Faculty Bibliography

The COVID-19 pandemic was an unparalleled stressor that enhanced isolation. Loneliness has been identified as an epidemic by the US Surgeon General. This study aimed to: (1) characterize longitudinal trajectories of loneliness during the acute phase of the COVID-19 pandemic; (2) identify longitudinal mediators of the relationship of loneliness with anxiety and depression; and (3) examine how loneliness naturally clusters and identify factors associated with high loneliness. Two hundred and twenty-nine adults (78% female; mean age = 39.5 ± 13.8) completed an abbreviated version of the UCLA Loneliness Scale, Perceived Stress Scale, Emotion Regulation Questionnaire, State Anxiety Inventory, and Patient Health Questionnaire-8 longitudinally between April 2020 and 2021. Trajectory analyses demonstrated relatively stable loneliness over time, while anxiety and depression symptoms declined. Longitudinal analyses indicated that loneliness effects on anxiety and depression were both partially mediated by perceived stress, while emotion regulation capacity only mediated effects on anxiety. Three stable clusters of loneliness trajectories emerged (high, moderate, and low). The odds of moderate or high loneliness cluster membership were positively associated with higher perceived stress and negatively associated with greater cognitive reappraisal use. Our results demonstrate the important interconnections between loneliness and facets of mental health throughout the early phases of the pandemic and may inform targeted future interventions for loneliness work.

Myasthenia gravis (MG) is a chronic and severe disease of the skeletal neuromuscular junction (NMJ) in which the effects of neurotransmitters are attenuated, leading to muscle weakness. In the most common forms of autoimmune MG, antibodies attack components of the postsynaptic membrane, including the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). MuSK, a master regulator of NMJ development, associates with the low-density lipoprotein-related receptor 4 (Lrp4) to form the signaling receptor for neuronal Agrin, a nerve-derived synaptic organizer. Pathogenic antibodies to MuSK interfere with binding between MuSK and Lrp4, inhibiting the differentiation and maintenance of the NMJ. MuSK MG can be debilitating and refractory to treatments that are effective for AChR MG. We show here that recombinant antibodies, derived from MuSK MG patients, cause severe neuromuscular disease in mice. The disease can be prevented by a MuSK agonist antibody, presented either prophylactically or after disease onset. These findings suggest a therapeutic alternative to generalized immunosuppression for treating MuSK MG by selectively and directly targeting the disease mechanism.

Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.

Alzheimer's disease (AD) is a neurodegenerative disorder with limited therapeutic options. Accordingly, new approaches for prevention and treatment are needed. One focus is the human microbiome, the consortium of microorganisms that live in and on us, which contributes to human immune, metabolic, and cognitive development and that may have mechanistic roles in neurodegeneration. AD and Alzheimer's disease-related dementias (ADRD) are recognized as spectrum disorders with complex pathobiology. AD/ADRD onset begins before overt clinical signs, but initiation triggers remain undefined. We posit that disruption of the normal gut microbiome in early life leads to a pathological cascade within septohippocampal and cortical brain circuits. We propose investigation to understand how early-life microbiota changes may lead to hallmark AD pathology in established AD/ADRD models. Specifically, we hypothesize that antibiotic exposure in early life leads to exacerbated AD-like disease endophenotypes that may be amenable to specific microbiological interventions. We propose suitable models for testing these hypotheses.

Understanding sensory processing relies on the establishment of a consistent relationship between the stimulus space, its neural representation, and perceptual quality. In olfaction, the difficulty in establishing these links lies partly in the complexity of the underlying odor input space and perceptual responses. Based on the recently proposed primacy model for concentration invariant odor identity representation and a few assumptions, we have developed a theoretical framework for mapping the odor input space to the response properties of olfactory receptors. We analyze a geometrical structure containing odor representations in a multidimensional space of receptor affinities and describe its low-dimensional implementation, the primacy hull. We propose the implications of the primacy hull for the structure of feedforward connectivity in early olfactory networks. We test the predictions of our theory by comparing the existing receptor-ligand affinity and connectivity data obtained in the fruit fly olfactory system. We find that the Kenyon cells of the insect mushroom body integrate inputs from the high-affinity (primacy) sets of olfactory receptors in agreement with the primacy theory.

