Faculty Bibliography

OBJECTIVES/UNASSIGNED:Although cardiac function is truly vital, and can be adversely affected by many diseases, conventional quantitative global function analysis from images is largely limited to assessing the cardiac volumes at end-diastole and end-systole, and the associated ejection fraction, due to the time-consuming associated image segmentation. Advances in AI-assisted cardiac image segmentation can potentially enable more detailed analysis of the dynamic changes in cardiac volumes over the cardiac cycle, in clinically practical times, but there are now no standardized ways to analyze such data. In this work, we propose a systematic approach to the analysis of dynamic global cardiac function from imaging data. DESIGN/UNASSIGNED:We use some cardiac magnetic resonance imaging (CMR) data here to illustrate this approach, but the methods are not limited to MRI. The focus here is on the technical approach, rather than on potential clinical applications. Representative short-axis cine CMRs from 19 normal subjects and 22 patients with clinical diagnosis of "heart failure with preserved ejection fraction" were analyzed for ventricular volumes over the cardiac cycle. The resulting data were used to calculate a set of dynamic global function variables. RESULTS/UNASSIGNED:A set of representative measures of the timing and rates of ventricular emptying and filling is promising as compact means to characterize dynamic global function. CONCLUSIONS/UNASSIGNED:More efficient cardiac segmentation offers the potential to characterize dynamic global cardiac function, through a set of representative measures of the timing and rates of ventricular emptying and filling.

Larry Young had a huge impact on the study of neuropeptides and social behavior. Here I give an autobiographical perspective on how Larry and his work influenced the field and my own career.

Oral cancer is one of the most painful malignancies, with pain driven primarily by algogenic mediators in the tumor microenvironment, including nerve growth factor (NGF). Although NGF monoclonal antibodies alleviate cancer pain in patients, clinical development was halted because of adverse effects, highlighting the need for safer alternatives. Neuropilin-1 (NRP1), a nonenzymatic NGF coreceptor, mediates NGF and tropomyosin receptor kinase A (TrkA) signaling, yet its role in cancer pain is unknown. We found that NRP1 is robustly coexpressed with TrkA in peptidergic nociceptors of mouse trigeminal ganglia. NRP1 antagonists inhibited NGF-induced sensitization of transient receptor potential vanilloid 1 in isolated trigeminal nociceptors and reduced NGF-induced periorbital mechanical allodynia in mice. Conditioned medium from human tongue squamous carcinoma HSC-3 cells contained NGF and sensitized transient receptor potential vanilloid 1 in trigeminal nociceptors and induced periorbital mechanical allodynia. Immunoneutralization of NGF and NRP1 blockade inhibited these effects. Our results show that NRP1 is a necessary coreceptor for the pronociceptive effects of NGF/TrkA signaling in the trigeminal system and implicate NGF and NRP1 in oral cancer pain. Current oral cancer pain management strategies, including opioids, are inadequate and are burdened by unacceptable side effects. By abrogating the actions of growth factors, including NGF, NRP1-targeted therapies represent an alternative approach to mitigate cancer pain and possibly slow tumor growth.

BACKGROUND: ("Dutch") transgenic mice develop aging-related learning deficits and accumulate endogenously generated non-fibrillar aggregates (NFAs) of amyloid beta (Aβ) and amyloid precursor protein α-carboxy terminal fragments. NFA-Aβ correlates with synaptic loss and memory deficits more closely than does fibrillar Aβ. METHODS: mice. RESULTS: mice developed physiological abnormalities in post-tetanic potentiation, synaptic fatigue, synaptic vesicle replenishment, and an aging-related reduction in mitochondrial complex I activity. Single-cell RNA sequencing showed that excitatory neurons exhibited an altered transcriptomic profile involving "protein translation" and "oxidative phosphorylation." DISCUSSION/CONCLUSIONS:Accumulation of NFA-Aβ alters neuronal metabolism but does not activate inflammation. Depletion of all forms of Aβ may be required to eliminate Aβ toxicity with anti-amyloid antibodies.

BACKGROUND:Raghib syndrome is a congenital anomaly that is caused by a persistent left superior vena cava draining into the left atrium, unroofed coronary sinus, and atrial septal defect. It can lead to cyanosis, cryptogenic strokes, pulmonary hypertension, and arrythmias. CASE SUMMARY/METHODS:A 60-year-old woman presented with palpitations due to atrial flutter. Cardiac imaging, including computed tomography, transesophageal echocardiography, and magnetic resonance imaging, confirmed bilateral superior vena cavae, with the left superior vena cava draining into the left atrium and minimal right-to-left shunting (3%). She was managed with anticoagulation and underwent regular follow-up without complications. DISCUSSION/CONCLUSIONS:Diagnosis of Raghib syndrome relies on multimodality imaging. In cases with minimal symptoms and left-to-right shunting, conservative management with biannual follow-up may be sufficient. TAKE-HOME MESSAGES/CONCLUSIONS:Multimodality imaging is crucial in confirming anatomy and characterizing flow dynamics in cyanotic congenital heart disease. In patients with Raghib syndrome without cyanosis, conservative management with anticoagulation may be a safe alternative to surgical intervention.

