{"title":"Discovery of a Novel Orally Active Ketamine Derivative with Dual Analgesic and Antidepressant Activities, Lacking Psychomimetic Effects.","authors":"Syed Muzzammil Masaud, Humaira Nadeem, Babar Murtaza, Abida Shamim","doi":"10.1021/acschemneuro.4c00887","DOIUrl":"10.1021/acschemneuro.4c00887","url":null,"abstract":"<p><p>This study investigated the synthesis, characterization, and in silico analysis of novel <i>N</i>-acetamide ketamine derivatives aimed at evaluating their analgesic, anesthetic, and antidepressant properties. The synthesis commenced with the preparation of chloroacetylamide derivatives, which were subsequently reacted with ketamine hydrochloride, yielding 16 derivatives <b>k</b><sub><b>1</b></sub> to <b>k</b><sub><b>16</b></sub>. These compounds were characterized through H<sup>1</sup> NMR, C<sup>13</sup> NMR, mass spectroscopy (EIMS), and elemental analysis, followed by an assessment of their physicochemical properties. The analgesic efficacy of all of the synthesized derivatives was evaluated using the acetic acid-induced writhing test via intraperitoneal administration. The best-performing molecule was further evaluated for analgesic (acetic acid-induced writhing test, tail suspension test (TST), and hot plate test) and anti-inflammatory (carrageenan-induced paw edema) activities. For antidepressant effects, all derivatives were compared with ketamine in a lipopolysaccharide-induced model of depression in mice through the forced swimming test, open field test (OFT), sucrose preference test (SPT), and TST. It was observed that among all the derivatives, molecule <b>k</b><sub><b>1</b></sub> demonstrated comparable analgesic activity to ketamine. Further, compound <b>k</b><sub><b>1</b></sub> also exhibited the highest antidepressant potential during the forced swimming test, OFT, SPT, and TST. <b>k</b><sub><b>1</b></sub> was further compared with ketamine for their activities intraperitoneally and orally where <b>k</b><sub><b>1</b></sub> exhibited comparable antidepressant effects to ketamine. Henceforth, the psychomimetic potential of <b>k</b><sub><b>1</b></sub> was evaluated through loss of righting reflex and Y-maze tests. Very interestingly, these tests indicated approximately no psychomimetic activity of <b>k</b><sub><b>1</b></sub> compared to ketamine intraperitoneally and orally. Finally, molecular docking studies were conducted targeting the NMDA receptor at the JC09 ketamine binding pocket (PDB ID: 7EU7), where all synthesized derivatives exhibited significant binding affinities relative to ketamine. These findings suggest that the newly synthesized <i>N</i>-acetamide ketamine derivative <b>k</b><sub><b>1</b></sub> possesses promising pharmacological profiles, warranting further exploration.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"932-944"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical NeurosciencePub Date : 2025-03-05Epub Date: 2025-02-12DOI: 10.1021/acschemneuro.4c00803
Priyanka Singh, Nagesh Y Kadam, Rajlaxmi Panigrahi, Arpit Mehrotra, Krishna Upadhayay, Madhumita Dey, Arpit Tyagi, Muhammad Aquib, Janni Nielsen, Giulia Kleijwegt, Prashant Singh, Abhishek Sharma, Alka Rao, Daniel E Otzen, Ashutosh Kumar, Deepak Sharma
{"title":"Sulfamerazine as a Potential Modulator against α-Synuclein Aggregation and Associated Toxicity.","authors":"Priyanka Singh, Nagesh Y Kadam, Rajlaxmi Panigrahi, Arpit Mehrotra, Krishna Upadhayay, Madhumita Dey, Arpit Tyagi, Muhammad Aquib, Janni Nielsen, Giulia Kleijwegt, Prashant Singh, Abhishek Sharma, Alka Rao, Daniel E Otzen, Ashutosh Kumar, Deepak Sharma","doi":"10.1021/acschemneuro.4c00803","DOIUrl":"10.1021/acschemneuro.4c00803","url":null,"abstract":"<p><p>Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. The presence of Lewy bodies, primarily consisting of amyloid aggregates of the protein α-synuclein (α-Syn), is a common feature seen in dopaminergic neurons in (PD) patients. In the present study, we screened 2320 FDA-approved drugs and found 3 lead molecules, sulfamerazine, lathosterol, and tamoxifen, that reproducibly inhibited α-Syn fibrillation. Dose-response studies showed that sulfamerazine and lathosterol are relatively more potent than tamoxifen in inhibiting α-Syn aggregation. Among the lead compounds, sulfamerazine showed a significant reduction in α-Syn aggregation and associated toxicity in <i>Caenorhabditis elegans</i> model of PD. Sulfamerazine also reduced the accumulation of α-Syn aggregates in neuronal SH-SY5Y cells. Microscale thermophoresis confirmed the binding of sulfamerazine to α-Syn. NMR studies corroborated the binding of sulfamerazine with α-Syn and show that upon interaction, α-Syn is sequestered into large soluble dispersed assemblies, which is similar to as seen in transmission electron microscopy. We conclude that sulfamerazine and its derivatives hold promise as therapeutic agents against Parkinson's disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"880-894"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical NeurosciencePub Date : 2025-03-05Epub Date: 2025-02-23DOI: 10.1021/acschemneuro.4c00435
