Editorial Cite This: ACS Chem. Neurosci. 2018, 9, 1−4
pubs.acs.org/chemneuro
Editors’ Favorites of 2017
T
he 2017 year was terrific for ACS Chemical Neuroscience. We once again broke records for citations and submissions, and set new records within the ACS for numbers of papers downloaded. Moreover, the quality and impact of manuscripts published in ACS Chemical Neuroscience continued to increase. Similar to 2016,1 I asked our Editors to choose their favorite papers of 2017 to highlight here, and to provide additional exposure for these exciting papers. As before, this was a challenging proposition, as there were so many exciting and impactful papers published in ACS Chemical Neuroscience during 2017. My first selection, and personal favorite of 2017, is an exceptional review titled, “Hitchhiker’s Guide to Voltammetry: Acute and Chronic Electrodes for in Vivo Fast-Scan Cyclic Voltammetry”,2 which is destined to be highly cited and utilized as an authoritative guide for investigators engaged in voltammetry research. This Review identifies key considerations for the use of FSCV to study neurotransmission in awake, behaving animals, with a focus on measurements of striatal dopamine. Paul Phillips at the University of Washingtion, Mark Wightman at the University of North Carolina, and coauthors delineated experimental design and data collection criteria and, importantly, methods for in vivo calibration. The core concepts and techniques reviewed will extend beyond striatal dopamine to other neurochemicals and other brain regions. This is the guide to the art and practice of in vivo voltammetry. Craig W. Lindsley, Editor-in-Chief
substances from the brain. Importantly, Raper and Galvan determined that CNO is metabolized to clozapine, a drug used to treat schizophrenia. Thus, CNO, via its metabolites, is likely to activate endogenous dopamine and serotonin receptors, in addition to artificially transfected DREADD receptors, confounding its use in the study of neural circuits. In August, this hypothesis was further substantiated in rodents in a paper appearing in the magazine Science.4 Craig W. Lindsley, Editorin-Chief
My pick for Editors’ favorites of 2017 is a Review by Katherine Brimblecombe and Stephanie Cragg at the University of Oxford on the striatum.5 There have been many reviews on this fascinating brain structure. In fact, a PubMed search for “striatum and review” retrieved 5397 citations between 1956 and 2017. Why did I pick this Review as a favorite? Do we not know everything we need to know about this node of the basal ganglia, named for the “stripes” of gray and white matter that interdigitate the structure? The answer is a resounding “no”! In the earliest years of its study, the corpus striatum was thought to mediate motor regulatory functions. However, application of early methodologies (e.g., lesions) failed to identify its role in behavior definitively (for example, see ref 6). Decades later, we know much more about striatal involvement in motor, reward, and cognitive functions. I selected the Brimblecombe and Cragg Review because of the exceptional manner in which what is known is interspersed with questions that remain specificially regarding the namesake topographical organization of striatum and its relevance to physiology and behavior. The striosome (patch network) forms a “three-dimensional labyrinth-like structure that interdigitates the matrix.”5 While we know much about differential localization of receptors (e.g., dopamine D1 and D2 receptors, μ-opioid receptors), neurotransmitters (e.g., dopamine, γaminobutyric acid), and neuropeptides (e.g., substance P, endogenous opioids), we know appreciably less about the segregated vs interactional relationships between striosome and matrix compartments. The Brimblecombe and Cragg Review is clear in demonstrating what we know, what we need to know, and how contemporary technologies will be useful (or not) in continuing to uncover the secrets of the striatum. Kathryn A. Cunningham, Associate Editor
Another paper I find myself rereading, published in the March 2017 issue of ACS Chemical Neuroscience, is titled, “Metabolism and Distribution of Clozapine-N-oxide: Implications for Nonhuman Primate Chemogenetics.”3 Jessica Raper and Adriana Galvan of the Yerkes National Primate Research Center and Emory University in Atlanta, GA and their colleagues uncovered a major limitation associated with the use of a popular designer receptor exclusively activated by designer drugs (DREADD). Prior to using this DREADD in nonhuman primates, Raper et al. carried out pharmacokinetic studies with the DREADD ligand clozapine-N-oxide (CNO). These authors discovered that subcutaneous injection of CNO to rhesus monkeys only produced low cerebrospinal fluid levels of CNO, suggesting that very little of a peripherally administered dose is available to activate brain DREADDs based on the human muscarinic receptor. They found that CNO is a substrate for P-glycoprotein, which extrudes foreign © 2018 American Chemical Society
Special Issue: Precision Medicine in Brain Cancer Published: January 17, 2018 1
DOI: 10.1021/acschemneuro.8b00001 ACS Chem. Neurosci. 2018, 9, 1−4
ACS Chemical Neuroscience
Editorial
