Molecular BrainPub Date : 2024-08-07DOI: 10.1186/s13041-024-01129-y
Ivana A Souza, Maria A Gandini, Md Yousof Ali, Franz Kricek, George Skouteris, Gerald W Zamponi
{"title":"Determinants of interactions of a novel next-generation gabapentinoid NVA1309 and mirogabalin with the Cavα2δ-1 subunit.","authors":"Ivana A Souza, Maria A Gandini, Md Yousof Ali, Franz Kricek, George Skouteris, Gerald W Zamponi","doi":"10.1186/s13041-024-01129-y","DOIUrl":"10.1186/s13041-024-01129-y","url":null,"abstract":"<p><p>NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within a triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared the effects of NVA1309 with Mirogabalin, a gabapentinoid drug with higher affinity for the voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which is approved for post-herpetic neuralgia in Japan, Korea and Taiwan. Both NVA1309 and mirogabalin inhibit Cav2.2 currents in vitro and decrease Cav2.2 plasma membrane expression with higher efficacy than pregabalin. Mutagenesis of the classical binding residue arginine R243 and the newly identified binding residue lysine K615 reverse the effect of mirogabalin on Cav2.2 current, but not that of NVA1309.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"54"},"PeriodicalIF":3.3,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902412","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":"Astrocytic activation increases blood flow in the adult olfactory bulb.","authors":"Takashi Ogino, Masakazu Agetsuma, Masato Sawada, Hiroyuki Inada, Junichi Nabekura, Kazunobu Sawamoto","doi":"10.1186/s13041-024-01126-1","DOIUrl":"10.1186/s13041-024-01126-1","url":null,"abstract":"<p><p>Activation of astrocytes after sensory stimulation has been reported to be involved in increased blood flow in the central nervous system. In the present study, using a chemogenetic method to induce astrocyte activation in mice without sensory stimulation, we found that astrocytic activation led to increased blood flow in the olfactory bulb, suggesting that astrocyte activation is sufficient for increasing blood flow in the olfactory bulb. The technique established here will be useful for studying the mechanisms underlying sensory input-dependent blood flow increases.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"52"},"PeriodicalIF":3.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11301997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897835","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}
Molecular BrainPub Date : 2024-08-06DOI: 10.1186/s13041-024-01123-4
Ying Su, Aimei Liu, Hongguang Chen, Qingjie Chen, Bo Zhao, Runze Gao, Kangwei Zhang, Tie Peng, Zhenwang Zhang, Changhan Ouyang, Dan Zhu
{"title":"Research progress of brain organoids in the field of diabetes.","authors":"Ying Su, Aimei Liu, Hongguang Chen, Qingjie Chen, Bo Zhao, Runze Gao, Kangwei Zhang, Tie Peng, Zhenwang Zhang, Changhan Ouyang, Dan Zhu","doi":"10.1186/s13041-024-01123-4","DOIUrl":"10.1186/s13041-024-01123-4","url":null,"abstract":"<p><p>Human embryonic stem cells and human induced pluripotent stem cells may be used to create 3D tissues called brain organoids. They duplicate the physiological and pathological characteristics of human brain tissue more faithfully in terms of both structure and function, and they more precisely resemble the morphology and cellular structure of the human embryonic brain. This makes them valuable models for both drug screening and in vitro studies on the development of the human brain and associated disorders. The technical breakthroughs enabled by brain organoids have a significant impact on the research of different brain regions, brain development and sickness, the connections between the brain and other tissues and organs, and brain evolution. This article discusses the development of brain organoids, their use in diabetes research, and their progress.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"53"},"PeriodicalIF":3.