Alexandra K Brooke, Sarbeshwar Ojha, Daniel P Murrow, Ashley E Ross
{"title":"Purinergic Receptor P2Y1 Modulates Catecholamine Signaling in Murine Mesenteric Lymph Nodes.","authors":"Alexandra K Brooke, Sarbeshwar Ojha, Daniel P Murrow, Ashley E Ross","doi":"10.1021/acschemneuro.4c00435","DOIUrl":"10.1021/acschemneuro.4c00435","url":null,"abstract":"<p><p>Neuroimmune communication is crucial for the body's response to physiological challenges, homeostasis, and immune stress response. Adrenergic and purinergic neurotransmission in the sympathetic nervous system is vital for this communication. This study achieves the first co-detection of adenine-based purines and catecholamines in mesenteric lymph nodes via fast-scan cyclic voltammetry. Additionally, we reveal that manipulating an ATP receptor can impact catecholamine signaling in the lymph node for the first time. The G-protein-coupled receptor P2Y1, which controls intracellular Ca<sup>2+</sup> levels, was targeted with the antagonist MRS2179. MRS2179 decreased catecholamine concentrations, increased inter-event times, and prolonged event durations. These results suggest that events became smaller, less frequent, and longer-lasting, possibly attributable to decreased intracellular Ca<sup>2+</sup> levels. These findings indicate that ATP release in the lymph node can partially regulate norepinephrine signaling, providing mechanistic insight into sympathetic neuronal neurotransmitter control. A deeper understanding of more complicated neuroimmune mechanisms could potentially influence the development of therapeutic strategies in immunology and neurobiology.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"772-780"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical NeurosciencePub Date : 2025-03-05Epub Date: 2025-02-14DOI: 10.1021/acschemneuro.4c00790
Shweta R Malvankar, Michael S Wolfe
{"title":"Effects of Transmembrane Phenylalanine Residues on γ-Secretase-Mediated Notch-1 Proteolysis.","authors":"Shweta R Malvankar, Michael S Wolfe","doi":"10.1021/acschemneuro.4c00790","DOIUrl":"10.1021/acschemneuro.4c00790","url":null,"abstract":"<p><p>γ-Secretase is a presenilin-containing intramembrane aspartyl protease complex that cleaves within the transmembrane domain (TMD) of nearly 150 substrates, with the amyloid precursor protein (APP) being the most well studied. APP cleavage by γ-secretase generates amyloid β-peptides (Aβ) that pathologically deposit in Alzheimer's disease. The APP TMD substrate undergoes initial endoproteolysis (ε-cleavage) followed by processive carboxypeptidase trimming of long Aβ intermediates in ∼tripeptide intervals. Although γ-secretase cleavage of Notch1 is essential in developmental biology and is altered in many cancers, the processing of this cell-surface receptor is relatively understudied. Only one sequence specificity rule is known for γ-secretase substrate processing: Aromatic residues such as phenylalanine are not tolerated in the P2' position with respect to any processing event on the APP TMD. Here we show using biochemical and mass spectrometry (MS) techniques that this specificity rule holds for Notch1 as well. Analysis of products from the reactions of a purified enzyme complex and Notch1 TMD substrate variants revealed that P2' Phe relative to ε-site cleavage reduced proteolysis and shifted initial cleavage N-terminally by one residue. Double Phe mutation near the ε site resulted in reduced proteolysis with shifting to two major initial cleavage sites, one N-terminally and one C-terminally, both of which avoid Phe in the P2' position. Additionally, three natural Phe residues were mutated to the corresponding residues in the APP TMD, which led to increased ε proteolysis. Thus, Phe residues can affect the enzyme reaction rate as well as cleavage site specificity in the Notch1 TMD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"844-855"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical NeurosciencePub Date : 2025-03-05Epub Date: 2025-02-21DOI: 10.1021/acschemneuro.5c00032