RATIONALE/BACKGROUND:Aggression is an innate social behavior prevalent across animal species. However, in modern human society, inter-personal aggression is considered disruptive and detrimental to both families and communities. Clinically, antipsychotics, which primarily target dopamine (DA) receptors, have been widely used to suppress hyper-aggression. However, the mechanisms underlying the effect of the antipsychotics remain incompletely understood. OBJECTIVES/OBJECTIVE:We reviewed key steps in brain DA synthesis and summarized genetic and pharmacological evidence supporting the role of the mesolimbic DA system in aggression. Next, we discussed recent circuit studies that elucidate the DA action in modulating aggression-related brain regions. These lines of evidence collectively suggest that DA acts on different brain regions to facilitate aggression and self-learning, and signals the valence of the fighting experience.

Toxicity of prenatal ethanol leading to fetal alcohol spectrum disorders (FASDs) has been linked to disturbances in retinoic acid (RA) signaling necessary for embryonic development. While ethanol exposure in the postnatal day 7 (P7) mice, which induces immediate neurodegeneration and long-lasting GABAergic cell loss and behavioral deficits, has been used for the third trimester FASD model, involvement of RA signaling in the process has not been well explored. Using RARE-LacZ reporter mice that express β-galactosidase (β-Gal) under the control of retinoic acid response element (RARE), we examined RA signaling activity of the forebrains of P8 and P30 mice with or without P7 ethanol treatment. In all experimental groups, β-Gal was expressed mainly in the hippocampus with the strongest expression in the granule cell layer of dentate gyrus. In addition, β-Gal was expressed in pyramidal neurons and parvalbumin (PV) neurons in CA1-3 pyramidal layer and in astrocytes scattered around the CA1-3 region although PV neurons were only examined at P30 because of the low PV expression at P8. β-Gal was also expressed in the anteroventral/anteromedial (AV/AM) thalamus and the retrosplenial (Rs) and Tbr1-positive (+) layer 6 cortices. β-Gal-expressing PV neurons were also found in the cortex such as Rs, while β-Gal was barely detected in somatostatin neurons in any brain regions examined. Such region and cell specific β-Gal expression was significantly higher in P8 brains than P30 brains in various brain regions. P7 ethanol reduced β-Gal expression in the CA1-3 pyramidal layer, Tbr1 + cortical layer 6, and the AV/AM thalamus at P8 or P30 or both. Although P7 ethanol decreased PV cells in CA2-3 pyramidal layers as reported, it decreased β-Gal+ PV cells more drastically. The active RA signaling found in PV neurons and the effects of P7 ethanol on the signaling suggest that reduced RA signaling by P7 ethanol may disturb PV cell maturation and enhance long-lasting brain abnormalities.

Oxytocin modulates social information processing by altering excitatory-inhibitory balance at the microcircuit level, but how such local modulation gives rise to selective processing at the level of distributed brain systems remains unclear. Here, we investigated the effects of oxytocin on large-scale neurodynamics across cortico-limbic network in the mouse brain using multisite local field potential recordings. Oxytocin selectively enhanced neural responses to infant calls in the auditory cortex (AC) and medial prefrontal cortex (mPFC). These enhancements occurred while baseline activity was reduced, indicating increased signal-to-noise ratio rather than a global increase in excitability. During auditory steady-state responses (ASSRs), oxytocin increased prefrontal phase coherence without altering ASSR power. During rest, oxytocin induced a transient, broadband reduction in spontaneous spectral power across regions. Despite this reduction in activity, analyses of interregional interactions revealed a selective increase in low-theta phase coupling and directional connectivity of AC→mPFC. Session-level analyses showed that stronger bottom-up AC→mPFC coupling was associated with lower prefrontal power, consistent with a gating or disinhibitory network regime favoring sensory-to-prefrontal information transfer. Multivariate analyses showed that oxytocin/saline conditions were reliably discriminable using supervised classification models, with specific contributions from spectral power, phase-locking, and Granger-causal connectivity features. Conversely, unsupervised dimensionality reduction did not identify a distinct low-dimensional manifold separating conditions, although a modest shift in the centroid of neural state space was observed. Together, these results indicate that oxytocin reduces background neural activity while selectively enhancing sensory-prefrontal network interactions, providing a systems-level account linking local inhibitory modulation to selective processing of socially salient infant cues.