Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neuroscience Institute
Total Results:
13474
A PIECE OF MY MIND. A Wild Rotation
PMID: 27533153
ISSN: 1538-3598
CID: 3332572
l-Cystine Diamides as l-Cystine Crystallization Inhibitors for Cystinuria
l-Cystine bismorpholide (1a) and l-cystine bis(N'-methylpiperazide) (1b) were seven and twenty-four times more effective than l-cystine dimethyl ester (CDME) in increasing the metastable supersaturation range of l-cystine, respectively, effectively inhibiting l-cystine crystallization. This behavior can be attributed to inhibition of crystal growth at microscopic length scale, as revealed by atomic force microscopy. Both 1a and 1b are more stable than CDME, and 1b was effective in vivo in a knockout mouse model of cystinuria.
PMCID:5774851
PMID: 27409142
ISSN: 1520-4804
CID: 2211532
Drosophila SLC5A11 Mediates Hunger by Regulating K+ Channel Activity
Hunger is a powerful drive that stimulates food intake. Yet, the mechanism that determines how the energy deficits that result in hunger are represented in the brain and promote feeding is not well understood. We previously described SLC5A11-a sodium/solute co-transporter-like-(or cupcake) in Drosophila melanogaster, which is required for the fly to select a nutritive sugar over a sweeter nonnutritive sugar after periods of food deprivation. SLC5A11 acts on approximately 12 pairs of ellipsoid body (EB) R4 neurons to trigger the selection of nutritive sugars, but the underlying mechanism is not understood. Here, we report that the excitability of SLC5A11-expressing EB R4 neurons increases dramatically during starvation and that this increase is abolished in the SLC5A11 mutation. Artificial activation of SLC5A11-expresssing neurons is sufficient to promote feeding and hunger-driven behaviors; silencing these neurons has the opposite effect. Notably, SLC5A11 transcript levels in the brain increase significantly when flies are starved and decrease shortly after starved flies are refed. Furthermore, expression of SLC5A11 is sufficient for promoting hunger-driven behaviors and enhancing the excitability of SLC5A11-expressing neurons. SLC5A11 inhibits the function of the Drosophila KCNQ potassium channel in a heterologous expression system. Accordingly, a knockdown of dKCNQ expression in SLC5A11-expressing neurons produces hunger-driven behaviors even in fed flies, mimicking the overexpression of SLC5A11. We propose that starvation increases SLC5A11 expression, which enhances the excitability of SLC5A11-expressing neurons by suppressing dKCNQ channels, thereby conferring the hunger state.
PMCID:4980193
PMID: 27397890
ISSN: 1879-0445
CID: 2180102
Fiberless multicolor neural optoelectrode for in vivo circuit analysis
Maximizing the potential of optogenetic approaches in deep brain structures of intact animals requires optical manipulation of neurons at high spatial and temporal resolutions, while simultaneously recording electrical data from those neurons. Here, we present the first fiber-less optoelectrode with a monolithically integrated optical waveguide mixer that can deliver multicolor light at a common waveguide port to achieve multicolor modulation of the same neuronal population in vivo. We demonstrate successful device implementation by achieving efficient coupling between a side-emitting injection laser diode (ILD) and a dielectric optical waveguide mixer via a gradient-index (GRIN) lens. The use of GRIN lenses attains several design features, including high optical coupling and thermal isolation between ILDs and waveguides. We validated the packaged devices in the intact brain of anesthetized mice co-expressing Channelrhodopsin-2 and Archaerhodopsin in pyramidal cells in the hippocampal CA1 region, achieving high quality recording, activation and silencing of the exact same neurons in a given local region. This fully-integrated approach demonstrates the spatial precision and scalability needed to enable independent activation and silencing of the same or different groups of neurons in dense brain regions while simultaneously recording from them, thus considerably advancing the capabilities of currently available optogenetic toolsets.
PMCID:4971539
PMID: 27485264
ISSN: 2045-2322
CID: 2227832
Anti-conformation monoclonal antibody effective in pre-clinical treatment of full Alzheimer's disease animal models by targeting pathological oligomeric forms of A beta and modified Tau [Meeting Abstract]
ISI:000383610402477
ISSN: 1521-4141
CID: 2283602
A physiological and behavioral system for hearing restoration with cochlear implants
Cochlear implants are neuroprosthetic devices that provide hearing to deaf patients, although outcomes are highly variable even with prolonged training and use. The central auditory system must process cochlear implant signals, but it is unclear how neural circuits adapt - or fail to adapt - to such inputs. Understanding these mechanisms is required for development of next-generation neuroprosthetics that interface with existing neural circuits and enable synaptic plasticity to improve perceptual outcomes. Here we describe a new system for cochlear implant insertion, stimulation, and behavioral training in rats. Animals were first ensured to have significant hearing loss via physiological and behavioral criteria. We developed a surgical approach for multi-channel (2-channel or 8-channel) array insertion, comparable to implantation procedures and depth in humans. Peripheral and cortical responses to stimulation were used to objectively program the implant. Animals fitted with implants learned to use them for an auditory-dependent task that assesses frequency detection and recognition, in a background of environmentally- and self-generated noise, and ceased responding appropriately to sounds when the implant was temporarily inactivated. This physiologically-calibrated and behaviorally-validated system provides a powerful opportunity to study the neural basis of neuroprosthetic device use and plasticity.