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897836","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":"Involvement of posterior hypothalamic CaMKII-positive neurons in ADHD-like behaviors in mice.","authors":"Changwoo Lee, Changsu Woo, Gyeong Ryeong Ma, Kyuhyun Choi, Shin Jung Kang, Ki Soon Shin","doi":"10.1186/s13041-024-01122-5","DOIUrl":"10.1186/s13041-024-01122-5","url":null,"abstract":"<p><p>This study explores the behavioral effects of modulating CaMKII-positive (CaMKII+) neurons in the posterior hypothalamus (PH). Utilizing a chemogenetic approach in mice, we discovered that the activation of CaMKII + neurons within the PH is associated with heightened locomotor activity, reduced social interaction, and impulsive behavior unrelated to anxiety or avoidance. These observed behaviors share a significant resemblance with characteristics commonly found in attention deficit and hyperactivity disorder (ADHD). Notably, treatment with clonidine, which is frequently prescribed for ADHD, effectively reduced impulsive behaviors in our mouse model. Our findings uncover the role of the PH that has not been previously explored and suggest a possible involvement of the PH in the manifestation of ADHD-like behaviors.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"51"},"PeriodicalIF":3.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893848","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}
Molecular BrainPub Date : 2024-08-02DOI: 10.1186/s13041-024-01125-2
Soon-Gu Kwon, Hoon-Seong Choi, Seo-Yeon Yoon, Dae-Hyun Roh, Jang-Hern Lee
{"title":"Intraplantar aminoglutethimide, a P450scc inhibitor, reduced the induction of mechanical allodynia in a rat model of thrombus-induced ischemic pain.","authors":"Soon-Gu Kwon, Hoon-Seong Choi, Seo-Yeon Yoon, Dae-Hyun Roh, Jang-Hern Lee","doi":"10.1186/s13041-024-01125-2","DOIUrl":"10.1186/s13041-024-01125-2","url":null,"abstract":"<p><p>Neuroactive steroids (NASs) directly affect neuronal excitability. Despite their role in the nervous system is intimately linked to pain control, knowledge is currently limited. This study investigates the peripheral involvement of NASs in chronic ischemic pain by targeting the cytochrome P450 side-chain cleavage enzyme (P450scc). Using a rat model of hind limb thrombus-induced ischemic pain (TIIP), we observed an increase in P450scc expression in the ischemic hind paw skin. Inhibiting P450scc with intraplantar aminoglutethimide (AMG) administration from post-operative day 0 to 3 significantly reduced the development of mechanical allodynia. However, AMG administration from post-operative day 3 to 6 did not affect established mechanical allodynia. In addition, we explored the role of the peripheral sigma-1 receptor (Sig-1R) by co-administering PRE-084 (PRE), a Sig-1R agonist, with AMG. PRE reversed the analgesic effects of AMG during the induction phase. These findings indicate that inhibiting steroidogenesis with AMG alleviates peripheral ischemic pain during the induction phase via Sig-1Rs.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"50"},"PeriodicalIF":3.3,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879113","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":"Neurexin-3 in the paraventricular nucleus of the hypothalamus regulates body weight and glucose homeostasis independently of food intake.","authors":"Mingdao Mu, Haoyu Sun, Shuyan Geng, Tianxiang Xu, Chuanyao Sun, Zixu Zhang, Sibie Meng, Moyi Li, An Liu, Zhiyuan Yang, Wei Xie","doi":"10.1186/s13041-024-01124-3","DOIUrl":"10.1186/s13041-024-01124-3","url":null,"abstract":"<p><p>Neurexin-3 (Nrxn3) has been genetically associated with obesity, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the role of Nrxn3 in the paraventricular nucleus of the hypothalamus (PVN) in regulating energy balance and glucose homeostasis. We found that Nrxn3 expression in the PVN was upregulated in response to metabolic stressors, including cold exposure and fasting. Using Cre-loxP technology, we selectively ablated Nrxn3 in CaMKIIα-expressing neurons of the PVN in male mice. This genetic manipulation resulted in marked weight gain attributable to increased adiposity and impaired glucose tolerance, without affecting food intake. Our findings identify PVN CaMKIIα-expressing neurons as a critical locus where Nrxn3 modulates energy balance by regulating adipogenesis and glucose metabolism, independently of appetite. These results reveal a novel neural mechanism potentially linking Nrxn3 dysfunction to obesity pathogenesis, suggesting that targeting PVN Nrxn3-dependent neural pathways may inform new therapeutic approaches for obesity prevention and treatment.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"49"},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875361","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}
