Faculty Bibliography

Interactions between axons and Schwann cells are essential for the acquisition of Schwann cell radial and longitudinal polarity and myelin sheath assembly. In the internode, the largest of these longitudinal domains, axon-Schwann cell interactions are mediated by the Nectin-like (Necl) cell adhesion proteins, also known as SynCAMs or Cadms. In particular, Necl-1/Cadm3 expressed on the axon surface binds to Necl-4/Cadm4 expressed along the adaxonal membrane of myelinating Schwann cells. Necl-4 promotes myelination in vitro and is required for the timely onset of myelination and the fidelity of the organization of the myelin sheath and the internode in vivo. A key question is the identity of the downstream effectors of Necl-4 that mediate its effects. The cytoplasmic terminal region (CTR) of Necl-4 contains a PDZ-domain binding motif. Accordingly, we used the CTR of Necl-4 in an unbiased proteomic screen of PDZ-domain proteins. We identify Par-3, a multi-PDZ domain containing protein of the Par-aPKC polarity complex previously implicated in myelination, as an interacting protein. Necl-4 and Par-3 are colocalized along the inner Schwann cell membrane and coprecipitate from Schwann cell lysates. The CTR of Necl-4 binds to the first PDZ domain of Par-3 thereby recruiting Par-3 to sites of Necl-4/Necl-1 interaction. Knockdown of Necl-4 perturbs Par-3 localization to the inner membrane of Schwann cells in myelinating co-cultures. These findings implicate interactions of Necl-1/Necl-4 in the recruitment of Par-3 to the Schwann cell adaxonal membrane and the establishment of Schwann cell radial polarity.

Efforts to scale neuroimaging towards the direct visualization of mammalian brain-wide neuronal activity have faced major challenges. Although high-resolution optical imaging of the whole brain in small animals has been achieved ex vivo, the real-time and direct monitoring of large-scale neuronal activity remains difficult, owing to the performance gap between localized, largely invasive, optical microscopy of rapid, cellular-resolved neuronal activity and whole-brain macroscopy of slow haemodynamics and metabolism. Here, we demonstrate both ex vivo and non-invasive in vivo functional optoacoustic (OA) neuroimaging of mice expressing the genetically encoded calcium indicator GCaMP6f. The approach offers rapid, high-resolution three-dimensional snapshots of whole-brain neuronal activity maps using single OA excitations, and of stimulus-evoked slow haemodynamics and fast calcium activity in the presence of strong haemoglobin background absorption. By providing direct neuroimaging at depths and spatiotemporal resolutions superior to optical fluorescence imaging, functional OA neuroimaging bridges the gap between functional microscopy and whole-brain macroscopy.

Cortical responses to sensory inputs vary across repeated presentations of identical stimuli, but how this trial-to-trial variability impacts detection of sensory inputs is not fully understood. Using multi-channel local field potential (LFP) recordings in primary somatosensory cortex (S1) of the awake mouse, we optimized a data-driven cortical state classifier to predict single-trial sensory-evoked responses, based on features of the spontaneous, ongoing LFP recorded across cortical layers. Our findings show that, by utilizing an ongoing prediction of the sensory response generated by this state classifier, an ideal observer improves overall detection accuracy and generates robust detection of sensory inputs across various states of ongoing cortical activity in the awake brain, which could have implications for variability in the performance of detection tasks across brain states.

Familial dysautonomia (Riley-Day syndrome, hereditary sensory and autonomic neuropathy type III) is a rare autosomal recessive disease characterized by impaired development of primary sensory and autonomic neurons resulting in a severe neurological phenotype, which includes arterial baroreflex and chemoreflex failure with high frequency of sleep-disordered breathing and sudden death during sleep. Although a rare disease, familial dysautonomia represents a unique template to study the interactions between sleep-disordered breathing and abnormal chemo- and baroreflex function. In patients with familial dysautonomia, ventilatory responses to hypercapnia are reduced, and to hypoxia are almost absent. In response to hypoxia, these patients develop paradoxical hypoventilation, hypotension, bradycardia, and potentially, death. Impaired ventilatory control due to chemoreflex failure acquires special relevance during sleep when conscious control of respiration withdraws. Overall, almost all adult (85%) and pediatric (95%) patients have some degree of sleep-disordered breathing. Obstructive apnea events are more frequent in adults, whereas central apnea events are more severe and frequent in children. The annual incidence rate of sudden death during sleep in patients with familial dysautonomia is 3.4 per 1000 person-year, compared to 0.5-1 per 1000 person-year of sudden unexpected death in epilepsy. This review summarizes recent developments in the understanding of sleep-disordered breathing in patients with familial dysautonomia, the risk factors for sudden death during sleep, and the specific interventions that could prevent it.

The most important variable leading to uric acid stones is low urine pH. Major causal conditions associated with low urine pH are metabolic syndrome and diabetes. In the study by Maalouf et al., treatment of uric acid stone formers with pioglitazone led to small but significant increases in urine pH. Pioglitazone will not supplant alkali administration to prevent uric acid stones, but the study helps confirm that insulin resistance is an important cause of low urine pH that causes uric acid stones.

G protein-coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. Within the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication amongst cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of over one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have revealed that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs, and has revealed opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract.

