A5091615894- Nicotinic Acetylcholine Receptors Study
- Receptor Mechanisms and Signaling
- Neurotransmitter Receptor Influence on Behavior
- Cholinesterase and Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- Insect and Pesticide Research
- Chemical synthesis and alkaloids
- Photoreceptor and optogenetics research
- Down syndrome and intellectual disability research
- Neuroscience and Neural Engineering
- Heat shock proteins research
- Nanotechnology research and applications
- Genomics and Chromatin Dynamics
- Protist diversity and phylogeny
- Transgenic Plants and Applications
- Neuroscience, Education and Cognitive Function
- Genetic and Kidney Cyst Diseases
- Signaling Pathways in Disease
- Olfactory and Sensory Function Studies
- Analog and Mixed-Signal Circuit Design
- Various Chemistry Research Topics
- EEG and Brain-Computer Interfaces
- Renal and related cancers
- Microtubule and mitosis dynamics
Defense Advanced Research Projects Agency
2019-2022
University of Colorado Boulder
2007-2018
University of Colorado System
2016
Yale University
2003-2016
University of Pennsylvania
2011-2014
Duke University
2014
University of Florida
2014
W. M. Keck Foundation
2014
VA Connecticut Healthcare System
2014
Connecticut Mental Health Center
2013
Understanding effects of chronic nicotine requires identifying the neurons and synapses whose responses to itself, endogenous acetylcholine, are altered by continued exposure drug. To address this problem, we developed mice α4 nicotinic receptor subunits replaced normally functioning fluorescently tagged subunits, providing quantitative studies regulation at micrometer resolution. Chronic increased fluorescence in several regions; among these, midbrain hippocampus were assessed functionally....
Nicotinic acetylcholine receptor (nAChR) agonists stimulate the release of GABA from GABAergic nerve terminals, but nAChR subtypes that mediate this effect have not been elucidated. The studies reported here used synaptosomes derived cortex, hippocampus, striatum, and thalamus wild-type α4-, α5-, α7-, β2-, β4-null mutant mice to identify involved in (ACh)-evoked release. Null mutation genes encoding α4 or β2 subunits resulted complete loss ACh-stimulated [<sup>3</sup>H]GABA all four brain...
Chronic nicotine treatment elicits a brain region-selective increase in the number of high-affinity agonist binding sites, phenomenon termed up-regulation. Nicotine-induced up-regulation α4β2-nicotinic acetylcholine receptors (nAChRs) cell cultures results from increased assembly and/or decreased degradation nAChRs, leading to nAChR protein levels. To evaluate whether mouse an subunit proteins, C57BL/6 mice were treated with by chronic intravenous infusion. Tissue sections prepared, and...
We generated a mouse line harboring an autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) mutation: the α4 nicotinic receptor S248F knock-in strain. In this mouse, modest nicotine doses (1–2 mg/kg) elicit novel behavior termed dystonic arousal complex (DAC). The DAC includes stereotypical head movements, body jerking, and forelimb dystonia; these behaviors resemble some core features of ADNFLE. A marked Straub tail is additional component DAC. Similar to attacks in ADNFLE, can be...
Firm attachments between kinetochores and dynamic spindle microtubules (MTs) are important for accurate chromosome segregation. Centromere protein F (CENP-F) has been shown to include two MT-binding domains, so it may participate in this key mitotic process. Here, we show that the N-terminal domain of CENP-F prefers curled oligomers tubulin relative MT walls by approximately fivefold, suggesting contribute firm bonds flared plus ends MTs. A polypeptide from CENP-F's C terminus also bound...
Background: The finding that most people with alcoholism are also heavy smokers prompted several research groups to evaluate the effects of ethanol on neuronal nicotinic acetylcholine receptor (nAChR) function. Data collected in vitro indicate physiologically relevant concentrations inhibit functional activation homomeric α7 nAChRs, which one abundant nAChR subtypes expressed mammalian brain. studies outlined here used gene knockout (null mutant) mice potential role nAChRs modulating...
