Faculty Bibliography

Alveolar hypoventilation defined by an increase in PaCO2 occurs due to either reduced minute ventilation and/or increased dead space. Mild alveolar hypoventilation may be observed in healthy subjects during sleep. Sleep hypoventilation is accentuated in disease states with potential carryover to the daytime, producing chronic hypercapnia during wakefulness due to failure of compensation during sleep and/or during wakefulness. Elevation of blood bicarbonate concentration, although appropriate to defend blood pH, provides a mechanism for perpetuation of a chronic hypercapnic state due to blunting of respiratory drive. 2014 Elsevier Inc. All rights reserved

Measuring the synthesis of new proteins in the context of a much greater number of pre-existing proteins can be difficult. To overcome this obstacle, bioorthogonal noncanonical amino acid tagging (BONCAT) can be combined with stable isotope labeling by amino acid in cell culture (SILAC) for comparative proteomic analysis of de novo protein synthesis (BONLAC). In the present study, we show that alkyne resin-based isolation of L-azidohomoalanine (AHA) labeled proteins using azide/alkyne cycloaddition minimizes contamination from pre-existing proteins. Using this approach, we isolated and identified 7414 BONCAT-labeled proteins. The nascent proteome isolated by BONCAT was very similar to the steady-state proteome, though transcription factors were highly enriched by BONCAT. About 30% of the methionine residues were replaced by AHA in our BONCAT samples, which allowed for identification of methionine-containing peptides. There was no bias against low methionine proteins by BONCAT at the proteome level. When we applied the BONLAC approach to screen for brain-derived neurotrophic factor (BDNF)-induced protein synthesis, 53 proteins were found to be significantly up-regulated two hours after BDNF stimulation. Our study demonstrated that the newly synthesized proteome, even after a short period of stimulation, can be efficiently isolated by BONCAT and analyzed to a depth that is similar to that of the steady-state proteome.

The efficient coding hypothesis posits that sensory systems maximize information transmitted to the brain about the environment. We develop a precise and testable form of this hypothesis in the context of encoding a sensory variable with a population of noisy neurons, each characterized by a tuning curve. We parameterize the population with two continuous functions that control the density and amplitude of the tuning curves, assuming that the tuning widths vary inversely with the cell density. This parameterization allows us to solve, in closed form, for the information-maximizing allocation of tuning curves as a function of the prior probability distribution of sensory variables. For the optimal population, the cell density is proportional to the prior, such that more cells with narrower tuning are allocated to encode higher-probability stimuli and that each cell transmits an equal portion of the stimulus probability mass. We also compute the stimulus discrimination capabilities of a perceptual system that relies on this neural representation and find that the best achievable discrimination thresholds are inversely proportional to the sensory prior. We examine how the prior information that is implicitly encoded in the tuning curves of the optimal population may be used for perceptual inference and derive a novel decoder, the Bayesian population vector, that closely approximates a Bayesian least-squares estimator that has explicit access to the prior. Finally, we generalize these results to sigmoidal tuning curves, correlated neural variability, and a broader class of objective functions. These results provide a principled embedding of sensory prior information in neural populations and yield predictions that are readily testable with environmental, physiological, and perceptual data.

Structural asymmetry of whole brain white matter (WM) pathways, i.e., the connectome, has been demonstrated using fiber tractography based on diffusion tensor imaging (DTI). However, DTI-based tractography fails to resolve axonal fiber bundles that intersect within an imaging voxel, and therefore may not fully characterize the extent of asymmetry. The goal of this study was to assess structural asymmetry with tractography based on diffusional kurtosis imaging (DKI), which improves upon DTI-based tractography by delineating intravoxel crossing fibers. DKI images were obtained from 42 healthy subjects. By using automatic segmentation, gray matter (GM) was parcellated into anatomically defined regions of interest (ROIs). WM pathways were reconstructed with both DKI- and DTI-based tractography. The connectivity between the ROIs was quantified with the streamlines connecting the ROIs. The asymmetry index (AI) was utilized to quantify hemispheric differences in the connectivity of cortical ROIs and of links interconnecting cortical ROIs. Our results demonstrated that leftward asymmetrical ROIs and links were observed in frontal, parietal, temporal lobes, and insula. Rightward asymmetrical ROI and links were observed in superior frontal lobe, cingulate cortex, fusiform, putamen, and medial temporal lobe. Interestingly, these observed structural asymmetries were incompletely identified with DTI-based tractography. These results suggest that DKI-based tractography can improve the identification of asymmetrical connectivity patterns, thereby serving as an additional tool in the evaluation of the structural bases of functional lateralization.