Kentaro Yashiro, Yuzo Iwaki, Hirohito Urata, Masaya Kokubo, Takahiro Mori, Yoko Sekioka, Koichi Isami, Junya Kato, Joshua Wieting, Kevin M McGowan, Thomas M Bridges, Olivier Boutaud, Darren W Engers, Jerod S Denton, Haruto Kurata, Craig W Lindsley
{"title":"Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator <i>In Vivo</i> Tool Compound.","authors":"Kentaro Yashiro, Yuzo Iwaki, Hirohito Urata, Masaya Kokubo, Takahiro Mori, Yoko Sekioka, Koichi Isami, Junya Kato, Joshua Wieting, Kevin M McGowan, Thomas M Bridges, Olivier Boutaud, Darren W Engers, Jerod S Denton, Haruto Kurata, Craig W Lindsley","doi":"10.1021/acschemneuro.5c00032","DOIUrl":"10.1021/acschemneuro.5c00032","url":null,"abstract":"<p><p>Herein we describe our initial work on the K<sub>2</sub>P family of potassium ion channels with the chemical optimization and characterization of a novel series of TWIK-Related K+ Channel (TREK)-1/2 dual activators and TREK-2 preferring activators derived from a high-throughput screening hit. The exercise provided TREK activators with good CNS penetration and others with low CNS exposure to enable exploration of both central and peripheral TREK activation. From this, ONO-2920632 (VU6011887 = <b>19b</b>) emerged as a reasonably potent (human Tl<sup>+</sup>; TREK-1 EC<sub>50</sub> = 2.8 μM (95% <i>E</i><sub>max</sub>), TREK-2 EC<sub>50</sub> = 0.30 μM (184% <i>E</i><sub>max</sub>)), first-generation CNS penetrant (rat K<sub>p</sub> = 0.37) <i>in vivo</i> tool compound with selectivity versus the other K<sub>2</sub>P channels (>91-fold selective vs TASK1, TASK2, TASK3, TRAAK, TWIK2, and 31-fold selective vs TRESK) and no significant activity in a large ancillary pharmacology panel. ONO-2920632 (VU6011887) displayed robust, dose dependent efficacy when dosed orally in a mouse pain model (acetic acid writhing assay), where it was equipotent at 3 mg/kg to the assay standard indomethacin at 10 mg/kg. The therapeutic potential of TREK channel activation has long been hampered by a lack of selective, small molecule tools, and this work provides a variety of <i>in vivo</i> tool compounds for the community.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"960-967"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Restricts Inflammatory Progression through Limiting Macrophage Infiltration in DRG and Sciatic Nerve during Diabetic Peripheral Neuropathy.","authors":"Peng Dai, Peng Wang, Xin Chen, Shuyun Feng, Fancan Wu, Xueqin Zheng, Zaisheng Qin","doi":"10.1021/acschemneuro.5c00021","DOIUrl":"10.1021/acschemneuro.5c00021","url":null,"abstract":"<p><p>Diabetic peripheral neuropathy (DPN) is a prevalent complication affecting over half of individuals with diabetes. This study investigates the role of mesencephalic Astrocyte-derived neurotrophic factor (MANF) in DPN progression and its potential as a therapeutic target. Using a streptozotocin (STZ)-induced diabetic mouse model, we analyzed MANF expression in the dorsal root ganglia (DRG) and sciatic nerve and assessed the effects of recombinant human MANF (rhMANF) administration on DPN symptoms. Our findings show significant upregulation of MANF protein levels in the DRG of diabetic mice, along with an increased presence of MANF-expressing macrophages in both the DRG and sciatic nerve. Intravenous administration of rhMANF from Day 7 to Day 21 post-STZ injection yielded multiple beneficial outcomes. Notably, rhMANF treatment alleviated mechanical hypoalgesia, as measured by the paw mechanical withdrawal threshold (PMWT), and enhanced sciatic nerve conduction, improving motor nerve conduction velocity (MNCV). Additionally, it increased intradermal nerve density, indicated by more PGP9.5-positive nerve fibers in the plantar skin of treated diabetic mice. These improvements were associated with reduced macrophage infiltration in the DRG and sciatic nerve, marked by fewer CD68 and Iba-1 positive cells, and inhibition of inflammatory signaling pathways. Specifically, rhMANF treatment decreased NF-κB p65 phosphorylation and suppressed p38 MAPK phosphorylation, indicating reduced inflammation. In summary, our research underscores MANF's potential as a novel therapeutic target for DPN, particularly due to its anti-inflammatory properties. Further exploration of MANF could lead to the development of more effective treatments for this debilitating aspect of diabetes.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"945-959"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical NeurosciencePub Date : 2025-03-05Epub Date: 2025-02-13DOI: 10.1021/acschemneuro.4c00655
