Faculty Bibliography

Oxytocin is a small, nine amino acid peptide synthesized and released mostly in the brain. It was discovered first as a hormone that facilitates labor and lactation but has since attracted interest for having important roles in social bonding. Although sometimes informally called a 'love hormone', this is erroneous and does not accurately reflect the biological action of oxytocin across different contexts. Here we provide an overview of the organization of the oxytocin system, which subserves different biological functions that ultimately coordinate physiological and behavioral states supporting reproductive success (Figure 1).

BACKGROUND:Primary hyperoxaluria (PH) is a family of three rare, autosomal recessive genetic disorders that can result in recurrent kidney stones, progressive chronic kidney disease (CKD), and kidney failure. PH prevalence is underestimated due to its varying presentation and lack of awareness; delays in diagnosis can lead to substantial burdens on the healthcare system. METHODS:This retrospective, observational claims analysis evaluated disease burden and cost of care in patients who had PH, PH with CKD, or CKD alone. Data from the Merative MarketScan Commercial Claims and Encounters databases and the Centers for Medicare and Medicaid Services Medicare Fee-for-Service Limited Data Set were assessed during the study period of January 1, 2017, to December 31, 2021. PH prevalence was calculated based on the sample population within each data source. RESULTS:The study sample included 326 patients who had PH; applying projection factors to the US population, an estimated 4500 patients had a diagnosis of PH in 2021. Among these patients, 37% were estimated to have PH with CKD (65% of whom had early CKD, 33% had advanced CKD, and 2% had stage reported as unknown). Patients who had CKD alone (n = 845) were matched with patients who had PH with CKD (n = 169). Patients who had PH with CKD were significantly more burdened with kidney stones (p < 0.01) than patients who had CKD alone. Higher rates of pharmacotherapy and medical treatments were observed in patients who had PH with CKD versus patients who had CKD alone. Median semi-annual total all-cause healthcare costs were greater in patients who had PH with CKD than in patients with CKD alone, regardless of CKD stage ($54,154 in patients who had PH with advanced CKD vs. $35,016 in patients with advanced CKD alone; $9,784 in patients who had PH with early CKD vs. $5,572 in patients with early CKD alone). CONCLUSIONS:CKD stage progression among patients who had PH is associated with increasing all-cause costs, suggesting that early diagnosis and treatment of PH to limit the progression to advanced CKD could represent an opportunity to alleviate not only PH symptoms, but also the healthcare cost burden.

Inflammation drives various diseases, including cardiovascular, neurodegenerative, and oncological disorders, by altering immune cell dynamics in hematopoietic niches. The bone marrow is the primary site for hematopoietic stem and progenitor cell activity. Here, we present a novel, noninvasive approach using multispectral optoacoustic tomography (MSOT) to track oxygenation dynamics in the murine calvarial bone marrow during acute systemic inflammation induced by lipopolysaccharide (LPS). Our MSOT system provided real-time, label-free imaging of hemoglobin oxygen saturation (sO₂), revealing significant reductions in sO₂ levels in lipopolysaccharide-treated mice, indicative of increased oxygen consumption. Co-registration with microCT enabled precise vascular mapping. Hypoxia was confirmed by ex vivo Pimonidazole staining and optical imaging and was associated with elevated neutrophil counts and enhanced hematopoietic activation. These findings demonstrate MSOT's potential for noninvasive imaging of marrow oxygenation, offering insights into inflammation-driven hematopoietic activation and supporting the development of therapies targeting oxygen-sensitive pathways.

Although many internalized G protein-coupled receptors (GPCRs) continue to signal, the mechanisms and outcomes of intracellular GPCR signaling are uncertain due to the challenges of measuring organelle-specific signals and of selectively antagonizing receptors in intracellular compartments. Herein, genetically encoded biosensors targeted to the plasma membrane and early endosomes were used to analyze compartmentalized signaling of protease-activated receptor 2 (PAR₂); the propensity of nanoparticles (NPs) to accumulate in endosomes was leveraged to preferentially antagonize intracellular PAR₂ signaling of pain. PAR₂ agonists evoked sustained activation of PAR₂, Gαq, and β-arrestin-1 in early endosomes and activated extracellular signal regulated kinase (ERK) in the cytosol and nucleus, measured with targeted biosensors. Fluorescent dendrimer and core-shell polymeric NPs accumulated in endosomes of HEK293T cells, colonic epithelial cells, and nociceptors, detected by confocal microscopy. NPs efficiently encapsulated and slowly released AZ3451, a negative allosteric PAR₂ modulator. NP-encapsulated AZ3451, but not unencapsulated AZ3451, rapidly and completely reversed PAR₂, Gαq, and β-arrestin-1 activation in early endosomes and ERK activation in the cytosol and nucleus. When administered into the mouse colon lumen, fluorescent dendrimer NPs accumulated in endosomes of colonocytes and polymeric NPs accumulated in neurons, sites of PAR₂ expression. Both NP formulations of AZ3451, but not unencapsulated AZ3451, caused long-lasting analgesia and normalized aberrant behavior in preclinical models of inflammatory bowel disease. These results provide evidence that PAR₂ endosomal signaling mediates pain and that nanomedicines that antagonize PAR₂ in endosomes effectively relieve pain. NP-mediated delivery may improve the efficacy of other GPCR antagonists for treatment of diverse diseases.

