Pub Date : 2024-10-28eCollection Date: 2024-10-01DOI: 10.1371/journal.pbio.3002838
Aijun Liu, Yezhou Liu, Geng Chen, Wenping Lyu, Fang Ye, Junlin Wang, Qiwen Liao, Lizhe Zhu, Yang Du, Richard D Ye
Chemerin is an adipokine with chemotactic activity to a subset of leukocytes. Chemerin binds to 3 G protein-coupled receptors, including chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C chemokine receptor-like 2 (CCRL2). Here, we report that GPR1 is capable of Gi signaling when stimulated with full-length chemerin or its C-terminal nonapeptide (C9, YFPGQFAFS). We present high-resolution cryo-EM structures of Gi-coupled GPR1 bound to full-length chemerin and to the C9 peptide, respectively. C9 insertion into the transmembrane (TM) binding pocket is both necessary and sufficient for GPR1 signaling, whereas the full-length chemerin uses its bulky N-terminal core for interaction with a β-strand located at the N-terminus of GPR1. This interaction involves multiple β-strands of full-length chemerin, forming a β-sheet that serves as a "lid" for the TM binding pocket and is energetically expensive to remove as indicated by molecular dynamics simulations with free energy landscape analysis. Combining results from functional assays, our structural model explains why C9 is an activating peptide at GPR1 and how the full-length chemerin uses a "two-site" model for enhanced interaction with GPR1.
螯合素是一种脂肪因子,对部分白细胞具有趋化活性。螯合素与 3 种 G 蛋白偶联受体结合,包括趋化因子样受体 1(CMKLR1)、G 蛋白偶联受体 1(GPR1)和 C-C 趋化因子样受体 2(CCRL2)。在这里,我们报告了 GPR1 在全长螯合素或其 C 端非肽(C9,YFPGQFAFS)的刺激下能够发出 Gi 信号。我们展示了分别与全长螯合素和 C9 肽结合的 Gi 偶联 GPR1 的高分辨率冷冻电镜结构。C9 插入跨膜(TM)结合口袋对于 GPR1 信号传导是必要且充分的,而全长螯合素则利用其笨重的 N 端核心与位于 GPR1 N 端的 β 链相互作用。这种相互作用涉及到全长螯合素的多条 β 链,形成了一个 β 片层,作为 TM 结合袋的 "盖子",根据分子动力学模拟和自由能谱分析,去除它的能量代价很高。结合功能测试的结果,我们的结构模型解释了为什么 C9 是 GPR1 的激活肽,以及全长螯合素如何使用 "双位点 "模型来增强与 GPR1 的相互作用。
{"title":"Structure of G protein-coupled receptor GPR1 bound to full-length chemerin adipokine reveals a chemokine-like reverse binding mode.","authors":"Aijun Liu, Yezhou Liu, Geng Chen, Wenping Lyu, Fang Ye, Junlin Wang, Qiwen Liao, Lizhe Zhu, Yang Du, Richard D Ye","doi":"10.1371/journal.pbio.3002838","DOIUrl":"10.1371/journal.pbio.3002838","url":null,"abstract":"<p><p>Chemerin is an adipokine with chemotactic activity to a subset of leukocytes. Chemerin binds to 3 G protein-coupled receptors, including chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C chemokine receptor-like 2 (CCRL2). Here, we report that GPR1 is capable of Gi signaling when stimulated with full-length chemerin or its C-terminal nonapeptide (C9, YFPGQFAFS). We present high-resolution cryo-EM structures of Gi-coupled GPR1 bound to full-length chemerin and to the C9 peptide, respectively. C9 insertion into the transmembrane (TM) binding pocket is both necessary and sufficient for GPR1 signaling, whereas the full-length chemerin uses its bulky N-terminal core for interaction with a β-strand located at the N-terminus of GPR1. This interaction involves multiple β-strands of full-length chemerin, forming a β-sheet that serves as a \"lid\" for the TM binding pocket and is energetically expensive to remove as indicated by molecular dynamics simulations with free energy landscape analysis. Combining results from functional assays, our structural model explains why C9 is an activating peptide at GPR1 and how the full-length chemerin uses a \"two-site\" model for enhanced interaction with GPR1.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28eCollection Date: 2024-10-01DOI: 10.1371/journal.pbio.3002863
Minghui Zhao, Yumeng Xin, Haoyun Deng, Zhentao Zuo, Xiaoying Wang, Yanchao Bi, Ning Liu
Animals guide their behaviors through internal representations of the world in the brain. We aimed to understand how the macaque brain stores such general world knowledge, focusing on object color knowledge. Three functional magnetic resonance imaging (fMRI) experiments were conducted in macaque monkeys: viewing chromatic and achromatic gratings, viewing grayscale images of their familiar fruits and vegetables (e.g., grayscale strawberry), and viewing true- and false-colored objects (e.g., red strawberry and green strawberry). We observed robust object knowledge representations in the color patches, especially the one located around TEO: the activity patterns could classify grayscale pictures of objects based on their memory color and response patterns in these regions could translate between chromatic grating viewing and grayscale object viewing (e.g., red grating-grayscale images of strawberry), such that classifiers trained by viewing chromatic gratings could successfully classify grayscale object images according to their memory colors. Our results showed direct positive evidence of object color memory in macaque monkeys. These results indicate the perceptually grounded knowledge representation as a conservative memory mechanism and open a new avenue to study this particular (semantic) memory representation with macaque models.
