Faculty Bibliography

Astrocytes differentiate and mature during postnatal development, but the molecular mechanisms linking their maturation to neuronal function remain unclear. We investigated the role of Wnt/β-catenin signaling and its effector, the transcription factor TCF7L2, in postnatal astrocytes using single-nucleus RNA sequencing, imaging, morphometric analysis, microdialysis, and electrophysiology in Tcf7l2 conditional knockout (cKO) mice. Loss of Tcf7l2 caused widespread transcriptional dysregulation in astrocytes, particularly in genes related to amino acid and ion transport, as well as membrane potential regulation. These mice showed disrupted amino acid homeostasis, astrocyte swelling, and impaired extracellular potassium clearance in the somatosensory cortex. These astrocytic changes were accompanied by altered gene expression in cortical pyramidal neurons, reduced excitability, and a hyperpolarized resting membrane potential. Our results suggest that astrocytic TCF7L2 is crucial in coordinating ion and amino acid transport in adulthood, thereby contributing to maintaining extracellular homeostasis and supporting neuronal function. This study identifies TCF7L2 as a key regulator of astrocyte-mediated neurophysiological support and underscores the importance of its role in astrocyte maturation during postnatal development.

BACKGROUND:Familial dysautonomia (FD) is a hereditary neurodevelopmental disorder caused by aberrant splicing of the ELP1 gene, leading to a tissue-specific reduction in ELP1 protein expression. Preclinical models indicate that increasing ELP1 levels can mitigate disease manifestations. A blood-based ELP-1 protein assay may provide a reliable way to monitor gene target engagement. DESIGN AND METHODS/METHODS:Using a newly developed radioimmunoassay, we quantified ELP1 protein levels in peripheral blood samples collected from 59 homozygous FD patients carrying the IVS20 + 6T>C mutation and 66 heterozygous carriers. To assess the reproducibility of the measurement, replicate samples were collected in 43 participants. Longitudinal variability was evaluated in 22 participants who underwent repeat sampling 1 year later. RESULTS: = 0.827, p < 0.001). An ELP1 threshold of 492 pg/mL yielded a sensitivity of 80.2% (CI of 70.6 to 87.2%) and a specificity of 98.2% (95% CI of 90%-99%) with a positive likelihood ratio of 46.5, indicating that individuals with FD were over 46 times more likely to have ELP1 levels below this threshold compared to non-affected carriers. CONCLUSION/CONCLUSIONS:Blood ELP1 levels are robust and reproducible, with concentrations below 492 pg/mL strongly indicative of disease. Moreover, given their longitudinal stability, ELP1 can serve as a marker of target engagement to evaluate the efficacy of gene-targeted therapies aimed at correcting ELP1 gene splicing and protein production.

Aging is often accompanied by a decline in mobility across species, which can be improved by aerobic exercise, even in individuals with Parkinson's disease. We showed previously that 30 days of voluntary wheel-running exercise in young male mice leads to enhanced release of the motor-system transmitter, dopamine (DA), in ex vivo corticostriatal slices. Here we tested whether voluntary exercise also increases DA release in aging (12 months old) mice of both sexes, and whether this is associated with improved motor performance. Mice were allowed unlimited access to a rotating (runners) or a locked (controls) wheel for 30 days. Motor behavior was then assessed, and electrically evoked DA release was quantified in slices from these animals using fast-scan cyclic voltammetry. Although daily running distance for females was nearly twice that of males, runners of both sexes showed comparable increases in evoked DA release in dorsolateral striatum and in nucleus accumbens core and shell compared to age- and sex-matched controls. Runners of both sexes showed an increase in locomotion velocity and improved motor coordination. Thus, voluntary exercise boosts striatal DA release and improves motor performance in aging mice, providing new insights into the benefits of exercise in aging humans.

Prostate MRI has transformed lesion detection and risk stratification in prostate cancer, but its impact is constrained by the high cost of the exam, variability in interpretation, and limited scalability. False negatives, false positives, and moderate inter-reader agreement undermine reliability, while long acquisition times restrict throughput. Artificial intelligence (AI) offers potential solutions to address many of the limitations of prostate MRI in the clinical management pathway. Machine learning-based triage can refine patient selection to optimize resources. Deep learning reconstruction enables accelerated acquisition while preserving diagnostic quality, with multiple FDA-cleared products now in clinical use. Ongoing development of automated quality assessment and artifact correction aims to improve reliability by reducing nondiagnostic exams. In image interpretation, AI models for lesion detection and clinically significant prostate cancer prediction achieve performance comparable to radiologists, and the PI-CAI international reader study has provided the strongest evidence to date of non-inferiority at scale. More recent work extends MRI-derived features into prognostic modeling of recurrence, metastasis, and functional outcomes. This review synthesizes progress across five domains-triage, accelerated acquisition and reconstruction, image quality assurance, diagnosis, and prognosis-highlighting the level of evidence, validation status, and barriers to adoption. While acquisition and reconstruction are furthest along, with FDA-cleared tools and prospective evaluations, triage, quality control, and prognosis remain earlier in development. Ensuring equitable performance across populations, incorporating uncertainty estimation, and conducting prospective workflow trials will be essential to move from promising prototypes to routine practice. Ultimately, AI could accelerate the adoption of prostate MRI toward a scalable platform for earlier detection and population-level prostate cancer management. EVIDENCE LEVEL: N/A TECHNICAL EFFICACY: 3.