BACKGROUND:Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting "Solving Neurodegeneration," (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma and other neurodegenerative diseases. This review summarizes outcomes from the 2023 "Solving Neurodegeneration 2" meeting, a forum for CFC3 and CFC4 to share updates, problem solve, plan future research collaborations, and identify areas of unmet need or opportunity in glaucoma and the broader field of neurodegenerative disease research. MAIN BODY/METHODS:We summarize the recent progress in the field of neurodegenerative disease research and present the newest challenges and opportunities moving forward. While translatability and disease complexity continue to pose major challenges, important progress has been made in identifying neuroprotective targets and understanding neuron-glia-vascular cell interactions. New challenges involve improving our understanding of the disease microenvironment and timeline, identifying the optimal approach(es) to neuronal replacement, and finding the best drug combinations and synergies for neuroprotection. We propose solutions to common research questions, provide prescriptive recommendations for future studies, and detail methodologies, strategies, and approaches for addressing major challenges at the forefront of neurodegenerative disease research. CONCLUSIONS:This review is intended to serve as a research framework, offering recommendations and approaches to validating neuroprotective targets, investigating rare cell types, performing cell-specific functional characterizations, leveraging novel adaptations of scRNAseq, and performing single-cell sorting and sequencing across neurodegenerative diseases and disease models. We focus on modeling neurodegeneration using glaucoma and other neurodegenerative pathologies to investigate the temporal and spatial dynamics of neurodegenerative disease pathogenesis, suggesting researchers aim to identify pan-neurodegenerative drug targets and drug combinations leverageable across neurodegenerative diseases.

Human retrotransposon insertions are often associated with diseases. In the case of the neurodegenerative X-Linked Dystonia-Parkinsonism disease, a human-specific SINE-VNTR-Alu subfamily F retrotransposon was inserted in intron 32 of the TAF1 gene. Here, we genomically rewrote a portion of the mouse Taf1 allele with the corresponding 78-kb XDP patient derived TAF1 allele. In mESCs, the presence of the intronic SVAs-rather than the hybrid gene structure-reduces hyTAF1 levels. This leads to transcriptional downregulation of genes with TATA box enriched in their promoters and triggering apoptosis. Chromatin and transcriptome profiling revealed that intronic SVAs are actively transcribed, forming barriers that likely impede transcription elongation. In mice, neuronal lineage TAF1 humanization resulted lethality of male progeny within two months. XDP male mice had severe atrophy centered on the striatum-the same affected brain region in XDP patients. Lastly, CRISPRa-mediated activation of hyTAF1 restored mESC viability, suggesting boosting TAF1 transcription as a therapeutic approach.

Theories propose that speech production can be approximated as a temporal reversal of speech perception. For example, phonological code is assumed to precede phonetic encoding in the motor system during speech production. However, empirical neural evidence directly testing the temporal order hypothesis remains scarce, mostly because of motor artifacts in non-invasive electrophysiology recordings and the requirements of both temporal and spatial precision. In this study, we investigated the neural dynamics of speech production using stereotactic electroencephalography (sEEG). In both onset latency analysis and representational similarity analysis (RSA), activation in the auditory region of the posterior superior temporal gyrus (pSTG) was observed before articulation, suggesting the availability of auditory phonological code before production. Surprisingly, the activation in the motor region of the inferior frontal gyrus (IFG) preceded that of pSTG, suggesting that the phonological code in the auditory domain may not necessarily be activated before the encoding in the motor domain during speech production.

Neurons process information by integrating thousands of synaptic inputs along their dendrites. Understanding the computational principles underlying neuronal information processing requires a reliable measure of synaptic conductance dynamics that accurately represents the input sources before signal integration and processing. Prevailing approaches to measuring synaptic conductances typically employ a voltage clamp at the soma of a neuron and assume the neuron as an isopotential point when processing electrical signals. However, owing to the presence of the well-known space clamp effect, the measurement of synaptic conductances through these methods often leads to significant errors, impeding the elucidation of dendritic signal features and subsequent signal integration processes. To address this issue, here we first develop a two-step clamp method at the soma that separately recovers the mean and time constant information of local synaptic conductance on the dendrite with high accuracy when a neuron receives a single synaptic input. Furthermore, under in vivo conditions of multiple synaptic inputs, we propose an intercept method to extract effective net excitatory and inhibitory synaptic conductances from measurements of synaptic currents at the soma. Both methods are grounded in mathematical perturbation analyses of a conductance-based passive cable model and are validated across multiple biologically detailed multicompartment neuron models with active channels, including Purkinje neuron, pyramidal neuron, and fast-spiking interneuron. Results demonstrate that our methods effectively circumvent the space clamp effect, offering reliable means to assess the role of measured conductances and synaptic activity in neuronal information processing.

Mothers exhibit an increased appetite to cope with the energetic demands of lactation. A new study has identified a neural circuit that interfaces between food seeking and pup caring.