{"title":"Object color knowledge representation occurs in the macaque brain despite the absence of a developed language system.","authors":"Minghui Zhao, Yumeng Xin, Haoyun Deng, Zhentao Zuo, Xiaoying Wang, Yanchao Bi, Ning Liu","doi":"10.1371/journal.pbio.3002863","DOIUrl":"10.1371/journal.pbio.3002863","url":null,"abstract":"<p><p>Animals guide their behaviors through internal representations of the world in the brain. We aimed to understand how the macaque brain stores such general world knowledge, focusing on object color knowledge. Three functional magnetic resonance imaging (fMRI) experiments were conducted in macaque monkeys: viewing chromatic and achromatic gratings, viewing grayscale images of their familiar fruits and vegetables (e.g., grayscale strawberry), and viewing true- and false-colored objects (e.g., red strawberry and green strawberry). We observed robust object knowledge representations in the color patches, especially the one located around TEO: the activity patterns could classify grayscale pictures of objects based on their memory color and response patterns in these regions could translate between chromatic grating viewing and grayscale object viewing (e.g., red grating-grayscale images of strawberry), such that classifiers trained by viewing chromatic gratings could successfully classify grayscale object images according to their memory colors. Our results showed direct positive evidence of object color memory in macaque monkeys. These results indicate the perceptually grounded knowledge representation as a conservative memory mechanism and open a new avenue to study this particular (semantic) memory representation with macaque models.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28eCollection Date: 2024-10-01DOI: 10.1371/journal.pbio.3002860
Carlos Pascual-Caro, Jaime de Juan-Sanz
To enable transmission of information in the brain, synaptic vesicles fuse to presynaptic membranes, liberating their content and exposing transiently a myriad of vesicular transmembrane proteins. However, versatile methods for quantifying the synaptic translocation of endogenous proteins during neuronal activity remain unavailable, as the fast dynamics of synaptic vesicle cycling difficult specific isolation of trafficking proteins during such a transient surface exposure. Here, we developed a novel approach using synaptic cleft proximity labeling to capture and quantify activity-driven trafficking of endogenous synaptic proteins at the synapse. We show that accelerating cleft biotinylation times to match the fast dynamics of vesicle exocytosis allows capturing endogenous proteins transiently exposed at the synaptic surface during neural activity, enabling for the first time the study of the translocation of nearly every endogenous synaptic protein. As proof-of-concept, we further applied this technology to obtain direct evidence of the surface translocation of noncanonical trafficking proteins, such as ATG9A and NPTX1, which had been proposed to traffic during activity but for which direct proof had not yet been shown. The technological advancement presented here will facilitate future studies dissecting the molecular identity of proteins exocytosed at the synapse during activity, helping to define the molecular machinery that sustains neurotransmission in the mammalian brain.
{"title":"Monitoring of activity-driven trafficking of endogenous synaptic proteins through proximity labeling.","authors":"Carlos Pascual-Caro, Jaime de Juan-Sanz","doi":"10.1371/journal.pbio.3002860","DOIUrl":"10.1371/journal.pbio.3002860","url":null,"abstract":"<p><p>To enable transmission of information in the brain, synaptic vesicles fuse to presynaptic membranes, liberating their content and exposing transiently a myriad of vesicular transmembrane proteins. However, versatile methods for quantifying the synaptic translocation of endogenous proteins during neuronal activity remain unavailable, as the fast dynamics of synaptic vesicle cycling difficult specific isolation of trafficking proteins during such a transient surface exposure. Here, we developed a novel approach using synaptic cleft proximity labeling to capture and quantify activity-driven trafficking of endogenous synaptic proteins at the synapse. We show that accelerating cleft biotinylation times to match the fast dynamics of vesicle exocytosis allows capturing endogenous proteins transiently exposed at the synaptic surface during neural activity, enabling for the first time the study of the translocation of nearly every endogenous synaptic protein. As proof-of-concept, we further applied this technology to obtain direct evidence of the surface translocation of noncanonical trafficking proteins, such as ATG9A and NPTX1, which had been proposed to traffic during activity but for which direct proof had not yet been shown. The technological advancement presented here will facilitate future studies dissecting the molecular identity of proteins exocytosed at the synapse during activity, helping to define the molecular machinery that sustains neurotransmission in the mammalian brain.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-25DOI: 10.1371/journal.pbio.3002894
Uma R Mohan, Joshua Jacobs
Invasive brain stimulation is used to treat individuals with episodic memory loss; however, studies to date report both enhancement and impairment of memory. This Essay discusses the sources of this variability, and suggests a path towards developing customized stimulation protocols for more consistent memory enhancement.