Molecular BrainPub Date : 2024-07-29DOI: 10.1186/s13041-024-01116-3
Sushil Gaire, Jiawei An, Haijie Yang, Keon Ah Lee, Manisha Dumre, Eun Jeong Lee, Sang-Myun Park, Eun-Hye Joe
{"title":"Systemic inflammation attenuates the repair of damaged brains through reduced phagocytic activity of monocytes infiltrating the brain.","authors":"Sushil Gaire, Jiawei An, Haijie Yang, Keon Ah Lee, Manisha Dumre, Eun Jeong Lee, Sang-Myun Park, Eun-Hye Joe","doi":"10.1186/s13041-024-01116-3","DOIUrl":"10.1186/s13041-024-01116-3","url":null,"abstract":"<p><p>In this study, we examined how systemic inflammation affects repair of brain injury. To this end, we created a brain-injury model by stereotaxic injection of ATP, a damage-associated molecular pattern component, into the striatum of mice. Systemic inflammation was induced by intraperitoneal injection of lipopolysaccharide (LPS-ip). An analysis of magnetic resonance images showed that LPS-ip reduced the initial brain injury but slowed injury repair. An immunostaining analysis using the neuronal marker, NeuN, showed that LPS-ip delayed removal of dead/dying neurons, despite the fact that LPS-ip enhanced infiltration of monocytes, which serve to phagocytize dead cells/debris. Notably, infiltrating monocytes showed a widely scattered distribution. Bulk RNAseq analyses showed that LPS-ip decreased expression of genes associated with phagocytosis, with PCR and immunostaining of injured brains confirming reduced levels of Cd68 and Clec7a, markers of phagocytic activity, in monocytes. Collectively, these results suggest that systemic inflammation affects properties of blood monocytes as well as brain cells, resulting in delay in clearing damaged cells and activating repair processes.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"47"},"PeriodicalIF":3.3,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792929","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}
Molecular BrainPub Date : 2024-07-29DOI: 10.1186/s13041-024-01119-0
Ge Feng, Zongkai Wu, Leyi Yang, Kaimeng Wang, Hebo Wang
{"title":"β-hydroxybutyrate and ischemic stroke: roles and mechanisms.","authors":"Ge Feng, Zongkai Wu, Leyi Yang, Kaimeng Wang, Hebo Wang","doi":"10.1186/s13041-024-01119-0","DOIUrl":"10.1186/s13041-024-01119-0","url":null,"abstract":"<p><p>Stroke is a significant global burden, causing extensive morbidity and mortality. In metabolic states where glucose is limited, ketone bodies, predominantly β-hydroxybutyrate (BHB), act as alternative fuel sources. Elevated levels of BHB have been found in the ischemic hemispheres of animal models of stroke, supporting its role in the pathophysiology of cerebral ischemia. Clinically, higher serum and urinary BHB concentrations have been associated with adverse outcomes in ischemic stroke, highlighting its potential utility as a prognostic biomarker. In both animal and cellular models, exogenous BHB administration has exhibited neuroprotective effects, reduction of infarct size, and improvement of neurological outcomes. In this review, we focus on the role of BHB before and after ischemic stroke, with an emphasis on the therapeutic potential and mechanisms of ketone administration after ischemic stroke.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"48"},"PeriodicalIF":3.3,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792930","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}
Molecular BrainPub Date : 2024-07-24DOI: 10.1186/s13041-024-01121-6
Wing Lam Yu, Zizhen Zhang, Gerald W Zamponi