My other choice for Editors’ favorites of 2017 is a selfish one, based on my long-standing interests in the therapeutic applications of serotonin 5-HT2C receptors (5-HT2CRs).7 I share this interest with my colleague Guy Higgins of InterVivo Solutions Inc., who commented on this in a Perspective in ACS Chemical Neuroscience.8 The 5-HT2C receptors are widely distributed throughout the basal ganglia, limbic system, and prefrontal cortex in mammals, and are poised to mediate serotonin-dependent effects on appetite, cognition, mood, movement, and sleep. Dysfunctional 5-HT2C receptor signaling has been implicated in neuropsychiatric disorders (e.g., anxiety, depression, substance use) and neuropathological conditions (e.g., Alzheimers, schizophrenia), as well as in obesity and metabolic disorders (for reviews, see refs 9 and 10). Despite advances in understanding therapeutic potential inherent in 5-HT2CR pharmacology, we lack appropriate methods for determination of 5-HT2CR expression in vivo, relative to closely homologous 5-HT2A and 5-HT2B receptors. Furthermore, while 5-HT2CRs are expressed abundantly in the choroid plexus, expression levels in brain nuclei are much lower, and therefore more difficult to detect employing noninvasive methodologies, such as positron emission tomography (PET). A key paper by Kim et al. (Republic of Korea) reports on the initial characterization of a new PET radiotracer for 5-HT2CRs, 4-(3-[18F]fluorophenethoxy)-pyrimidine (18F-FPP).7 In rats, 18 F-FPP labeled receptor populations not only in the choroid plexus, but also in regions with modest expression (e.g., frontal cortex, striatum, and thalamus). Pretreatment with the FDAapproved antiobesity medication lorcaserin (Belviq) blocked 18 F-FPP labeling, in keeping with 5-HT2CR-specific expression in vivo. Following up on this important research with analyses of 18F-FPP in humans and other species will provide scientists and clinicians with a key tool to explore the roles of 5-HT2CRs in normal and pathological states. Each Editor was asked to identify two top 2017 publications, a difficult task in light of the excellent papers published this year in ACS Chemical Neuroscience. Nonetheless, I feel additionally compelled to highlight two Viewpoints. The first is “Caring about Power Analysis,” authored by Jennifer Murray, Scott Barrett, Rebecca Brock, and Rick Bevins at the University of NebraskaLincoln, which presents a down-to-earth, cogent discussion of how and why to improve rigor and reproducibility in scientific reports with a focus on sample sizes.11 The second is “Why I’m Not a Cognitive Psychologist... or a Behaviorist... or a Biologist.” Written by newly minted Ph.D., Erik J. Garcia (Kansas State University), this Viewpoint is a thoughtful consideration of how to grow wholistically as a scientist in the current climate.12 Kudos to these and all of our 2017 authors! Kathryn A. Cunningham, Associate Editor
As an Editor with ACS Chemical Neuroscience, one gets to see how our field is evolving by watching conversations between authors and reviewers. For me, 2017 stands out due to the unique creativity authors brought to this conversation, the flexibility that reviewers had for new ideas, and the application of ideas from other fields to chemical neuroscienceall of which are the hallmarks of ACS Chemical Neuroscience that our Editors strive to cultivate and maintain. Reflecting on papers published in 2017, the first article that came to mind was a Review by Peter Tonge at Stony Brook University titled “Drug−Target Kinetics in Drug Discovery”.13 This paper stands out not only because it was one of the most read articles of the year in ACS Chemical Neuroscience, but because it reminds us of the major disconnects that exist between kinetics and thermodynamics that emerge when moving from biochemical assays to in vivo pharmacology. Chemical neuroscience is uniquely kineticyour brain is constantly processing and adaptingincluding to stimuli associated with reading this text! We need to consider implications of timedomains and nonequilibrium outcomes when designing experiments to probe chemical neuroscience so as to build on the principles outlined by Tonge in his Review. Jacob M. Hooker, Associate Editor
My other 2017 favorite article was rooted in my own research on neuroinflammation and radiotracer development. The field of neuroinflammation, however you choose to define it, is evolving quickly. New concepts for therapy and new drug targets are emerging that will differentiate microglial activation phenotypes. Despite intense interest, there is a dearth of tools to study immune activation in the CNS, and few tools have the potential to translate to human use. In what I think is a remarkable show of creativity, chemical biology intuition, and rigorous experimental imaging, Robert Mach of the University of Pennsylvania and his colleagues developed a PET radiotracer named [18F]ROStrace.14 This tool provides a f unctional readout of oxidative potential that will enable new insights into the mechanisms of neurodegenerative disorders (a starting point!). I eagerly await the progression of this work through preclinical models and into human neuroimaging studies. Jacob M. Hooker, Associate Editor 2
