Journal: ACS Chemical Neuroscience

Abbreviation

ACS Chem. Neurosci.

Publisher

American Chemical Society

Journal Volumes

ISSN

1948-7193

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2013 - 201962020 - 20259
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Publications 1 - 10 of 15
  • New Technologies to Investigate Neuropeptides at Scale
    Item type: Journal Article
    Patriarchi, Tommaso (2022)
    ACS Chemical Neuroscience
    Neuropeptides are some of the most elusive molecules to monitor in neuroscience. Detecting their release and spread in brain tissue requires the development and use of advanced technologies that enable specific neuropeptide measurements with high spatial and temporal resolution. This Viewpoint highlights some of the emerging tools and techniques that are already advancing our knowledge of neuropeptide physiology and discusses possible future developments.
  • A Tph2(GFP) Reporter Stem Cell Line To Model in Vitro and in Vivo Serotonergic Neuron Development and Function
    Item type: Journal Article
    Pacini, Giulia; Marino, Attilio; Migliarini, Sara; et al. (2017)
    ACS Chemical Neuroscience
  • On-Surface Aggregation of alpha-Synuclein at Nanomolar Concentrations Results in Two Distinct Growth Mechanisms
    Item type: Journal Article
    Rabe, Michael; Soragni, Alice; Reynolds, Nicholas P.; et al. (2013)
    ACS Chemical Neuroscience
  • Superresolution Imaging of Amyloid Fibrils with Binding-Activated Probes
    Item type: Journal Article
    Ries, Jonas; Udayar, Vinod; Soragni, Alice; et al. (2013)
    ACS Chemical Neuroscience
  • Channel Activities of the Full-Length Prion and Truncated Proteins
    Item type: Journal Article
    Wu, Jinming; Wang, Xue; Lakkaraju, Asvin; et al. (2024)
    ACS Chemical Neuroscience
    Prion diseases are fatal neurodegenerative disorders characterized by the conversion of the cellular prion protein (PrP (c)) into a misfolded prion form, which is believed to disrupt the cellular membranes. However, the exact mechanisms underlying prion toxicity, including the formation of membrane pores, are not fully understood. The prion protein consists of two domains: a globular domain (GD) and a flexible N-terminus (FT) domain. Although a proximal polybasic amino acid (FT(23-31) sequence of FT is a prerequisite for cellular membrane permeabilization, other functional domain regions may modulate its effects. Through single-channel electrical recordings and cryo-electron microscopy (cryo-EM), we discovered that the FT(23-50) fragment forms pore-shaped oligomers and plays a dominant role in membrane permeabilization within the full-length mouse prion protein (mPrP(23-230)). In contrast, the FT(51-110) domain or the C-terminal domain downregulate the channel activity of FT(23-50) and mPrP(23-230). The addition of prion mimetic antibody, POM1 significantly amplifies mPrP(23-230) membrane permeabilization, whereas POM1_Y104A, a mutant that binds to PrP but cannot elicit toxicity, has a negligible effect on membrane permeabilization. Additionally, the anti-N-terminal antibody POM2 or Cu2+ binds to the FT domain, subsequently enhancing the FT(23-110) channel activity. Importantly, our setup provides a novel approach without an external fused protein to examine the channel activity of truncated PrP in the lipid membranes. We therefore propose that the primary N-terminal residues are essential for membrane permeabilization, while other functional segments of PrP play a vital role in modulating the pathological effects of PrP-mediated neurotoxicity.
  • Seeing the Spikes: The Future of Targetable Synthetic Voltage Sensors
    Item type: Review Article
    Fiala, Tomas; Sulzer, David; Sames, Dalibor (2025)
    ACS Chemical Neuroscience
    Measuring the transduction of electrical signals within neurons is a key capability in neuroscience. Fluorescent voltage sensitive dyes (VSDs) were early tools that complemented classical electrophysiology by enabling the optical recording of membrane potential changes from many cells simultaneously. Recent advances in the VSD field have led to bright and highly sensitive sensors that can be targeted to the desired cell populations in live brain tissue. Despite this progress, recently, protein-based genetically encoded voltage indicators (GEVIs) have become the go-to tools for targeted voltage imaging in complex environments. In this Perspective, we summarize progress in developing targetable VSDs, discuss areas where these synthetic sensors are or could become relevant, and outline hurdles that need to be overcome to promote the routine use of targetable VSDs in neuroscience research.
  • Rimota-Gd: Paramagnetic Probe for In Vivo MRI Studies of the Cannabinoid 1 Receptor Distribution in the Mouse Brain
    Item type: Journal Article
    Ouyang, Qi; Zhao, Fei; Ye, Jingjing; et al. (2024)
    ACS Chemical Neuroscience
    The cannabinoid 1 receptor (CB1) is highly expressed in the central nervous system, where its physiological functions include the regulation of energy balance, pain, and addiction. Herein, we develop and validate a technique to use magnetic resonance imaging (MRI) to investigate the distribution of CB1 across mouse brains with high spatial resolution, expanding previously described in vitro studies and in vivo studies with positron emission tomography (PET). To support the MRI investigations, we developed a ligand that is specific for in vivo neuroimaging of CB1. By chemically conjugating the CB1 antagonist rimonabant acid to a gadolinium chelator, we obtained the paramagnetic probe Rimota-Gd. The specificity of binding of rimonabant acid to CB1 and the relaxation enhancement by the paramagnetic gadolinium permit MRI-based localization of CB1. We used Rimota-Gd to investigate the spatial distribution of CB1 across the mouse brain and compared the results with an investigation using the PET radioligand [F-18]MK-9470. Rimota-Gd opens the door for in vivo MRI imaging of CB1 and provides a roadmap for the study of other receptors by whole-brain images with high spatial and temporal resolution.
