Recent increases in creatine supplementation have facilitated research assessing creatine’s benefits, albeit mixed results on its waste product creatinine-- a marker for creatine metabolism and kidney health. Though strides are being made to meaningfully contextualize the effect of creatine’s decomposition on cognition, varied results necessitate a larger longitudinal evaluation. The Adult Aging Brain Connectome (AABC) release 2 data longitudinally assesses cognition, lifestyle factors, and functional imaging in a large sample of healthy geriatric participants. These data was condensed to 1537 HCA participants for precision, and we used R to evaluate the relationship between Creatinine (mg/dL) and two cognitive factors, Fluid IQ and Crystallized IQ, from a factor analysis of data from a comprehensive cognitive battery. The analysis of creatinine levels and crystallized intelligence yielded a non-significant correlation (p = 0.0704). However, creatinine levels and fluid cognition demonstrated a highly significant Pearson’s product moment correlation (p = 3.67e-15), indicating that heightened creatinine levels were related to decreased fluid cognition. The quartile stratification of creatinine levels yielded a nonlinear negative correlation (p = 3.8e-08). By correlationally assessing biomarkers like creatinine, there is opportunity to use top down effects to gain heightened understanding of the foundational roles of metabolism and inflammation as potential predictors for various degrees of memory deterioration in aging.

Rare genetic disorders that affect creatine transport in the brain are associated with neurodevelopmental decline and intellectual disability, highlighting the need for precise methods to evaluate therapeutic delivery in neural tissue. This project focuses on how brain tissue preparation and imaging workflows can be optimized to assess viral vector distribution and gene expression in a mouse model of neurodevelopmental disease. Brain samples were collected from treated and control mice and processed through a detailed histological pipeline. Tissue was sectioned using a vibratome to preserve structural integrity, then carefully localized to defined anatomical regions based on bregma coordinates. Sections were prepared for fluorescence-based staining, including fluorescence in situ hybridization and immunohistochemistry, to visualize target gene expression and cellular features. These stained samples were then imaged using high resolution fluorescence microscopy to capture spatial patterns of signal distribution across brain regions. Observations from this workflow emphasize the importance of precision at each stage, from tissue handling to imaging, in generating clear and interpretable results. This work establishes reproducible methodological strategies to support the study of therapeutic interventions for rare neurodevelopmental disorders.

CS-1103, a molecular sequestrant, does not cross the blood-brain barrier; it binds to fentanyl in the plasma with high affinity and accelerates its clearance via urine. By rapidly reducing plasma concentrations of fentanyl, CS-1103 can pull ligands off opioid receptors without displacing them with another ligand. Thus, we hypothesize that CS-1103 will elicit less physical withdrawal behaviors in opioid-dependent states and blunt naloxone-induced withdrawal behaviors. Adult male and female C57Bl/6 mice were made fentanyl dependent via orally-self-administration for 8 or 14 days. On the last day of fentanyl administration, the mice were given IP injections with either CS-1103 or vehicle followed by naloxone 1.5 hrs later. The mice were scored for global withdrawal behaviors immediately after injection. Data was analyzed via unpaired student t-tests or 2-way ANOVAs. In the 8-day model, CS-1103 pretreatment in male mice did not significantly alter naloxone-precipitated global withdrawal score compared to vehicle. Pre-treatment with higher dosage of CS-1103 in the 14 day fentanyl exposure model did not significantly reduce naloxone-precipitated withdrawal, but withdrawal scores from post-vehicle/CS-1103 injections were not significantly higher than the former either, suggesting a partial reduction of withdrawal behaviors. Further studies with larger sample sizes may have the statistical power to elucidate the efficacy of CS-1103 in reducing aversive withdrawal symptoms in opioid-dependent states.

Autism Spectrum Disorder (ASD) is a highly heritable disease that affects approximately 2.3% of children in the United States. Rare and de novo mutations impact ~10% of individuals with ASD and are often associated with more severe symptoms. Mutations in chromatin remodelers have been demonstrated to disrupt key developmental processes such as differentiation, cell-type specification, and maturation. More specifically, mutations in a particular chromatin remodeling complex, the SWI/SNF complex, are responsible for a syndromic form of ASD, Coffin-Siris syndrome, which presents with global developmental delay. The SWI/SNF complex is also implicated in other neurodevelopmental disorders (NDDs). To better understand the role of this complex throughout neurodevelopment, we investigate ARID1B and SMARCC2, which encode for the two components of the SWI/SNF complex most implicated in ASD. Knocking out these two genes in isogenic induced pluripotent stem cells (iPSCs), followed by directed differentiation into excitatory cortical neurons, a cell type highly impacted in ASD, and comprehensive downstream phenotyping, we aim to define how loss of these genes influences neurodevelopment. Using bioinformatics, imaging tools, and biological experiments, we hypothesize that the loss of these genes will result in profound changes in cellular development and protein-level networks related to proliferation, differentiation, and maturation.

Huntington’s disease (HD) is a dominantly inherited, fatal late-onset neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the HTT gene. Despite ubiquitous expression of the mutant HTT allele across tissues, HD exhibits selective vulnerability of medium spiny neurons (MSNs) in the striatum. A key unresolved question is how the endogenous huntingtin protein (Htt) is distributed within neurons and whether polyglutamine expansion alters its localization to distinct neuronal compartments. Proper intracellular localization of Htt is essential for its roles in vesicular transport, synaptic function, and neuronal signaling. We hypothesize that mislocalization of full-length mutant Htt (mHtt) contributes to the vulnerability of striatal MSNs. Current approaches to visualize Htt rely on epitope-specific antibodies that cannot reliably distinguish endogenous full-length Htt from Htt fragments, which are abundant in disease-vulnerable cells. To visualize endogenous full-length Htt in MSNs, I generated embryonic primary striatal neuron cultures from HD mouse models expressing hemagglutinin-tagged wild-type or mutant Htt protein. Using these cultures, I examined how polyglutamine-expanded mHtt alters the subcellular localization of endogenous full-length Htt in striatal neurons.