DOI: 10.1021/acschemneuro.8b00001 ACS Chem. Neurosci. 2018, 9, 1−4
ACS Chemical Neuroscience
Editorial
among papers published in this area in ACS Chemical Neuroscience in 2017 was “Directed Evolution of Key Residues in Fluorescent Protein Inverses the Polarity of Voltage Sensitivity in the Genetically Encoded Indicator ArcLight” by Jelena Platisa, Vincent Pieribone, and coauthors at the John B. Pierce Laboratory, Inc. and Yale University.19 This paper, also published in the March issue and featured on its cover, describes the mutagenic evolution of a genetically encoded voltage indicator (GEVI). A number of genetically encoded calcium indicators are widely used to investigate single neuron activity over large numbers of neurons via fluorescence microscopy. However, changes in intracellular calcium levels are only a proxy for activity. Indicators directed to specific neuronal populations, that are sensitive to modulations in membrane potential, would afford a direct readout of cell activity. Platisa, Pieribone, and coauthors overcame a key obstacle along the path to practical GEVIs. An existing sensor that they previously developed, called ArcLight, suffers from reduced fluorescence associated with membrane depolarization. By discovering three key amino acids and directing their evolution, a new sensor, Marina, was produced that detects neuronal depolarization by increased fluorescence. The properties of Marina were favorable enough to detect even subthreshold events in mammalian neurons. Anne M. Andrews, Associate Editor
The year 2017 was memorable as it marked the third time that ACS Chemical Neuroscience published two special issues near-and-dear to me. The first was the February 2017 issue focused on Monitoring Molecules in Neuroscience (http:// pubs.acs.org/toc/acncdm/8/2). The second was the May 2017 issue of ACS Chemical Neuroscience devoted to Serotonin Research (http://pubs.acs.org/toc/acncdm/8/5). While there were many favorites for me in these two special issues, I wanted to take this opportunity to highlight two papers that appeared in our March issue. The first is titled “Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins” by Tyler Johson of the Dominican University of California, Jennifer Whistler of the University of California, San Francisco, and their colleagues from the National Institute of Mental Health Drug Discovery Program and the University of California, Santa Cruz.15 This paper illustrates a creative approach for identifying new lead compounds from aquatic organisms. Most of us are well aware of the powerful uses and misuses of current opiods. In 2015 (the most recent year with complete CDC statistics), there were 33,000 opiod-related drug deaths in the United Statesthat number is expected to rise for 2016 and 2017. The compounds in the Johnson and Whistler study were identified via high-throughput screening and LC-MS purification. They showed unusual properties relative to current opiod medications in that they activated μ-opiod receptormediated G-protein and β-arrestin/endocytic pathways. This “balanced” mechanism of action is important because it more closely resembles that of endogenous endorphins, which are good analgesics yet show reduced tolerance and dependence liabilities. The ability to identify receptor ligands having “biased” vs. balanced action toward individual or multiple intracellular signaling pathways, respectively is reinvigorating pharmaceutical research aimed at developing better medications with improved side-effect profiles.16 The novel scaffolds identified from marine sponges by the Johnson−Whistler team may provide new opportunites to produce opiod drugs to treat pain and other medical conditions having reduced potential for missuse and overdose. Beyond this paper, there were other examples of biased ligand development reported in ACS Chemical Neuroscience in 2017.17,18 Anne M. Andrews, Associate Editor
In all, 2017 was an extraordinary year at ACS Chemical Neuroscience. We wish all of our authors, reviewers, readers, and staff Happy New Year and look forward to continued growth and increased impact in 2018.
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Craig W. Lindsley, Editor-in-Chief Kathryn A. Cunningham, Associate Editor Jacob M. Hooker, Associate Editor Anne M. Andrews, Associate Editor AUTHOR INFORMATION
ORCID
Craig W. Lindsley: 0000-0003-0168-1445 Kathryn A. Cunningham: 0000-0002-4257-1739 Jacob M. Hooker: 0000-0002-9394-7708 Anne M. Andrews: 0000-0002-1961-4833 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) Lindsley, C. W., Hooker, J. M., Cunningham, K. A., and Andrews, A. M. (2017) Editor’s Favorites of 2016. ACS Chem. Neurosci. 8 (1), 1−3. (2) Rodeberg, N. T., Sandberg, S. G., Johnson, J. A., Phillips, P. E. M., and Wightman, R. M. (2017) Hitchhiker’s Guide to Voltammetry: Acute and Chronic Electrodes for in Vivo Fast-Scan Voltammetry. ACS Chem. Neurosci. 8 (2), 221−234. (3) Raper, J., Morrison, R. D., Daniels, J. S., Howell, L., Bachevalier, J., Wichmann, T., and Galvan, A. (2017) Metabolism and Distribution of Clozapine-N-oxide: Implications for Nonhuman Primate Chemogenetics. ACS Chem. Neurosci. 8 (7), 1570−1576.