Valeria Parrales, Guillaume Arcile, Louise Laserre, Sébastien Normant, Géraldine Le Goff, Christian Da Costa Noble, Jamal Ouazzani, Noelle Callizot, Stéphane Haïk, Chérif Rabhi, Nicolas Bizat
{"title":"Neuroprotective Effect of <i>Withaferin</i> Derivatives toward MPP<sup>+</sup> and 6-OHDA Toxicity to Dopaminergic Neurons.","authors":"Valeria Parrales, Guillaume Arcile, Louise Laserre, Sébastien Normant, Géraldine Le Goff, Christian Da Costa Noble, Jamal Ouazzani, Noelle Callizot, Stéphane Haïk, Chérif Rabhi, Nicolas Bizat","doi":"10.1021/acschemneuro.4c00655","DOIUrl":"10.1021/acschemneuro.4c00655","url":null,"abstract":"<p><p>Parkinson's disease is a neurodegenerative proteinopathy that primarily affects mesencephalic dopaminergic neurons. This dopaminergic depletion can be phenotypically reproduced in various experimental models through the administration of two neurotoxins: N-methyl-4-phenylpyridinium (MPP<sup>+</sup>) and 6-hydroxydopamine (6-OHDA). The mechanisms underlying the cell death processes induced by these toxins remain a subject of debate. In this context, studies suggest that oxidative-stress-related processes may contribute to the dysfunction and death of dopaminergic neurons. Therefore, investigating pharmacological compounds that can counteract these processes remains crucial for developing therapeutic strategies targeting these neuropathological mechanisms. <i>Withania somnifera</i> (L.) <i>Dunal</i>, commonly known as <i>ashwagandha</i>, is a plant whose roots are used in Ayurvedic medicine to treat various ailments, including those affecting the central nervous system. The active compound <i>Withaferin-A</i> (<i>WFA</i>), a steroid lactone from the <i>withanolide</i> group, is reported to possess antioxidant properties. In this study, we explored the potential neuroprotective effects of <i>WFA</i> and two of its molecular derivatives, <i>cr-591</i> and <i>cr-777</i>, which contain, respectively, an additional cysteine or glutathione chemical group, known for their antiradical properties. We demonstrated that <i>WFA</i> and its two derivatives, <i>cr-591</i> and <i>cr-777</i>, protect the integrity and function of dopaminergic neurons exposed to the neurotoxins MPP<sup>+</sup> and 6-OHDA both in vitro, using primary mesencephalic neuron cultures from rodents, and in vivo, using the nematode <i>Caenorhabditis elegans</i>.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"802-817"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical NeurosciencePub Date : 2025-03-05DOI: 10.1021/acschemneuro.4c0081910.1021/acschemneuro.4c00819
Irum Waheed, Talal Sikandri, Sumbal Zaheen, Muhammad Mahtab Aslam Khan Khakwani, Zhaowu An, Tingting Liu, Chaoyang Zhu and Jianshe Wei*,
{"title":"Evaluating the Molecular Interactions between Type 2 Diabetes Mellitus and Parkinson’s Disease: Role of Antidiabetic Drugs as Promising Therapeutics","authors":"Irum Waheed, Talal Sikandri, Sumbal Zaheen, Muhammad Mahtab Aslam Khan Khakwani, Zhaowu An, Tingting Liu, Chaoyang Zhu and Jianshe Wei*, ","doi":"10.1021/acschemneuro.4c0081910.1021/acschemneuro.4c00819","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00819https://doi.org/10.1021/acschemneuro.4c00819","url":null,"abstract":"<p >Evidence from previous research demonstrates a relationship between diabetes mellitus (DM) and Parkinson’s disease (PD). T2DM is associated with chronic glucose dysregulation, as an etiological factor. It inhibits neuronal function through disrupted insulin signaling and oxidative stress, which ultimately lead to the loss of dopaminergic neurons in the substantia nigra (SN). Interactions between T2DM and PD were analyzed by gene expression, coexpression, and gene set enrichment via NCBI and STRING databases following pathways like KEGG and Reactome. The study identified nine key gene interactions through published literature on different databases and search engines that are involved in the progression of these chronic diseases. Furthermore, some genetic and nongenetic risk factors, gene mutations and environmental factors, are also involved in the progression of T2DM and PD. This review highlights the limitations of currently available drug treatments for these diseases and examines modern therapeutic approaches to address neurodegenerative and metabolic abnormalities. We critically assess the current experimental methodologies aimed at unraveling the pathophysiological mechanisms linking PD and T2DM while addressing the key challenges impeding a comprehensive understanding of the concurrent emergence of these debilitating age-related conditions.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"988–999 988–999"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical NeurosciencePub Date : 2025-03-05Epub Date: 2025-02-12DOI: 10.1021/acschemneuro.4c00771