Neurodegeneration and synaptic dysfunction observed in Alzheimer's disease (AD) have been associated with progressive decrease in neuronal activity. Here, we investigated the effects of Notoginsenoside R1 (NTR1), a major saponin isolated from Panax notoginseng, on neuronal excitability and assessed the beneficial effects of NTR1 on synaptic and memory deficits under the Abeta-enriched conditions in vivo and in vitro. We assessed the effects of NTR1 on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular and intracellular recording techniques. We found that NTR1 increased the membrane excitability of CA1 pyramidal neurons in hippocampal slices by lowering the spike threshold possibly through a mechanism involving in the inhibition of voltage-gated K(+) currents. In addition, NTR1 reversed Abeta1-42 oligomers-induced impairments in long term potentiation (LTP). Reducing spontaneous firing activity with 10 nM tetrodotoxin (TTX) abolished the protective effect of NTR1 against Abeta-induced LTP impairment. Finally, oral administration of NTR1 improved the learning performance of the APP/PS1 mouse model of AD. Our work reveals a novel mechanism involving in modulation of cell strength, which contributes to the protective effects of NTR1 against Abeta neurotoxicity.

Multi-contrast magnetic resonance imaging (MRI) is a useful technique to aid clinical diagnosis. This paper proposes an efficient algorithm to jointly reconstruct multiple T1/T2-weighted images of the same anatomical cross section from partially sampled k-space data. The joint reconstruction problem is formulated as minimizing a linear combination of three terms, corresponding to a least squares data fitting, joint total variation (TV) and group wavelet-sparsity regularization. It is rooted in two observations: 1) the variance of image gradients should be similar for the same spatial position across multiple contrasts; 2) the wavelet coefficients of all images from the same anatomical cross section should have similar sparse modes. To efficiently solve this problem, we decompose it into joint TV regularization and group sparsity subproblems, respectively. Finally, the reconstructed image is obtained from the weighted average of solutions from the two subproblems, in an iterative framework. Experiments demonstrate the efficiency and effectiveness of the proposed method compared to existing multi-contrast MRI methods.

Precisely how rhythms support neuronal communication remains obscure. We investigated interregional coordination of gamma oscillations using high-density electrophysiological recordings in the rat hippocampus and entorhinal cortex. We found that 30-80 Hz gamma dominated CA1 local field potentials (LFPs) on the descending phase of CA1 theta waves during navigation, with 60-120 Hz gamma at the theta peak. These signals corresponded to CA3 and entorhinal input, respectively. Above 50 Hz, interregional phase-synchronization of principal cell spikes occurred mostly for LFPs in the axonal target domain. CA1 pyramidal cells were phase-locked mainly to fast gamma (>100 Hz) LFP patterns restricted to CA1, which were strongest at the theta trough. While theta phase coordination of spiking across entorhinal-hippocampal regions depended on memory demands, LFP gamma patterns below 100 Hz in the hippocampus were consistently layer specific and largely reflected afferent activity. Gamma synchronization as a mechanism for interregional communication thus rapidly loses efficacy at higher frequencies.