PMCID:4995281
PMID: 27281743
ISSN: 1522-1598
CID: 2136552
Recording extracellular neural activity in the behaving monkey using a semichronic and high-density electrode system
We describe a technique to semichronically record the cortical extracellular neural activity in the behaving monkey employing commercial high-density electrodes. After the design and construction of low cost microdrives that allow varying the depth of the recording locations after the implantation surgery, we recorded the extracellular unit activity from pools of neurons at different depths in the presupplementary motor cortex (pre-SMA) of a rhesus monkey trained in a tapping task. The collected data were processed to classify cells as putative pyramidal cells or interneurons on the basis of their waveform features. We also demonstrate that short time cross-correlogram occasionally yields unit pairs with high short latency (<5 ms), narrow bin (<3 ms) peaks, indicative of monosynaptic spike transmission from pre- to postsynaptic neurons. These methods have been verified extensively in rodents. Finally, we observed that the pattern of population activity was repetitive over distinct trials of the tapping task. These results show that the semichronic technique is a viable option for the large-scale parallel recording of local circuit activity at different depths in the cortex of the macaque monkey and other large species.
PMCID:4978789
PMID: 27169505
ISSN: 1522-1598
CID: 2250162
Resolving power for the diffusion orientation distribution function
PURPOSE: The diffusion orientation distribution function (dODF) is primarily used for white matter fiber tractography. Here the resolving power of the dODF is investigated for a simple diffusion model of two intersecting axonal fiber bundles. METHODS: The resolving power for the dODF is evaluated using the Sparrow criterion. This is determined for the exact dODF and also for q-space imaging (QSI), q-ball, and kurtosis approximations. RESULTS: Based on theoretical and numerical calculations, the resolving power is found to depend on the eigenvalues of the diffusion model and on the degree of radial weighting for the dODF. The resolving powers of the QSI and q-ball dODFs improve with increased b-value. The kurtosis dODF has a resolving power similar to that of the exact dODF. CONCLUSION: The dODFs, whether exact or approximate, have finite resolving powers that limit their sensitivity to fiber crossings. The resolving powers for the different dODFs considered here provide convenient benchmarks for assessing and comparing their performance. Magn Reson Med, 2015. (c) 2015 Wiley Periodicals, Inc.
PMID: 26444579
ISSN: 1522-2594
CID: 2038332
Progression from respiratory dysfunction to failure in late-onset Pompe disease
To identify determinants of respiratory disease progression in late-onset Pompe disease (LOPD), we studied relationships between pulmonary function, respiratory muscle strength, gas exchange, and respiratory control. Longitudinal evaluation of 22 LOPD patients (mean age 38 years) was performed at 6-month intervals for 6-24 months. Measurements included vital capacity (VC), maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), tidal volume (VT), dead space (VD), and ventilatory response to CO2. Although reduction in VC correlated with MIP and MEP (p < 0.0001), some patients had normal VC despite reduced MIP and MEP (5 [23%] and 9 [41%] patients, respectively). Daytime hypercapnia was associated with reduced VC (<60% predicted) and MIP (<40% predicted). Moreover, chronic hypercapnia was associated with elevated VD/VT (>/=0.44) due to falling VT ( approximately 300 ml), compatible with reduced efficiency of CO2 clearance. The presence of hypercapnia and/or ventilatory support was associated with reduced ventilatory responsiveness to CO2 (
PMID: 27297666
ISSN: 1873-2364
CID: 2145062
Evaluation of breast cancer using intravoxel incoherent motion (IVIM) histogram analysis: comparison with malignant status, histological subtype, and molecular prognostic factors
PURPOSE: To examine heterogeneous breast cancer through intravoxel incoherent motion (IVIM) histogram analysis. MATERIALS AND METHODS: This HIPAA-compliant, IRB-approved retrospective study included 62 patients (age 48.44 +/- 11.14 years, 50 malignant lesions and 12 benign) who underwent contrast-enhanced 3 T breast MRI and diffusion-weighted imaging. Apparent diffusion coefficient (ADC) and IVIM biomarkers of tissue diffusivity (Dt), perfusion fraction (fp), and pseudo-diffusivity (Dp) were calculated using voxel-based analysis for the whole lesion volume. Histogram analysis was performed to quantify tumour heterogeneity. Comparisons were made using Mann-Whitney tests between benign/malignant status, histological subtype, and molecular prognostic factor status while Spearman's rank correlation was used to characterize the association between imaging biomarkers and prognostic factor expression. RESULTS: The average values of the ADC and IVIM biomarkers, Dt and fp, showed significant differences between benign and malignant lesions. Additional significant differences were found in the histogram parameters among tumour subtypes and molecular prognostic factor status. IVIM histogram metrics, particularly fp and Dp, showed significant correlation with hormonal factor expression. CONCLUSION: Advanced diffusion imaging biomarkers show relationships with molecular prognostic factors and breast cancer malignancy. This analysis reveals novel diagnostic metrics that may explain some of the observed variability in treatment response among breast cancer patients. KEY POINTS: * Novel IVIM biomarkers characterize heterogeneous breast cancer. * Histogram analysis enables quantification of tumour heterogeneity. * IVIM biomarkers show relationships with breast cancer malignancy and molecular prognostic factors.
PMCID:4894831
PMID: 26615557
ISSN: 1432-1084
CID: 1863172