Individuals with DS develop Alzheimer's disease (AD) neuropathology, including endosomal-lysosomal system abnormalities and degeneration of basal forebrain cholinergic neurons (BFCNs). We investigated whether maternal choline supplementation (MCS) affects early endosome pathology within BFCNs using the Ts65Dn mouse model of DS/AD. Ts65Dn and disomic (2N) offspring from dams administered MCS were analyzed for endosomal pathology at 3-4 months or 10-12 months. Morphometric analysis of early endosome phenotype was performed on individual BFCNs using Imaris. The effects of MCS on the endosomal interactome were interrogated by relative co-expression (RCE) analysis. MCS effectively reduced age- and genotype-associated increases in early endosome number in Ts65Dn and 2N offspring, and prevented increases in early endosome size in Ts65Dn offspring. RCE revealed a loss of interactome cooperativity among endosome genes in Ts65Dn offspring that was restored by MCS. These findings demonstrate MCS rescues early endosome pathology, a driver of septohippocampal circuit dysfunction. The genotype-independent benefits of MCS on endosomal phenotype indicate translational applicability as an early-life therapy for DS as well as other neurodevelopmental/neurodegenerative disorders involving endosomal pathology.

Stroke is a leading cause of mortality and disability. Emergent diagnosis and intervention are critical, and predicated upon initial brain imaging; however, existing clinical imaging modalities are generally costly, immobile, and demand highly specialized operation and interpretation. Low-energy microwaves have been explored as a low-cost, small form factor, fast, and safe probe for tissue dielectric properties measurements, with both imaging and diagnostic potential. Nevertheless, challenges inherent to microwave reconstruction have impeded progress, hence conduction of microwave imaging remains an elusive scientific aim. Herein, we introduce a dedicated experimental framework comprising a robotic navigation system to translate blood-mimicking phantoms within a human head model. An 8-element ultra-wideband array of modified antipodal Vivaldi antennas was developed and driven by a two-port vector network analyzer spanning 0.6-9.0 GHz at an operating power of 1 mW. Complex scattering parameters were measured, and dielectric signatures of hemorrhage were learned using a dedicated deep neural network for prediction of hemorrhage classes and localization. An overall sensitivity and specificity for detection >0.99 was observed, with Rayleigh mean localization error of 1.65 mm. The study establishes the feasibility of a robust experimental model and deep learning solution for ultra-wideband microwave stroke detection.

Classic change blindness is the phenomenon where seemingly obvious changes that coincide with visual disruptions (such as blinks or brief blanks) go unnoticed by an attentive observer. Some early work into the causes of classic change blindness suggested that any pre-change stimulus representation is overwritten by a representation of the altered post-change stimulus, preventing change detection. However, recent work revealed that, even when observers do maintain memory representations of both the pre- and post-change stimulus states, they can still miss the change, suggesting that change blindness can also arise from a failure to compare the stored representations. Here, we studied slow change blindness, a related phenomenon that occurs even in the absence of visual disruptions when the change occurs sufficiently slowly, to determine whether it could be explained by conclusions from classic change blindness. Across three different slow change blindness experiments we found that observers who consistently failed to notice the change had access to at least two memory representations of the changing display. One representation was precise but short lived: a detailed representation of the more recent stimulus states, but fragile. The other representation lasted longer but was fairly general: stable but too coarse to differentiate the various stages of the change. These findings suggest that, although multiple representations are formed, the failure to compare hypotheses might not explain slow change blindness; even if a comparison were made, the representations would be too sparse (longer term stores) or too fragile (short-lived stores) for such comparison to inform about the change.

Glial cells in the peripheral nervous system (PNS), which arise from the neural crest, include axon-associated Schwann cells (SCs) in nerves, synapse-associated SCs at the neuromuscular junction, enteric glia, perikaryon-associated satellite cells in ganglia, and boundary cap cells at the border between the central nervous system (CNS) and the PNS. Here, we focus on axon-associated SCs. These SCs progress through a series of formative stages, which culminate in the generation of myelinating SCs that wrap large-caliber axons and of nonmyelinating (Remak) SCs that enclose multiple, small-caliber axons. In this work, we describe SC development, extrinsic signals from the axon and extracellular matrix (ECM) and the intracellular signaling pathways they activate that regulate SC development, and the morphogenesis and organization of myelinating SCs and the myelin sheath. We review the impact of SCs on the biology and integrity of axons and their emerging role in regulating peripheral nerve architecture. Finally, we explain how transcription and epigenetic factors control and fine-tune SC development and myelination.