Naozumi Araragi, Markus Petermann, Mototaka Suzuki, Matthew Larkum, Valentina Mosienko, Michael Bader, Natalia Alenina, Friederike Klempin
{"title":"Acute Optogenetic Stimulation of Serotonin Neurons Reduces Cell Proliferation in the Dentate Gyrus of Mice.","authors":"Naozumi Araragi, Markus Petermann, Mototaka Suzuki, Matthew Larkum, Valentina Mosienko, Michael Bader, Natalia Alenina, Friederike Klempin","doi":"10.1021/acschemneuro.4c00771","DOIUrl":"10.1021/acschemneuro.4c00771","url":null,"abstract":"<p><p>The dentate gyrus of the hippocampus is targeted by axons from serotonin raphe neurons, where the neurotransmitter modulates adult neurogenesis and antidepressant action, and mediates the neurogenic effect of running. Whether running-induced cell proliferation is directly mediated by serotonin remains unknown. Here, we took advantage of Tph2-ChR2-YFP transgenic mice in which the light-sensitive protein channelrhodopsin-2 (ChR2) is specifically expressed in tryptophan hydroxylase 2 (TPH2)-expressing neurons. We selectively activated serotonin neurons via optogenetics and determined the effect on cell proliferation in the dentate gyrus. Our data reveal a significant reduction in the number of newly generated cells upon overnight raphe stimulation. The decrease in cell proliferation was absent when serotonin neurons were light-activated for six consecutive nights. However, we observed an interhemispheric difference in BrdU-positive cell numbers. We conclude that acute network dynamics occur between serotonin raphe neurons and the hippocampus, directly affecting precursor cell proliferation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"781-789"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical NeurosciencePub Date : 2025-03-05Epub Date: 2025-02-24DOI: 10.1021/acschemneuro.4c00799
Cameron S Movassaghi, Rahul Iyer, Maya E Curry, Mila E Wesely, Miguel Alcañiz Fillol, Anne M Andrews
{"title":"SeroWare: An Open-Source Software Suite for Voltammetry Data Acquisition and Analysis.","authors":"Cameron S Movassaghi, Rahul Iyer, Maya E Curry, Mila E Wesely, Miguel Alcañiz Fillol, Anne M Andrews","doi":"10.1021/acschemneuro.4c00799","DOIUrl":"10.1021/acschemneuro.4c00799","url":null,"abstract":"<p><p>Voltammetry is widely used for fast, data-dense measurements of redox-active analytes in versatile environments, including the brain. Voltammetry requires minimal hardware beyond a potentiostat, a front-end amplifier, and a computer. Nonetheless, researchers must often develop or modify software packages for application-specific uses. Of the voltammetry software available, significant issues exist with source code inaccessible for updating or customization, nonconfigurable data processing procedures, and hardware incompatibilities. These limitations, coupled with the recent proliferation of waveform types and increased demands for high bandwidth data acquisition and efficient data processing, create the need for sophisticated, powerful, and flexible voltammetry software. We report developing \"SeroWare\", an open-source, end-to-end voltammetry acquisition and analysis software package designed to handle a wide variety of use cases encountered by voltammetry users. Although inspired by neurochemical analyses, this software is flexible, customizable, and compatible with open-source toolkits. The modular software architecture enables users to generate, acquire, and analyze voltammetry data of different types, ranging from pulse and sweep waveforms to fast and slow scans via easily accessible and exportable file formats. Template code is provided for communicating with a variety of standard external devices. We report several novel features for waveform applications and data flow. In-depth documentation in a User Guide and video tutorials are provided to enable new research directions, particularly regarding shareability and lowering the barriers to entry for new investigators.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"856-867"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}