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.

The autonomic nervous system (ANS) plays a vital role in health care for both acute care and chronic diseases. The traditional view of the ANS is to divide it into individual organ systems and study the separate components with a reductionist approach, which has been proven insufficient. Here, we argue that a holistic network-level view of the ANS is critical for generating new insights and deepening our understanding of its complex and dynamic functions. In this review, we treat the ANS as such a coordinated and dynamic network. We advocate for studying its interactions with major organ systems and the central nervous system using continuous and longitudinal monitoring in ambulatory and at-home settings rather than clinic-based snapshots. We first briefly review ANS physiology, then outline our network perspective, and finally highlight cutting-edge research directions and emerging engineering innovations in ANS monitoring, modeling, and modulation that benefit from this network-level view.

The locus coeruleus (LC) plays important roles in sleep/wake regulation and cognitive functions. LC neurons may be particularly sensitive to neural injury and serve as an early site of accumulation pathological tau in Alzheimer's disease. Obstructive sleep apnea (OSA) creates both chronic intermittent hypoxia and sleep fragmentation as potential insults to differentially sensitive neural populations including the locus coeruleus (LC). Using high field 7T imaging in cognitively normal older adults, we demonstrate that time spent with an oxygen saturation below 90% (T90), a measure of OSA's hypoxic burden, inversely correlates with LC structural integrity and explains significant variance in LC structural integrity after controlling for age, sex, and BMI. In contrast, other sleep variables such as the apnea-hypopnea index (AHI), total sleep time, and sleep efficiency did not contribute significant variance in LC structural integrity in this model. Thus, in the diagnosis of OSA, attention to hypoxic burden variables may be important in risk stratification for LC neural injury. This observation may inform future work determining whether mitigation of the hypoxemic burden from OSA can slow deterioration in LC integrity.

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.

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.

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.

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.