Introduction Bevacizumab is a standard treatment for glioblastomas (GBM), which targets VEGF-A and has been shown to increase angiogenic Epithelial Membrane Protein 2 (EMP2). Hypoxia-inducible factors (HIFs) 1α and 2α and the EMP2 axis are implicated in tumor-mediated invasion, DNA repair, and apoptosis. We evaluated the changes in HIF1α and HIF2α expression in matched pre- and post-bevacizumab GBM patient samples as potential biomarkers related to chemoresistance. Methods Nine newly diagnosed GBM patient samples were collected at initial surgery and recurrence post-bevacizumab. Immunohistochemistry (IHC) of HIF1α and HIF2α was conducted on the pre- and post-bevacizumab samples and scored by two independent pathologists. Results HIF2α expression increased in post-bevacizumab samples (p=0.08), trending towards significance, and non-significantly in HIF1α (p=0.33). Cox regression analysis reveals adjuvant treatments (DCVax, Ponatinib, VB 111, VEGF-Trap) showed no significant improvement in OS, progression-free survival (PFS), or symptom-free survival post-bevacizumab. Log-rank Mentel Cox test demonstrated a significant difference in OS of the upregulated HIF2a cohort (p=0.02). Upregulation of HIF1a was associated with a trend towards significance for PFS (p=0.10). Conclusion We present the first characterization of hypoxia-inducible factor expressions in matched pre- and post-bevacizumab-treated GBM samples. Bevacizumab treatment increased HIF2α expression, potentially implicated in chemoresistance.

Early life adversity (ELA) is a major risk factor for psychiatric disorders, in part due to its lasting impact on brain reward circuits such as the nucleus accumbens (NAc). Microglia, the brain’s resident immune cells, are essential for postnatal neural circuit refinement through synaptic pruning, but ELA has been shown to disrupt microglial function in stress-related brain regions. However, the specific effects of ELA on microglia-mediated synaptic pruning in the NAc remain poorly understood. This project addresses the question: Does ELA alter dendritic spine density in NAc neurons by disrupting microglial pruning during development? To investigate, we used the MORF3 transgenic mouse line, enabling sparse, high-resolution labeling of NAc neurons. Mice were exposed to ELA via the limited bedding and nesting (LBN) model from postnatal day 4-11, with controls reared under standard conditions. Dendritic spine densities were quantified at juvenile (P24) and adolescent (P42) stages using confocal microscopy and ImageJ analysis. Preliminary results suggest a trend toward lower dendritic spine densities in adolescent LBN mice compared to controls, though further data are needed for statistical validation. By elucidating how ELA affects microglia-mediated synaptic pruning in the NAc, this research advances our understanding of the cellular mechanisms linking early stress to long-term vulnerability for psychiatric disorders, and may inform the development of targeted interventions.

Effective decision-making is crucial for survival. In nature, animals consistently make significant decisions based on the availability of resources such as food, water, and mates, which are typically found in various locations. Consequently, navigation and decision-making are closely connected in the natural world. However, neuroscientific studies of decision-making usually test animals in confined areas where navigation and movement are largely irrelevant. In natural environments, resources often cluster in different locations. For instance, if you're craving Korean food, you can visit Koreatown, as that neighborhood offers many Korean dining options nearby. We have designed a behavioral task in which rats must learn to identify "neighborhoods" in a testing arena associated with increased or decreased reward probabilities. Can rats make value-based decisions in a changing environment? The orbitofrontal cortex (OFC) has long been recognized as important for decision-making, particularly in evaluating the value of different choices. However, the OFC is a large structure, and little is understood about how its subregions play complementary or coordinating roles in decisions that involve a navigational component. In ongoing research, we will examine how lesions in medial and lateral OFC subregions influence decision-making in this task. This study will determine whether one or both subregions are essential for rats to integrate spatial information with reward probability to make adaptive decisions in a naturalistic context.

Ischemic stroke produces an area of total cell death that forms the stroke core. We can inject hydrogels into the core to support neural repair in the stroke core, including the formation of new blood vessels (angiogenesis) and neuronal connections (through axonal sprouting and synaptogenesis). Specifically designed hydrogels are used to promote neural repair, including Microporous Annealed Particles (MAP), which consist of spherical microgel building blocks and a MAP scaffold with clustered VEGF nanoparticles (CLUVENA). Previous research has shown that MAP hydrogels promote astrocyte infiltration into the stroke core and modulate astrocyte and microglia away from neurotoxicity and towards a pro-repair phenotype. MAP hydrogels combined with CLUVENA (MAPcV) nanoparticles aims to re-establish the critical components of healthy, functioning tissue in the stroke core by using VEGF to enhance the brain's endogenous repair response. Specifically, this project aims to classify the neuronal subtypes with axons projecting into the hydrogel through a combination of virus injections, immunohistochemistry, and hybridization (ISH) chain reaction (HCR). We expect to see an increase in Parvalbumin-expressing (PV) interneurons projecting into the hydrogel as compared to other neuronal subtypes, as previous research has demonstrated PV neurons play a large role in post-injury repair and plasticity in the brain.

Neurodegenerative diseases are notoriously difficult to diagnose early due to a reliance on clinical symptoms and invasive procedures such as lumbar punctures. Extracellular vesicles (EVs) of central nervous system (CNS) origin have emerged as a minimally invasive blood-based biomarker platform, offering a “snapshot” of brain pathology. However, their isolation using magnetic Dynabeads often suffers from non-specific binding, confounding results. This study investigates two blocking strategies- horse serum and Fc blocking protein, to minimize this nonspecific binding while preserving antibody specificity toward oligodendroglial EVs. Commercially pooled human serum was used under six experimental conditions combining bead conjugation with or without MOG antibody and each blocker. EVs were isolated via ExoQuick precipitation, conjugated with Dynabeads, lysed, and quantified for alpha-synuclein using an MSD assay. Preliminary results suggest that Fc blocking improves specificity of EV capture, while horse serum demonstrates limited effect. Although not yet statistically significant, these trends point toward enhanced accuracy in CNS- EV isolation when Fc blocking is employed. Upon completion of all trials, further statistical analysis and multi-marker validation will confirm findings. This project optimizes immunoaffinity-based EV isolation protocols and has significant implications for the development of accessible, reliable and non-invasive diagnostic, monitoring and treatment evaluation tools for neurodegenerative disease.