLA) activity. Treatment with TGF{beta}1 significantly increased USP10 and Daam1 protein expression, PLA signal, and co-localization to actin stress fibers. Furthermore, Daam1 siRNA knockdown significantly reduced a) co-precipitation of USP10 and Daam1 on purified actin stress fibers, and b) {beta}1- and {beta}5-integrin ubiquitination resulting in increased v-, {beta}1-, and {beta}5-integrin total protein levels, v integrin recycling to the cell surface, and extracellular fibronectin (FN) organization. Together, our data suggest that Daam1 negatively regulates USP10s DUB activity and subsequently maintains integrin protein homeostasis.

cell biology↗

bioRxiv2020

Molecular and functional properties of PFC astrocytes during neuroinflammation-induced anhedonia

Astrocytes are widely implicated in CNS diseases, but their contributions to disease related phenotypes remain incompletely explored. Anhedonia accompanies several neurological and psychiatric diseases, including major depressive disorder (MDD) and Alzheimers disease (AD), both of which are associated with neuroinflammation. In order to explore how neuroinflammation affects astrocytes, we assessed medial prefrontal cortex (PFC) and visual cortex (VCX) astrocytic gene expression using a neuroinflammation mouse model that displayed anhedonia as a phenotype. In this model, anhedonia was reversed by the fast acting antidepressant ketamine. Astrocyte specific gene expression alterations included those related to immune cell signaling, intracellular Ca2+ signaling, cholesterol biosynthesis, and metabolic pathways. Such changes peaked when anhedonia was greatest, and reversed to normal when anhedonia subsided. However, region-specific molecular identities between PFC and VCX astrocytes were maintained throughout, implying that astrocyte identities do not converge during neuroinflammation. We also mapped anhedonia-related astrocyte and bulk tissue gene expression changes onto published PFC single cell RNA sequencing data, and compared them to MDD and AD post-mortem human tissue samples to identify shared mechanisms. Finally, we assessed how neuroinflammation affected mPFC neuronal properties and detected no alterations at a time point when there was strong astrocyte reactivity. Our data show that neuroinflammation can cause significant and reversible changes in astrocyte gene expression and mouse behaviour without obvious neurotoxicity or loss of essential homeostatic functions. Furthermore, gene expression signatures accompanying neuroinflammation reveal pathways shared with MDD and AD, which display neuroinflammation as a comorbidity in humans. Significance statementAstrocytes are widely implicated in brain diseases, but their contributions to disease-related phenotypes remain incompletely explored. To make inroads into this problem, we assessed medial prefrontal cortex (PFC) and visual cortex (VCX) astrocyte gene expression using a peripherally induced neuroinflammation mouse model that produced anhedonia - a phenotype associated with several brain disorders. Neuroinflammation caused reversible changes in mouse behaviour and astrocyte-specific gene expression changes, some of which were related to human post mortem data for major depressive disorder (MDD) and Alzheimers disease (AD), but without any clear evidence of neurotoxicity in PFC of mice. The astrocyte molecular alterations accompanying neuroinflammation-induced anhedonia will be informative to explore diverse brain disorders and the effects of neuroinflammation on the CNS more broadly.

neuroscience↗

bioRxiv2019

Injectable diblock copolypeptide hydrogel provides platform to maintain high local concentrations of taxol and local tumor control

IntroductionSurgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy.\n\nMethodsThe development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells.\n\nResultsThe DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model, of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to a high local concentration of paclitaxel and led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment.\n\nConclusionsThese findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

cancer biology↗