Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neuroscience Institute
Total Results:
13517
Behavioral and physiological measure for pitch matching between electrical and acoustical stimulation in cochlear implant patients
This study examines behavioral and physiological measures of pitch matching in cochlear implant (CI) users who have residual hearing in the contralateral ear. Subjects adjusted the frequency of an acoustic tone to match the pitch percept elicited by electrical stimulation in the other ear, when stimulation was alternating across two ears. In general, the selected acoustic frequencies did not line up perfectly with the center frequencies of the analysis bands corresponding to each stimulation electrode. Similar alternating electro-acoustic stimuli were used to record Auditory Evoked Potentials on 8 NH subjects and 3 CI patients. NH subjects were presented with a fixed tone in one ear, while tones in the other ear varied within a few octaves from the fixed tone. CI patients were stimulated with six different audible tones including their pitch-matched tones, while receiving electrical stimulation in the electrode. N1 latency for NH subjects was minimized when the same frequency was presented to both ears. Similarly, N1 latency for CI patients who are able to pitch match was minimized when the tone was at the pitch matched frequency of the stimulated electrode. These results suggest that N1 latency can be a possible objective measure of pitch matching. (Work supported by NIH/NIDCD 1K25DC010834-01;PI:Tan, PSC-CUNY;PI:Martin, and NIH/NIDCD R01-DC03937;PI:Svirsky.).
ORIGINAL:0010418
ISSN: 0001-4966
CID: 1899612
BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity
Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF(Val/Val)) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF(Met/Met)). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF(Met/Met) mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF(Met/Met) mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.
PMCID:3306891
PMID: 22218094
ISSN: 0893-133x
CID: 162952
Smelling on the fly: sensory cues and strategies for olfactory navigation in Drosophila
Navigating toward (or away from) a remote odor source is a challenging problem that requires integrating olfactory information with visual and mechanosensory cues. Drosophila melanogaster is a useful organism for studying the neural mechanisms of these navigation behaviors. There are a wealth of genetic tools in this organism, as well as a history of inventive behavioral experiments. There is also a large and growing literature in Drosophila on the neural coding of olfactory, visual, and mechanosensory stimuli. Here we review recent progress in understanding how these stimulus modalities are encoded in the Drosophila nervous system. We also discuss what strategies a fly might use to navigate in a natural olfactory landscape while making use of all these sources of sensory information. We emphasize that Drosophila are likely to switch between multiple strategies for olfactory navigation, depending on the availability of various sensory cues. Finally, we highlight future research directions that will be important in understanding the neural circuits that underlie these behaviors.
PMCID:3323672
PMID: 22221864
ISSN: 0959-4388
CID: 1072442
Delivery and Safety of Inhaled Interferon-gamma in Idiopathic Pulmonary Fibrosis
Abstract Background: Inhaled interferon-gamma aerosol (aINF-gamma) may be effective treatment for idiopathic pulmonary fibrosis (IPF). We evaluated safety and delivery of aIFN-gamma (100 mug 3 times/week) in 10 IPF patients using the I-neb (Philips Respironics, Parsippany, NJ). Methods: IFN-gamma activity in the aerosol was confirmed by viral inhibition. Ten patients with an average age of 68 diagnosed with IPF (American Thoracic Society/European Respiratory Society consensus guidelines) were enrolled. In vivo deposition was measured via a gamma camera. The nebulizer recorded patient adherence to therapy. Pulmonary function tests [PFTs, forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO)] and the 6-min walk test were measured at baseline, and every 12-14 weeks for 80 weeks. Bronchoalveolar lavage (BAL) of the middle lobe was performed at baseline and 28 weeks. BAL and plasma samples were analyzed for chemokines and cytokines, including INF-gamma. Results: All 10 patients tolerated 80 weeks of inhaled IFN-gamma well, with no systemic side effects. True adherence with aerosol treatment averaged 96.7+/-4.81% (+/-SEM). In vivo lung deposition averaged 65.4+/-4.8mug and oropharyngeal deposition 12.6+/-3.0 mug. BAL IFN-gamma increased 60-fold and profibrotic cytokines (FGP-2, Flt-3 ligand, IL-5) were significantly decreased; IFN-gamma plasma levels were unchanged. PFTs showed minimal change in FVC. Post hoc analysis indicated that the slope of decline in TLC and DLCO reversed after beginning therapy. The 6-min walk was unchanged. Conclusions: IFN-gamma is safe in IPF and can be effectively delivered to lung parenchyma. PFTs remained stable throughout the trial. Reversal of pretherapy PFT decline may define an end-point for future clinical trials.
PMID: 22360317
ISSN: 1941-2711
CID: 160160
Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo
More than 30 neurodegenerative diseases including Alzheimer disease (AD), frontotemporal lobe dementia (FTD), and some forms of Parkinson disease (PD) are characterized by the accumulation of an aggregated form of the microtubule-binding protein tau in neurites and as intracellular lesions called neurofibrillary tangles. Diseases with abnormal tau as part of the pathology are collectively known as the tauopathies. Methylthioninium chloride, also known as methylene blue (MB), has been shown to reduce tau levels in vitro and in vivo and several different mechanisms of action have been proposed. Herein we demonstrate that autophagy is a novel mechanism by which MB can reduce tau levels. Incubation with nanomolar concentrations of MB was sufficient to significantly reduce levels of tau both in organotypic brain slice cultures from a mouse model of FTD, and in cell models. Concomitantly, MB treatment altered the levels of LC3-II, cathepsin D, BECN1, and p62 suggesting that it was a potent inducer of autophagy. Further analysis of the signaling pathways induced by MB suggested a mode of action similar to rapamycin. Results were recapitulated in a transgenic mouse model of tauopathy administered MB orally at three different doses for two weeks. These data support the use of this drug as a therapeutic agent in neurodegenerative diseases.
