Faculty Bibliography

Corticotropin-releasing factor (CRF) that is released from the paraventricular nucleus (PVN) of the hypothalamus is essential for mediating stress response by activating the hypothalamic-pituitary-adrenal axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their neuronal dynamics on the timescale of behavior remain unknown. Here, our recordings of PVN CRF neuronal activity in freely behaving mice revealed that CRF neurons are activated immediately by a range of aversive stimuli. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli. Optogenetic activation or inhibition of PVN CRF neurons was sufficient to induce a conditioned place aversion or preference, respectively. Furthermore, conditioned place aversion or preference induced by natural stimuli was significantly decreased by manipulating PVN CRF neuronal activity. Together, these findings suggest that the rapid, biphasic responses of PVN CRF neurons encode the positive and negative valences of stimuli.

The sensitivity of multiple diffusion MRI (dMRI) parameters to longitudinal changes in white matter microstructure was investigated for the 3xTg-AD transgenic mouse model of Alzheimer's disease, which manifests both amyloid beta plaques and neurofibrillary tangles. By employing a specific dMRI method known as diffusional kurtosis imaging, eight different diffusion parameters were quantified to characterize distinct aspects of water diffusion. Four female 3xTg-AD mice were imaged at five time points, ranging from 4.5 to 18 months of age, and the diffusion parameters were investigated in four white matter regions (fimbria, external capsule, internal capsule and corpus callosum). Significant changes were observed in several diffusion parameters, particularly in the fimbria and in the external capsule, with a statistically significant decrease in diffusivity and a statistically significant increase in kurtosis. Our preliminary results demonstrate that dMRI can detect microstructural changes in white matter for the 3xTg-AD mouse model due to aging and/or progression of pathology, depending strongly on the diffusion parameter and anatomical region.

In the olfactory system, odor percepts retain their identity despite substantial variations in concentration, timing, and background. We study a novel strategy for encoding intensity-invariant stimulus identity that is based on representing relative rather than absolute values of stimulus features. For example, in what is known as the primacy coding model, odorant identities are represented by the conditions that some odorant receptors are activated more strongly than others. Because, in this scheme, odorant identity depends only on the relative amplitudes of olfactory receptor responses, identity is invariant to changes in both intensity and monotonic nonlinear transformations of its neuronal responses. Here we show that sparse vectors representing odorant mixtures can be recovered in a compressed sensing framework via elastic net loss minimization. In the primacy model, this minimization is performed under the constraint that some receptors respond to a given odorant more strongly than others. Using duality transformation, we show that this constrained optimization problem can be solved by a neural network whose Lyapunov function represents the dual Lagrangian and whose neural responses represent the Lagrange coefficients of primacy and other constraints. The connectivity in such a dual network resembles known features of connectivity in olfactory circuits. We thus propose that networks in the piriform cortex implement dual computations to compute odorant identity with the sparse activities of individual neurons representing Lagrange coefficients. More generally, we propose that sparse neuronal firing rates may represent Lagrange multipliers, which we call the dual brain hypothesis. We show such a formulation is well suited to solve problems with multiple interacting relative constraints.

PURPOSE/OBJECTIVE:The purpose of the study was to assess the differences in the concentration and function of urinary proteins between patients with cystine stones (CYS) and healthy controls (HC). We postulated that CYS and HC groups would demonstrate different proteomic profiles. METHODS:A pilot study was performed comparing urinary proteomes of 10 patients with CYS and 10 age- and gender-matched HC, using liquid chromatography-mass spectrometry. Proteins which met the selection criteria (i) ≥ 2 unique peptide identifications; (ii) ≥ twofold difference in protein abundance; and (iii) ≤ 0.05 p value for the Fisher's Exact Test were analyzed using Gene Ontology classifications. RESULTS:Of the 2097 proteins identified by proteomic analysis, 398 proteins were significantly different between CYS and HC. Of those, 191 were involved in transport processes and 61 in inflammatory responses. The majority were vesicle-mediated transport proteins (78.5%), and 1/3 of them were down-regulated; of those, 12 proteins were involved in endosomal transport (including 6 charged multivesicular body proteins (CHMP) and 3 vacuolar sorting-associated proteins) and 9 in transmembrane transport. Myosin-2 and two actin-related proteins were significantly up-regulated in the vesicle-mediated transport group. CONCLUSION/CONCLUSIONS:We provide proteomic evidence of impaired endocytosis, dysregulation of actin and myosin cytoskeleton, and inflammation in CYS. Endosomal transport proteins were down-regulated mainly through defective CHMP. These findings may contribute to further understanding of the pathogenesis of CYS, potentially affecting its management.