{"title":"Why does invasive brain stimulation sometimes improve memory and sometimes impair it?","authors":"Uma R Mohan, Joshua Jacobs","doi":"10.1371/journal.pbio.3002894","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002894","url":null,"abstract":"<p><p>Invasive brain stimulation is used to treat individuals with episodic memory loss; however, studies to date report both enhancement and impairment of memory. This Essay discusses the sources of this variability, and suggests a path towards developing customized stimulation protocols for more consistent memory enhancement.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1371/journal.pbio.3002896
Eduardo Fernandez, Jose Antonio Robles
The past 20 years have witnessed significant advancements in the field of visual prostheses, with developments spanning from early retinal implants to recent cortical approaches. This Perspective looks at some of the remaining challenges to achieve the ambitious clinical goals that these technologies could enable.
{"title":"Advances and challenges in the development of visual prostheses.","authors":"Eduardo Fernandez, Jose Antonio Robles","doi":"10.1371/journal.pbio.3002896","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002896","url":null,"abstract":"<p><p>The past 20 years have witnessed significant advancements in the field of visual prostheses, with developments spanning from early retinal implants to recent cortical approaches. This Perspective looks at some of the remaining challenges to achieve the ambitious clinical goals that these technologies could enable.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24eCollection Date: 2024-10-01DOI: 10.1371/journal.pbio.3002850
Sophie L Fayad, Lauren M Reynolds, Nicolas Torquet, Stefania Tolu, Sarah Mondoloni, Claire Nguyen, Amy Siriphanh, Robin Justo, Steve Didienne, Nicolas Debray, Cécile Viollet, Louis Raynaud, Yasmine Layadi, Coralie Fouquet, Bernadette Hannesse, Ana-Marta Capaz, Thomas Topilko, Nicolas Renier, Alexandre Mourot, Fabio Marti, Philippe Faure
Individual animals differ in their traits and preferences, which shape their social interactions, survival, and susceptibility to disease, including addiction. Nicotine use is highly heterogenous and has been linked to the expression of personality traits. Although these relationships are well documented, we have limited understanding of the neurophysiological mechanisms that give rise to distinct behavioral profiles and their connection to nicotine susceptibility. To address this question, we conducted a study using a semi-natural and social environment called "Souris-City" to observe the long-term behavior of individual male mice. Souris-City provided both a communal living area and a separate test area where mice engaged in a reward-seeking task isolated from their peers. Mice developed individualistic reward-seeking strategies when choosing between water and sucrose in the test compartment, which, in turn, predicted how they adapted to the introduction of nicotine as a reinforcer. Moreover, the profiles mice developed while isolated in the test area correlated with their behavior within the social environment, linking decision-making strategies to the expression of behavioral traits. Neurophysiological markers of adaptability within the dopamine system were apparent upon nicotine challenge and were associated with specific profiles. Our findings suggest that environmental adaptations influence behavioral traits and sensitivity to nicotine by acting on dopaminergic reactivity in the face of nicotine exposure, potentially contributing to addiction susceptibility. These results further emphasize the importance of understanding interindividual variability in behavior to gain insight into the mechanisms of decision-making and addiction.