PURPOSE/OBJECTIVE:We present a novel, geometrically adjustable, receive coil array whose diameter can be tailored to the subject in order to maximize sensitivity for a range of body sizes. THEORY AND METHODS/UNASSIGNED:A key mechanical feature of the size-adaptable receive array is its trellis structure that was motivated by similar structures found in gardening and fencing. Our implementation is a cylindrical trellis that features encircling, diagonally interleaved slats, which are linked together at intersecting points. The ensemble allows expansion or contraction to be controlled with the angle between the slats. This mechanical frame provides a base for radiofrequency coils wherein approximately constant overlap, and therefore coupling between adjacent elements, is maintained when the trellis is expanded or contracted. We demonstrate 2 trellis coil concepts for imaging lower extremity at 3T: a single-row 8-channel array built on a trellis support structure and a multirow 24-channel array in which the coil elements themselves form the trellis structure. RESULTS:We show that the adjustable trellis array can accommodate a range of subject sizes with robust signal-to-noise ratio, loading, and coupling. CONCLUSION/CONCLUSIONS:The trellis coil concept enables an array of surface coils to expand and contract with negligible effect on tuning, matching, and decoupling. This allows an encircling array to conform closely to anatomy of various sizes, which provides significant gains in signal-to-noise ratio.

BACKGROUND:The value of dynamic contrast-enhanced (DCE) sequences in prostate MRI compared with noncontrast MRI is controversial. PURPOSE/OBJECTIVE:To evaluate the population net benefit of risk stratification using DCE-MRI for detection of high-grade prostate cancer (HGPCA), with or without high spatiotemporal resolution DCE imaging. STUDY TYPE/METHODS:Decision curve analysis. POPULATION/METHODS:Previously published patient studies on MRI for HGPCA detection, one using DCE with golden-angle radial sparse parallel (GRASP) images and the other using standard DCE-MRI. FIELD STRENGTH/SEQUENCE/UNASSIGNED:GRASP or standard DCE-MRI at 3 T. ASSESSMENT/RESULTS:Each study reported the proportion of lesions with HGPCA in each Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) category (1-5), before and after reclassification of peripheral zone lesions from PI-RADS 3-4 based on contrast-enhanced images. This additional risk stratifying information was translated to population net benefit, when biopsy was hypothetically performed for: all lesions, no lesions, PI-RADS ≥3 (using NC-MRI), and PI-RADS ≥4 on DCE. STATISTICAL TESTS/UNASSIGNED:Decision curve analysis was performed for both GRASP and standard DCE-MRI data, translating the avoidance of unnecessary biopsies and detection of HGPCA to population net benefit. We standardized net benefit values for HGPCA prevalence and graphically summarized the comparative net benefit of biopsy strategies. RESULTS:For a clinically relevant range of risk thresholds for HGPCA (>11%), GRASP DCE-MRI with biopsy of PI-RADS ≥4 lesions provided the highest net benefit, while biopsy of PI-RADS ≥3 lesions provided highest net benefit at low personal risk thresholds (2-11%). In the same range of risk thresholds using standard DCE-MRI, the optimal strategy was biopsy for all lesions (0-15% risk threshold) or PI-RADS ≥3 on NC-MRI (16-33% risk threshold). DATA CONCLUSION/UNASSIGNED:GRASP DCE-MRI may potentially enable biopsy of PI-RADS ≥4 lesions, providing relatively preserved detection of HGPCA and avoidance of unnecessary biopsies compared with biopsy of all PI-RADS ≥3 lesions. J. Magn. Reson. Imaging 2019.

Statistical learning has been proposed as a possible mechanism by which individuals can become sensitive to the structures of language fundamental for speech perception. Since its description in human infants, statistical learning has been described in human adults and several non-human species as a general process by which animals learn about stimulus-relevant statistics. The neurobiology of statistical learning is beginning to be understood, but many questions remain about the underlying mechanisms. Why is the developing brain particularly sensitive to stimulus and environmental statistics, and what neural processes are engaged in the adult brain to enable learning from statistical regularities in the absence of external reward or instruction? This review will survey the statistical learning abilities of humans and non-human animals with a particular focus on communicative vocalizations. We discuss the neurobiological basis of statistical learning, and specifically what can be learned by exploring this process in both humans and laboratory animals. Finally, we describe advantages of studying vocal communication in rodents as a means to further our understanding of the cortical plasticity mechanisms engaged during statistical learning. We examine the use of rodents in the context of pup retrieval, which is an auditory-based and experience-dependent form of maternal behavior.

Children reared in impoverished environments are at risk for enduring psychological and physical health problems. Mechanisms by which poverty affects development, however, remain unclear. To explore one potential mechanism of poverty's impact on social-emotional and cognitive development, an experimental examination of a rodent model of scarcity-adversity was conducted and compared to results from a longitudinal study of human infants and families followed from birth (N = 1,292) who faced high levels of poverty-related scarcity-adversity. Cross-species results supported the hypothesis that altered caregiving is one pathway by which poverty adversely impacts development. Rodent mothers assigned to the scarcity-adversity condition exhibited decreased sensitive parenting and increased negative parenting relative to mothers assigned to the control condition. Furthermore, scarcity-adversity reared pups exhibited decreased developmental competence as indicated by disrupted nipple attachment, distress vocalization when in physical contact with an anesthetized mother, and reduced preference for maternal odor with corresponding changes in brain activation. Human results indicated that scarcity-adversity was inversely correlated with sensitive parenting and positively correlated with negative parenting, and that parenting fully mediated the association of poverty-related risk with infant indicators of developmental competence. Findings are discussed from the perspective of the usefulness of bidirectional-translational research to inform interventions for at-risk families.