BACKGROUND: Measurement of mitral annulus (MA) dynamics is an important component of the evaluation of left ventricular (LV) diastolic function; MA velocities are commonly measured using tissue Doppler imaging (TDI). This study aimed to examine the clinical potential of a semi-automated cardiovascular magnetic resonance (CMR) technique for quantifying global LV diastolic function, using 3D volume tracking of the MA with conventional cine-CMR images. METHODS: 124 consecutive patients with normal ejection fraction underwent both clinically indicated transthoracic echocardiography (TTE) and CMR within 2 months. Interpolated 3D reconstruction of the MA over time was performed with semi-automated atrioventricular junction (AVJ) tracking in long-axis cine-CMR images, producing an MA sweep volume over the cardiac cycle. CMR-based diastolic function was evaluated, using the following parameters: peak volume sweep rates in early diastole (PSRE) and atrial systole (PSRA), PSRE/PSRA ratio, deceleration time of sweep volume (DTSV), and 50% diastolic sweep volume recovery time (DSVRT50); these were compared with TTE diastolic measurements. RESULTS: Patients with TTE-based diastolic dysfunction (n = 62) showed significantly different normalized MA sweep volume profiles compared to those with TTE-based normal diastolic function (n = 62), including a lower PSRE (5.25 +/- 1.38 s-1 vs. 7.72 +/- 1.7 s-1), a higher PSRA (6.56 +/- 1.99 s-1 vs. 4.67 +/- 1.38 s-1), a lower PSRE/PSRA ratio (0.9 +/- 0.44 vs. 1.82 +/- 0.69), a longer DTSV (144 +/- 55 ms vs. 96 +/- 37 ms), and a longer DSVRT50 (25.0 +/- 11.0% vs. 15.6 +/- 4.0%) (all p < 0.05). CMR diastolic parameters were independent predictors of TTE-based diastolic dysfunction after adjusting for left ventricular hypertrophy, hypertension, and coronary artery disease. Good correlations were observed between CMR PSRE/PSRA and early-to-late diastolic annular velocity ratios (e'/a') measured by TDI (r = 0.756 to 0.828, p < 0.001). CONCLUSIONS: 3D MA sweep volumes generated by semi-automated AVJ tracking in routinely acquired CMR images yielded diastolic parameters that were effective in identifying patients with diastolic dysfunction when correlated with TTE-based variables.

Abnormal cortical circuits underlie some cognitive and psychiatric disorders, yet the molecular signals that generate normal cortical networks remain poorly understood. Semaphorin 7A (Sema7A) is an atypical member of the semaphorin family that is GPI-linked, expressed principally postnatally, and enriched in sensory cortex. Significantly, SEMA7A is deleted in individuals with 15q24 microdeletion syndrome, characterized by developmental delay, autism, and sensory perceptual deficits. We studied the role that Sema7A plays in establishing functional cortical circuitry in mouse somatosensory barrel cortex. We found that Sema7A is expressed in spiny stellate cells and GABAergic interneurons and that its absence disrupts barrel cytoarchitecture, reduces asymmetrical orientation of spiny stellate cell dendrites, and functionally impairs thalamocortically evoked synaptic responses, with reduced feed-forward GABAergic inhibition. These data identify Sema7A as a regulator of thalamocortical and local circuit development in layer 4 and provide a molecular handle that can be used to explore the coordinated generation of excitatory and inhibitory cortical circuits.

The number of physiological investigations in the mouse, mus musculus, has experienced a recent surge, paralleling the growth in methods of genetic targeting for microcircuit dissection and disease modeling. The introduction of optogenetics, for example, has allowed for bidirectional manipulation of genetically-identified neurons, at an unprecedented temporal resolution. To capitalize on these tools and gain insight into dynamic interactions among brain microcircuits, it is essential that one has the ability to record from ensembles of neurons deep within the brain of this small rodent, in both head-fixed and freely behaving preparations. To record from deep structures and distinct cell layers requires a preparation that allows precise advancement of electrodes towards desired brain regions. To record neural ensembles, it is necessary that each electrode be independently movable, allowing the experimenter to resolve individual cells while leaving neighboring electrodes undisturbed. To do both in a freely behaving mouse requires an electrode drive that is lightweight, resilient, and highly customizable for targeting specific brain structures. A technique for designing and fabricating miniature, ultralight weight, microdrive electrode arrays that are individually customizable and easily assembled from commercially available parts is presented. These devices are easily scalable and can be customized to the structure being targeted; it has been used successfully to record from thalamic and cortical regions in a freely behaving animal during natural behavior.