Seventy % of mammals copulate using repeated pelvic thrusting, while the transfer of sperm requires just a single intromission. Why did thrusting evolve to be the dominant form of sexual intercourse? In this study, we investigate how the rate of sexual pelvic thrusting changes with body size. By analyzing films of copulating mammals, from mice Mus musculus to elephants Elephantidae, we find that bigger animals thrust slower. The rate of pelvic thrusting decreases from 6 Hz for the pocket mouse Pergonathus to 1.3-1.8 Hz for humans to an absence of thrusting for the rhino Rhinocerotidae and elephant Elephantidae families. To understand this dependence on body size, we consider the spring-like behavior of the legs, which is associated with the elasticity of the body's muscles, tendons, and ligaments. For both running and thrusting, a maximum amplitude and great energy savings can be achieved if the system is oscillated at its resonant or natural frequency. Resonant frequencies, as measured through previous studies of running in dogs Canis familiaris and horses Equus ferus caballus, show good agreement with sexual thrusting frequencies. Running and sexual thrusting have nothing in common from a behavioral perspective, but from a physical perspective, they are both constrained by the same musculoskeletal systems, and both take advantage of resonance. Our findings may provide improved treatments for human sexual dysfunction as well as improving breeding strategies for domestic mammals.

Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially-expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of cell proliferation. We found that the expression of sFRP3, a Wnt signaling inhibitor, is altered in a seizure-dependent manner and might be regulated by ΔFosB, a seizure-induced transcription factor. Increasing sFRP3 expression prevented NSC depletion and improved spatial discrimination, suggesting that the loss of sFRP3 might mediate seizure-driven impairment in cognition in AD model mice, and perhaps also in AD.Significance statement There is increased incidence of seizures in individuals with Alzheimer's disease (AD), but it is unclear how seizures contribute to cognitive decline. Here, we uncover a molecular mechanism by which seizures in AD induce expression of a long-lasting transcription factor in the hippocampal dentate gyrus that suppresses expression of sFRP3, an inhibitor of neural stem cell division, accelerating the depletion of a finite pool of neural stem cells and dysregulating adult hippocampal neurogenesis. We found that restoring sFRP3 expression prevents accelerated use and depletion of neural stem cells and improves performance in an adult neurogenesis-dependent cognitive task. Our findings have implications for AD, epilepsy, and other neurological disorders that are accompanied by seizures.

Monitoring intracellular calcium is central to understanding cell signaling across nearly all cell types and organisms. Fluorescent genetically encoded calcium indicators (GECIs) remain the standard tools for in vivo calcium imaging, but require intense excitation light, leading to photobleaching, background autofluorescence and phototoxicity. Bioluminescent GECIs, which generate light enzymatically, eliminate these artifacts but have been constrained by low dynamic range and suboptimal calcium affinities. Here we show that CaBLAM ('calcium bioluminescence activity monitor'), an engineered bioluminescent calcium indicator, achieves an order-of-magnitude improvement in signal contrast and a tunable affinity matched to physiological cytosolic calcium. CaBLAM enables single-cell and subcellular activity imaging at video frame rates in cultured neurons and sustained imaging over hours in awake, behaving animals. These capabilities establish CaBLAM as a robust and general alternative to fluorescent GECIs, extending calcium imaging to regimes where excitation light is undesirable or infeasible.

BACKGROUND:Urinary stone disease with a clear genetic cause, monogenic stone disease (MSD), is increasingly recognized as a significant proportion of the total population. When MSD is suspected, genetic testing provides a firm diagnosis that can alter management and treatment. Here we present testing results from a large cohort with suspected MSD. METHODS:Subjects with features suggestive of MSD (early onset, family history, frequent stones, nephrocalcinosis [NC], and/or CKD) were recruited by the Rare Kidney Stone Consortium and genotyped for up to 160 known or candidate MSD genes via a targeted massively parallel sequencing (tMPS) panel. We compared clinical and biochemical features between genetically resolved MSD and unresolved individuals. RESULTS:Of 426 families (657 patients) enrolled, 145 (34%) were resolved with identified disease associated variants in 22 known MSD genes. Ninety-nine families were biallelic, 37 monoallelic, and 2 digenic. An additional 21 of the 231 screened family members were resolved. Genes identified in 10 or more families were: AGXT, HOGA1, SLC34A3, CYP24A1, SLC3A1, and CLCN5. Compared to the unresolved group, MSD probands had a lower baseline and last visit estimated glomerular filtration rate (eGFR), earlier age of stone presentation, and more stone events and procedures/year of life. The resolve rate was higher in those less than 16 years, and NC was seen earlier in the MSD group. Overall, NC was a risk factor for lower eGFR. Among the specific disorders, primary hyperoxaluria patients had the earliest age of stone and NC diagnosis, and as expected, the highest urinary oxalate level. CONCLUSIONS:Our study emphasizes the value of selecting patients enriched for factors associated with MSD, and comprehensive genetic testing to achieve a high yield of genetic diagnoses. Significant clinical and biochemical characteristics of MSD patients were defined. A definitive MSD diagnosis facilitates individualized management and strategies to delay disease progression in probands and affected family members.