  • Characterization of (R)- and (S)-[¹⁸F]OF-NB1 in Rodents as Positron Emission Tomography Probes for Imaging GluN2B Subunit-Containing N-Methyl-d-Aspartate Receptors
    Item type: Journal Article
    Ahmed, Hazem; Wallimann, Rahel; Gisler, Livio; et al. (2023)
    ACS Chemical Neuroscience
    The N-methyl-d-aspartate receptor (NMDAR) subtype 2B (GluN1/2B) is implicated in various neuropathologies. Given the lack of a validated radiofluorinated positron emission tomography (PET) probe for the imaging of GluN1/2B receptors, we comprehensively investigated the enantiomers of [¹⁸F]-OF-NB1 in rodents. Particularly, the (R)- and (S)- enantiomers were evaluated using in silico docking, in vitro autoradiography, in vivo PET imaging, and ex vivo biodistribution studies. A select panel of GluN1/2B antagonists (CP-101,606, CERC-301, and eliprodil) and the off-target sigma-1 receptor ligands (fluspidine and SA4503) were used to determine the specificity and selectivity of the tested enantiomers. Additionally, a nonmetal-mediated radiofluorination strategy was devised that harnesses the potential of diaryliodoniums in the nucleophilic radiofluorination of nonactivated aromatic compounds. Both enantiomers exhibited known GluN1/2B binding patterns; however, the R-enantiomer showed higher GluN1/2B-specific accumulation in rodent autoradiography and higher brain uptake in PET imaging experiments compared to the S-enantiomer. Molecular simulation studies provided further insights with respect to the difference in binding, whereby a reduced ligand-receptor interaction was observed for the S-enantiomer. Nonetheless, both enantiomers showed dose dependency when two different doses (1 and 5 mg/kg) of the GluN1/2B antagonist, CP-101,606, were used in the PET imaging study. Taken together, (R)-[¹⁸F]-OF-NB1 appears to exhibit the characteristics of a suitable PET probe for imaging of GluN2B-containing NMDARs in clinical studies.
  • Chemical Targeting of Rhodol Voltage-Sensitive Dyes to Dopaminergic Neurons
    Item type: Journal Article
    Fiala, Tomas; Mosharov, Eugene V.; Wang, Jihang; et al. (2022)
    ACS Chemical Neuroscience
    Optical imaging of changes in the membrane potential of living cells can be achieved by means of fluorescent voltage-sensitive dyes (VSDs). A particularly challenging task is to efficiently deliver these highly lipophilic probes to specific neuronal subpopulations in brain tissue. We have tackled this task by designing a solubilizing, hydrophilic polymer platform that carries a high-affinity ligand for a membrane protein marker of interest and a fluorescent VSD. Here, we disclose an improved design of polymer-supported probes for chemical, nongenetic targeting of voltage sensors to axons natively expressing the dopamine transporter in ex vivo mouse brain tissue. We first show that for negatively charged rhodol VSDs functioning on the photoinduced electron transfer principle, poly(ethylene glycol) as a carrier enables targeting with higher selectivity than the polysaccharide dextran in HEK cell culture. In the same experimental setting, we also demonstrate that incorporation of an azetidine ring into the rhodol chromophore substantially increases the brightness and voltage sensitivity of the respective VSD. We show that the superior properties of the optimized sensor are transferable to recording of electrically evoked activity from dopaminergic axons in mouse striatal slices after averaging of multiple trials. Finally, we suggest the next milestones for the field to achieve single-scan recordings with nongenetically targeted VSDs in native brain tissue.
  • Probing Chemical Complexity of Amyloid Plaques in Alzheimer’s Disease Mice using Hyperspectral Raman Imaging
    Item type: Journal Article
    Mrđenović, Dušan; Combes, Benjamin F.; Ni, Ruiqing; et al. (2024)
    ACS Chemical Neuroscience
    One of the distinctive pathological features of Alzheimer’s disease (AD) is the deposition of amyloid plaques within the brain of affected individuals. These plaques have traditionally been investigated using labeling techniques such as immunohistochemical imaging. However, the use of labeling can disrupt the structural integrity of the molecules being analyzed. Hence, it is imperative to employ label-free imaging methods for noninvasive examination of amyloid deposits in their native form, thereby providing more relevant information pertaining to AD. This study presents compelling evidence that label-free and nondestructive confocal Raman imaging is a highly effective approach for the identification and chemical characterization of amyloid plaques within cortical regions of an arcAβ mouse model of AD. Furthermore, this investigation elucidates how the spatial correlation of Raman signals can be exploited to identify robust Raman marker bands and discern proteins and lipids from amyloid plaques. Finally, this study uncovers the existence of distinct types of amyloid plaques in the arcAβ mouse brain, exhibiting significant disparities in terms of not only shape and size but also molecular composition.
Publications 1 - 10 of 15