PMCID:3405840
PMID: 22361619
ISSN: 1554-8635
CID: 2077002
Caloric restriction up-regulates hippocampal CA1 neuroprotective gene expression and reduces amyloid burden in an alzheimer's disease mouse model [Meeting Abstract]
OBJECTIVES/SPECIFIC AIMS: Th ere is no successful treatment or preventative measure for Alzheimer's disease (AD), a disorder characterized by altered amyloidbeta precursor (APP) processing, amyloid-beta (Abeta) aggregation, cell-type specific vulnerability, and cognitive deficits. Caloric restriction (CR) is a noninvasive dietary intervention that may prevent AD pathology. Previous studies have documented CRinduced AD pathology prevention through regional, low-resolution analysis. Th e effects of CR in selectively vulnerable hippocampal CA1 pyramidal neurons have not been demonstrated. METHODS/STUDY POPULATION: Th rough laser capture microdissection (LCM) and microarray analysis, we will investigate gene expression profiles of CA1 neurons isolated during pathology onset and later progression (5 and 15 mos.) from Tg2576 AD mice and nontransgenic littermates maintained on a 30% CR regimen versus ad libitum (AL) feeding. Abeta burden and APP metabolism are assessed as indicators of pathology and for correlation with high-throughput gene expression changes. RESULTS/ANTICIPATED RESULTS: We have identified CR-induced decreases in transcripts implicated in autophagy, synaptic transmission, transcription, and metabolism, as well as CR-specific increases in several kinase and phosphatase transcripts and qualitative reduction in Abeta peptides in CR-Tg2576 mice. We expect further characterization to support the hypothesis that CR induces increased neuronal efficiency, up-regulation of neuroprotective pathways, and decreased Abeta deposition in aged AL-Tg2576 mice. DISCUSSION/SIGNIFICANCE OF IMPACT: Alterations identified by these experiments may serve as targets in the development of therapeutic interventions. Additionally, this work may serve as the basis for further studies of CR-based dietary regimens as an AD pathology prevention option
EMBASE:70804110
ISSN: 1752-8054
CID: 463352
Physical review. E. Statistical, nonlinear, & soft matter physics. 2012:85(4 Pt 1).DOI: 10.1103/PhysRevE.85.041905
Tunable oscillations in the Purkinje neuron
In this paper, we experimentally study the dynamics of slow oscillations in Purkinje neurons in vitro, and derive a strong association with a forced parametric oscillator model. We observed the precise rhythmicity of these oscillations in Purkinje neurons, as well as a dynamic tunability of this oscillation using a photoswitchable compound. We found that this slow oscillation can be induced in every Purkinje neuron measured, having periods ranging between 10 and 25 s. Starting from a Hodgkin-Huxley model, we demonstrate that this oscillation can be externally modulated, and that the neurons will return to their intrinsic firing frequency after the forced oscillation is concluded. These findings signify an additional timing functional role of tunable oscillations within the cerebellum, as well as a dynamic control of a time scale in the brain in the range of seconds.
PMID: 22680496
ISSN: 1550-2376
CID: 2484972
Lyme Neuroborreliosis and Proton MR Spectroscopy: Preliminary Results from an Urban Referral Center Employing Strict CDC Criteria for Case Selection [Meeting Abstract]
ISI:000303204801418
ISSN: 0028-3878
CID: 166864
Guidelines for the use and interpretation of assays for monitoring autophagy [Guideline]
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
PMCID:3404883
PMID: 22966490
ISSN: 1554-8627
CID: 181862
Extracellular diffusion in laminar brain structures exemplified by hippocampus
Numerous brain structures are composed of distinct layers and such stratification has a profound effect on extracellular diffusion transport in these structures. We have derived a more general form of diffusion equation incorporating inhomogeneities in both the extracellular volume fraction (alpha) and diffusion permeability (theta). A numerical solution of this equation for a special case of layered environment was employed to analyze diffusion in the CA1 region of hippocampus where stratum pyramidale occupied by the bodies of principal neurons is flanked by stratum radiatum and stratum oriens. Extracellular diffusion in the CA1 region was measured in vitro by real-time iontophoretic and real-time pressure methods, and numerical analysis found that stratum pyramidale had a significantly smaller extracellular volume fraction (alpha=0.127) and lower diffusion permeability (theta=0.327) than the other two layers (alpha=0.218, theta=0.447). Stratum pyramidale thus functioned as a diffusion barrier for molecules attempting to cross it. We also demonstrate that unless the detailed properties of all layers are taken into account when diffusion experiments are interpreted, the extracted apparent parameters of the extracellular space lose their physical meaning and capacity to describe any individual layer. Such apparent parameters depend on diffusion distance and direction, giving a false impression of microscopic anisotropy and non-Gaussian behavior. This finding has implications for all diffusion mediated physiological processes as well as for other diffusion methods including integrative optical imaging and diffusion-weighted magnetic resonance imaging.
PMCID:3288711
PMID: 22230768
ISSN: 0165-0270
CID: 157477
