Tauopathy and blood-brain barrier (BBB) dysfunction are prominent neuropathologies of Alzheimer’s Disease (AD) and Vascular Dementia (VaD). These disease-associated features are correlated with dysfunction of pericytes, small contractile cells that line capillaries and play a critical role in BBB regulation. Here, we investigate tau-induced alterations in pericytes using a P301S (PS19) mouse model, which exhibits robust tauopathy at 6 months (mo.). Specifically, we aim to identify differences in pericyte numbers based on disease condition (Wild Type (WT) vs PS19) and progression (6 mo. PS19 vs 9 mo. PS19). To visualize and quantify pericytes, immunohistochemistry (IHC) and fluorescence microscopy were performed on coronal brain sections in the frontal and temporal cortices and hippocampus. To validate pericyte-specific IHC, a Tbx18-Cre-ERT-tdTomato transgenic mouse line was used to induce tdTomato expression within pericytes. tdTomato and IHC staining were colocalized, indicating pericyte-specific IHC staining. Additionally, pericytic quantifications showed significant reductions in the frontal cortex (p = 0.014) and the hippocampus (p = 0.010) of 9 mo. PS19 compared to 9 mo. WT mice. In the future, further quantification of pericytic function would be performed to assess changes with tau progression, and pericytic response to tau in vitro would be conducted to determine mechanistic links. By elucidating mechanisms of tau-pericyte interactions, pharmaceutical and genetic therapies modulating these pathways can be developed.

The cerebral cortex is organized into functional regions that enable high-level cognitive functions such as language, perception, and consciousness. How these areas emerge during gestation is still largely unknown. The thalamus, the brain’s sensory relay system, grows in parallel with the cortex in early embryonic development. We hypothesize that adult thalamic neurons help guide cortical stem cell fate. To test this, we grew and fused cortical and thalamic organoids, 3D stem cell models of the human brain. Through immunostaining and single-nuclei RNA-sequencing of fused thalamic-cortical organoids, we found evidence that thalamic neurons help facilitate upper-layer cortical neurogenesis. Additionally, experiments knocking out NRXN1, a synaptic protein, altered cortical fate decisions. Thus, our model proposes a physical mode of communication between adult thalamic neurons and cortical progenitors influences cortical patterning.

Mesial temporal lobe epilepsy (TLE) is associated with greater risk of Alzheimer’s disease (AD), possibly due to shared pathological features such as amyloid beta (Aβ42) and tau accumulation. This suggests that epilepsy severity correlates with, and perhaps predicts, AD onset. The study hypothesizes that greater cognitive impairment in TLE patients is associated with higher Aβ42 and tau levels (proxy for AD risk). The study used 17 patients who underwent temporal lobe resection. Cognitive function pre-resection was assessed with Brief Visuospatial Memory Test–Revised (BVMT-R), Trail Making Test (TMT; comprised of Trails A and B), and Wechsler Adult Intelligence Scale–Fourth Edition (WAIS-IV) Digit Span and Block Design. Aβ42 and tau were quantified from immunohistochemistry stains of resected mesial temporal lobe tissue. Trails A and tau were significantly correlated, and BVMT-R Trial 1 and Aβ42 were nearly significantly correlated. Regression models controlling for age, sex, and education showed no relationship between cognitive tests and tau, though there were associations between BVMT-R Trial 1 and Aβ42 and Digit Span and Aβ42. When BVMT-R Trial 1, BVMT-R Trial 3, Trails A, and Digit Span were used in the same model for Aβ42, R-squared was 0.76 (p<0.05). Overall, while tau was associated with few cognitive tests, BVMT-R was correlated and predictive of Aβ42, and regression models significantly predicted Aβ42 levels. These findings indicate potential for cognitive tests to be used in evaluating AD risk in TLE patients.

The Tsodyks-Markram (TM) model is a widely used framework for quantifying short-term synaptic plasticity (STP), yet how well its parameters can be recovered from electrophysiology recordings remains poorly characterized. This study systematically evaluates trace and parameter recovery across seven experimental stimulation protocols using artificial voltage traces generated with known ground-truth parameters. Results show that while trace recovery (R²) remained high across all protocols and noise levels, parameter recovery varied substantially — revealing a strong dissociation between trace fit quality and parameter accuracy that reflects the inherent degeneracy of the TM model. Protocols incorporating reset intervals or varied inter-spike intervals consistently outperformed fixed-interval protocols, particularly for τF and τD recovery under noisy conditions. A drift map analysis further characterized systematic biases in the fitting algorithm, showing directional and magnitude-dependent deviations from ground truth across parameter space. Last, we introduce a trace-weighting framework that differentially emphasizes distinct temporal regions of the synaptic response during optimization to improve parameter recovery. These analysis are extended to real experimental data from the Allen Institute to evaluate cross-protocol consistency.

Creatine is a high-energy compound that is crucial for various metabolic processes throughout the body, and disruptions in its synthesis and transport lead to severe complications. Creatine Deficiency Disorders (CDD) are a group of rare neurometabolic disorders that impact creatine synthesis and transport. It comprises three disorders: guanidinoacetate N-methyltransferase (GAMT) deficiency, L-arginine:glycine amidinotransferase (AGAT) deficiency, and Creatine Transporter Deficiency. The project at hand works to characterize two patient-derived induced pluripotent stem cells (iPSCs) that have GAMT deficiency to better understand the neurodevelopmental alterations that arise due dysfunction of the GAMT enzyme and analyze how different versions of the disorder lead to different phenotypic outcomes. GAMT deficiency disorder is a biosynthesis disorder resulting from the inability to convert guanidinoacetate into creatine, preventing transportation to target areas, including the muscles, heart and brain. This project incorporates the use of RT-qPCR, Western Blots, and immunocytochemistry to analyze the developmental alterations that arise from this mutation. Growth curve analysis will also be used to quantify the areas of expansion for all cell lines. Results from this project can be used to inform future studies involving the development of therapeutic intervention strategies to treat GAMT deficiency and possibly other CDDs, and will be used as a motivation for neuronal differentiation and organoid growth.