A Quick guide to singing mice.

Awareness of the human health impacts of exposure to air pollution is growing rapidly. For example, it has become evident that the adverse health effects of air pollution are more pronounced in disadvantaged populations. Policymakers in many jurisdictions have responded to this evidence by enacting initiatives that lead to lower concentrations of air pollutants, such as urban traffic restrictions. In this review, we focus on the interplay between advances in environmental exposure assessment and developments in policy. We highlight recent progress in the granular measurement of air pollutants and individual-level exposures, and how this has enabled focused local policy actions. Finally, we detail an illustrative study designed to link individual-level health-relevant exposures with economic, behavioral, biological, familial, and environmental variables.

Background: Deficits in myocardial conduction velocity (CV) are associated with ventricular arrhythmias and conduction block. Abnormal organization and expression of cardiac sodium channel NaV1.5 and gap junction protein Cx43, key determinants of myocardial CV, are known features of arrhythmogenic heart disease. We previously identified fibroblast growth factor homologous factor 2 (FHF2) as a modulator of CV through its effects on NaV1.5. The aim of this study was to investigate whether modulating junctional conductance synergizes with loss of FHF2 to create conduction reserve deficits and susceptibility for arrhythmias. Method(s): ECGs were acquired to characterize conduction intervals of 2-3 month old wildtype (WT), cardiomyocyte-specific Cx43 heterozygous (Cx43 cHet), FHF2 KO, and FHF2 KO/Cx43 cHet mice. ECGs were then acquired with increasing doses of a gap junction channel blocker, carbenoxolone (CBX). Result(s): WT, Cx43 cHet, and FHF2 KO mice had normal conduction while FHF2 KO/Cx43 cHet mice showed ventricular conduction slowing at baseline. FHF2 KO and FHF2 KO/Cx43 cHet mice showed ventricular conduction slowing with CBX in a dose dependent fashion. Lethal conduction slowing was observed in FHF2 KO/Cx43 cHet mice given 120mg/kg CBX. Conclusion(s): These results identify a key role for FHF2 in maintaining myocardial conduction reserve which protects against stressors that depress junctional conductance (aging, pharmacologic blockade, genetic deficiency) and subsequent arrhythmias. [Figure presented]2019 American College of Cardiology Foundation. All rights reserved

Ion channels facilitate the movement of ions across the plasma and organellar membranes. A recent symposium brought together scientists who study ion channels and transporters in immune cells, which highlighted advances in this emerging field and served to chart new avenues for investigating the roles of ion channels in immunity.

Multisensory integration is particularly important in the human olfactory system, which is highly dependent on non-olfactory cues, yet its underlying neural mechanisms are not well understood. In this study, we use intracranial electroencephalography techniques to record neural activity in auditory and olfactory cortices during an auditory-olfactory matching task. Spoken cues evoke phase locking between low frequency oscillations in auditory and olfactory cortices prior to odor arrival. This phase synchrony occurs only when the participant's later response is correct. Furthermore, the phase of low frequency oscillations in both auditory and olfactory cortical areas couples to the amplitude of high-frequency oscillations in olfactory cortex during correct trials. These findings suggest that phase synchrony is a fundamental mechanism for integrating cross-modal odor processing and highlight an important role for primary olfactory cortical areas in multisensory integration with the olfactory system.