The other research area I wanted to highlight involves the development and novel use of light-activated compounds and constructs to visualize, investigate, and control neurons. Key 3
DOI: 10.1021/acschemneuro.8b00001 ACS Chem. Neurosci. 2018, 9, 1−4
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(4) Gomez, J. L., Bonaventura, J., Lesniak, W., Mathews, W. B., SysaShah, P., Rodriguez, L. A., Ellis, R. J., Richie, C. T., Harvey, B. K., Dannals, R. F., Pomper, M. G., Bonci, A., and Michaelides, M. (2017) Chemogenetics Revealed: DREADD Occupancy and Activation via Converted Clozapine. Science 357 (6350), 503−507. (5) Brimblecombe, K. R., and Cragg, S. J. (2017) The Striosome and Matrix Compartments of the Striatum: A Path through the Labyrinth from Neurochemistry toward Function. ACS Chem. Neurosci. 8 (2), 235−242. (6) Edwards, D. J., and Bagg, H. J. (1923) Lesions of the Corpus Striatum by Radium Emanation and the Accompanying Structural and Functional Changes. Am. J. Physiol. 65 (1), 162−173. (7) Kim, J., Moon, B. S., Lee, B. C., Lee, H. Y., Kim, H. J., Choo, H., Pae, A. N., Cho, Y. S., and Min, S. J. (2017) A Potential PET Radiotracer for the 5-HT2C Receptor: Synthesis and in Vivo Evaluation of 4-(3-[18F]fluorophenethoxy)pyrimidine. ACS Chem. Neurosci. 8 (5), 996−1003. (8) Higgins, G. A. (2017) (18)F-FPP: A PET Ligand for the 5-HT2C Receptor? ACS Chem. Neurosci. 8 (5), 904−907. (9) Cunningham, K. A., and Anastasio, N. C. (2014) Serotonin at the Nexus of Impulsivity and Cue Reactivity in Cocaine Addiction. Neuropharmacology 76, 460−78. (10) Higgins, G. A., and Fletcher, P. J. (2015) Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders. ACS Chem. Neurosci. 6 (7), 1071−88. (11) Murray, J. E., Barrett, S. T., Brock, R. L., and Bevins, R. A. (2017) Caring about Power Analyses. ACS Chem. Neurosci. 8 (11), 2352−2354. (12) Garcia, E. J. (2017) Why I’m Not a Cognitive Psychologist... Or a Behaviorist... Or a Biologist. ACS Chem. Neurosci. 8 (10), 2100− 2101. (13) Tonge, P. J. (2017) Drug−Target Kinetics in Drug Discovery. ACS Chem. Neurosci., DOI: 10.1021/acschemneuro.7b00185. (14) Hou, C., Hsieh, C.-J., Li, S., Lee, H., Graham, T. J., Xu, K., Weng, C.-C., Doot, R. K., Chu, W., Chakraborty, S. K., Dugan, L. L., Mintun, M. A., and Mach, R. H. (2017) Development of a Positron Emission Tomography Radiotracer for Imaging Elevated Levels of Superoxide in Neuroinflammation. ACS Chem. Neurosci., DOI: 10.1021/acschemneuro.7b00385. (15) Johnson, T. A., Milan-Lobo, L., Che, T., Ferwerda, M., Lambu, E., McIntosh, N. L., Li, F., He, L., Lorig-Roach, N., Crews, P., and Whistler, J. L. (2017) Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins. ACS Chem. Neurosci. 8 (3), 473−485. (16) Andrews, A. M. (2017) Why Monitor Molecules in Neuroscience? ACS Chem. Neurosci. 8 (2), 211−212. (17) Xu, W., Wang, X., Tocker, A. M., Huang, P., Reith, M. E. A., LiuChen, L.-Y., Smith, A. B., and Kortagere, S. (2017) Functional Characterization of a Novel Series of Biased Signaling Dopamine D3 Receptor Agonists. ACS Chem. Neurosci. 8 (3), 486−500. (18) Liu, X., Zhao, L., Wang, Y., Zhou, J., Wang, D., Zhang, Y., Zhang, X., Wang, Z., Yang, D., Mou, L., and Wang, R. (2017) MELN16: A Series of Novel Endomorphin Analogs with Good Analgesic Activity and a Favorable Side Effect Profile. ACS Chem. Neurosci. 8 (10), 2180−2193. (19) Platisa, J., Vasan, G., Yang, A., and Pieribone, V. A. (2017) Directed Evolution of Key Residues in Fluorescent Protein Inverses the Polarity of Voltage Sensitivity in the Genetically Encoded Indicator ArcLight. ACS Chem. Neurosci. 8 (3), 513−523.
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DOI: 10.1021/acschemneuro.8b00001 ACS Chem. Neurosci. 2018, 9, 1−4