{"title":"Spared nerve injury leads to reduced activity of neurons projecting from the ventrolateral periaqueductal gray to the locus coeruleus.","authors":"Wing Lam Yu, Zizhen Zhang, Gerald W Zamponi","doi":"10.1186/s13041-024-01121-6","DOIUrl":"10.1186/s13041-024-01121-6","url":null,"abstract":"<p><p>The ventrolateral periaqueductal gray (vlPAG) serves as a central hub for descending pain modulation. It receives upstream projections from the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (vlOFC), and projects downstream to the locus coeruleus (LC) and the rostroventral medulla (RVM). While much research has focused on upstream circuits and the LC-RVM connection, less is known about the PAG-LC circuit and its involvement in neuropathic pain. Here we examined the intrinsic electrophysiological properties of vlPAG-LC projecting neurons in Sham and spared nerve injury (SNI) operated mice. Injection of the retrotracer Cholera Toxin Subunit B (CTB-488) into the LC allowed the identification of LC-projecting neurons in the vlPAG. Electrophysiological recordings from CTB-488 positive cells revealed that both GABAergic and glutamatergic cells that project to the LC exhibited reduced intrinsic excitability after peripheral nerve injury. By contrast, CTB-488 negative cells did not exhibit alterations in firing properties after SNI surgery. An SNI-induced reduction of LC projecting cells was confirmed with c-fos labeling. Hence, SNI induces plasticity changes in the vlPAG that are consistent with a reduction in the descending modulation of pain signals.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"46"},"PeriodicalIF":3.3,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759836","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}
Molecular BrainPub Date : 2024-07-23DOI: 10.1186/s13041-024-01115-4
Jaimie J Lee, Paulina S Scheuren, Hanwen Liu, Ryan W J Loke, Cornelia Laule, Catrina M Loucks, John L K Kramer
{"title":"The myelin water imaging transcriptome: myelin water fraction regionally varies with oligodendrocyte-specific gene expression.","authors":"Jaimie J Lee, Paulina S Scheuren, Hanwen Liu, Ryan W J Loke, Cornelia Laule, Catrina M Loucks, John L K Kramer","doi":"10.1186/s13041-024-01115-4","DOIUrl":"10.1186/s13041-024-01115-4","url":null,"abstract":"<p><p>Identifying sensitive and specific measures that can quantify myelin are instrumental in characterizing microstructural changes in neurological conditions. Neuroimaging transcriptomics is emerging as a valuable technique in this regard, offering insights into the molecular basis of promising candidates for myelin quantification, such as myelin water fraction (MWF). We aimed to demonstrate the utility of neuroimaging transcriptomics by validating MWF as a myelin measure. We utilized data from a normative MWF brain atlas, comprised of 50 healthy subjects (mean age = 25 years, range = 17-42 years) scanned at 3 Tesla. Magnetic resonance imaging data included myelin water imaging to extract MWF and T1 anatomical scans for image registration and segmentation. We investigated the inter-regional distributions of gene expression data from the Allen Human Brain Atlas in conjunction with inter-regional MWF distribution patterns. Pearson correlations were used to identify genes with expression profiles mirroring MWF. The Single Cell Type Atlas from the Human Protein Atlas was leveraged to classify genes into gene sets with high cell type specificity, and a control gene set with low cell type specificity. Then, we compared the Pearson correlation coefficients for each gene set to determine if cell type-specific gene expression signatures correlate with MWF. Pearson correlation coefficients between MWF and gene expression for oligodendrocytes and adipocytes were significantly higher than for the control gene set, whereas correlations between MWF and inhibitory/excitatory neurons were significantly lower. Our approach in integrating transcriptomics with neuroimaging measures supports an emerging technique for understanding and validating MRI-derived markers such as MWF.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"17 1","pages":"45"},"PeriodicalIF":3.3,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11264438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752162","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}