Abstract Immunolabeling of β2 and α4 subunits was quantitated in brain sections (14 μm) using [ 125 I]mAb 270 299, respectively. Specificity demonstrated by signal loss −/− sections, Even mild paraformaldehyde fixation severely affected immunolabeling, so this study used unfixed sections. autoradiography to map quantitate the effects subunit‐null mutations on their putative partner subunits' protein expression. 299 labeling nearly eliminated although dorsal interpeduncular nucleus (IPN)...
Ethanol modulates the functional activity of alpha4beta2 neuronal nicotinic cholinergic receptors (nAChR) when measured in vitro, but potential role nAChRs regulating behavioral effects ethanol is unknown. Recently, Tritto et al. (Tritto T, Stitzel JA, Marks MJ, Romm E, Collins AC (2002) Variability response to nicotine LSxSS RI strains: polymorphisms alpha4 and alpha6 receptor genes. Pharmacogenetics 12:197-208) reported that a polymorphism (A529T) nAChR subunit gene associated with...
Nicotine, the primary psychoactive component in tobacco smoke, produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors (nAChRs). <i>α</i>4<i>β</i>2 nAChRs are most abundant mammalian brain, and converging evidence shows that this subtype mediates rewarding reinforcing of nicotine. A number rare variants <i>CHRNA4</i> gene encode <i>α</i>4 nAChR subunit have been identified human subjects appear to be underrepresented a cohort smokers. We compared...
Neuronal nicotinic acetylcholine receptors (nAChRs) containing α4 and β2 subunits are the principal in mammalian central nervous system that bind nicotine with high affinity. These nAChRs involved dependence, mood disorders, neurodegeneration neuroprotection. However, our understanding of interactions between α4β2-containing (α4β2(∗)) other proteins remains limited. In this study, we identified interact α4β2(∗) a genedose dependent pattern by immunopurifying β2(∗) from mice differ subunit...
Abstract Nicotinic acetylcholine receptors (nAChRs) support the initiation and maintenance of smoking, but long-term changes occurring in protein complex as a result smoking nicotine tobacco are not known. Human studies animal models have also demonstrated that increasing cholinergic tone increases behaviors related to depression, suggesting nAChR-associated proteome could be altered individuals with mood disorders. We therefore immunopurified nAChRs associated proteins for quantitative...
Recent studies suggest that high-affinity neuronal nicotinic acetylcholine receptors (nAChRs) containing α4 and β2 subunits (α4β2*) functionally interact with G-protein-coupled dopamine (DA) D2 in basal ganglia. We hypothesized if a functional interaction between these exists, then mice expressing an M2 point mutation (Leu9′Ala) rendering nAChRs hypersensitive to ACh may exhibit altered sensitivity D2-receptor agonist. When challenged the D2R agonist, quinpirole (0.5–10 mg/kg), Leu9′Ala...
J. Neurochem. (2012) 122 , 48–57. Abstract Mouse superficial superior colliculus (SuSC) contains dense GABAergic innervation and diverse nicotinic acetylcholine receptor subtypes. Pharmacological genetic approaches were used to investigate the subunit compositions of receptors (nAChR) expressed on mouse SuSC terminals. [ 125 I]‐Epibatidine competition‐binding studies revealed that α3β2* α6β2* subtype‐selective peptide α‐conotoxin MII‐blocked binding 40 ± 5% nAChRs. Acetylcholine‐evoked 3...
SUMMARY Human trisomy 21 (Down syndrome) is the most common genetic cause of intellectual disability, and associated with complex perturbations in protein expression during development. Brain region-specific alterations neuronal density composition originate prenatally individuals, are presumed to underlie disability early onset neurodegeneration that characterizes Down syndrome. However, mechanisms by which chromosome aneuploidy drives central nervous system not well understood,...