{"title":"Individualistic reward-seeking strategies that predict response to nicotine emerge among isogenic male mice living in a micro-society.","authors":"Sophie L Fayad, Lauren M Reynolds, Nicolas Torquet, Stefania Tolu, Sarah Mondoloni, Claire Nguyen, Amy Siriphanh, Robin Justo, Steve Didienne, Nicolas Debray, Cécile Viollet, Louis Raynaud, Yasmine Layadi, Coralie Fouquet, Bernadette Hannesse, Ana-Marta Capaz, Thomas Topilko, Nicolas Renier, Alexandre Mourot, Fabio Marti, Philippe Faure","doi":"10.1371/journal.pbio.3002850","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002850","url":null,"abstract":"<p><p>Individual animals differ in their traits and preferences, which shape their social interactions, survival, and susceptibility to disease, including addiction. Nicotine use is highly heterogenous and has been linked to the expression of personality traits. Although these relationships are well documented, we have limited understanding of the neurophysiological mechanisms that give rise to distinct behavioral profiles and their connection to nicotine susceptibility. To address this question, we conducted a study using a semi-natural and social environment called \"Souris-City\" to observe the long-term behavior of individual male mice. Souris-City provided both a communal living area and a separate test area where mice engaged in a reward-seeking task isolated from their peers. Mice developed individualistic reward-seeking strategies when choosing between water and sucrose in the test compartment, which, in turn, predicted how they adapted to the introduction of nicotine as a reinforcer. Moreover, the profiles mice developed while isolated in the test area correlated with their behavior within the social environment, linking decision-making strategies to the expression of behavioral traits. Neurophysiological markers of adaptability within the dopamine system were apparent upon nicotine challenge and were associated with specific profiles. Our findings suggest that environmental adaptations influence behavioral traits and sensitivity to nicotine by acting on dopaminergic reactivity in the face of nicotine exposure, potentially contributing to addiction susceptibility. These results further emphasize the importance of understanding interindividual variability in behavior to gain insight into the mechanisms of decision-making and addiction.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11501037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24eCollection Date: 2024-10-01DOI: 10.1371/journal.pbio.3002859
Pablo Capilla-Lasheras, Nina Bircher, Antony M Brown, Xavier Harrison, Thomas Reed, Jennifer E York, Dominic L Cram, Christian Rutz, Lindsay Walker, Marc Naguib, Andrew J Young
Explaining the evolution of sex differences in cooperation remains a major challenge. Comparative studies highlight that offspring of the more philopatric sex tend to be more cooperative within their family groups than those of the more dispersive sex but we do not understand why. The leading "Philopatry hypothesis" proposes that the more philopatric sex cooperates more because their higher likelihood of natal breeding increases the direct fitness benefits of natal cooperation. However, the "Dispersal trade-off hypothesis" proposes that the more dispersive sex cooperates less because preparations for dispersal, such as extra-territorial prospecting, trade-off against natal cooperation. Here, we test both hypotheses in cooperatively breeding white-browed sparrow weavers (Plocepasser mahali), using a novel high-resolution automated radio-tracking method. First, we show that males are the more dispersive sex (a rare reversal of the typical avian sex difference in dispersal) and that, consistent with the predictions of both hypotheses, females contribute substantially more than males to cooperative care while within the natal group. However, the Philopatry hypothesis cannot readily explain this female-biased cooperation, as females are not more likely than males to breed within their natal group. Instead, our radio-tracking findings support the Dispersal trade-off hypothesis: males conduct pre-dispersal extra-territorial prospecting forays at higher rates than females and prospecting appears to trade-off against natal cooperation. Our findings thus highlight that the evolution of sex differences in cooperation could be widely attributable to trade-offs between cooperation and dispersal; a potentially general explanation that does not demand that cooperation yields direct fitness benefits.
{"title":"Evolution of sex differences in cooperation can be explained by trade-offs with dispersal.","authors":"Pablo Capilla-Lasheras, Nina Bircher, Antony M Brown, Xavier Harrison, Thomas Reed, Jennifer E York, Dominic L Cram, Christian Rutz, Lindsay Walker, Marc Naguib, Andrew J Young","doi":"10.1371/journal.pbio.3002859","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002859","url":null,"abstract":"<p><p>Explaining the evolution of sex differences in cooperation remains a major challenge. Comparative studies highlight that offspring of the more philopatric sex tend to be more cooperative within their family groups than those of the more dispersive sex but we do not understand why. The leading \"Philopatry hypothesis\" proposes that the more philopatric sex cooperates more because their higher likelihood of natal breeding increases the direct fitness benefits of natal cooperation. However, the \"Dispersal trade-off hypothesis\" proposes that the more dispersive sex cooperates less because preparations for dispersal, such as extra-territorial prospecting, trade-off against natal cooperation. Here, we test both hypotheses in cooperatively breeding white-browed sparrow weavers (Plocepasser mahali), using a novel high-resolution automated radio-tracking method. First, we show that males are the more dispersive sex (a rare reversal of the typical avian sex difference in dispersal) and that, consistent with the predictions of both hypotheses, females contribute substantially more than males to cooperative care while within the natal group. However, the Philopatry hypothesis cannot readily explain this female-biased cooperation, as females are not more likely than males to breed within their natal group. Instead, our radio-tracking findings support the Dispersal trade-off hypothesis: males conduct pre-dispersal extra-territorial prospecting forays at higher rates than females and prospecting appears to trade-off against natal cooperation. Our findings thus highlight that the evolution of sex differences in cooperation could be widely attributable to trade-offs between cooperation and dispersal; a potentially general explanation that does not demand that cooperation yields direct fitness benefits.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22eCollection Date: 2024-10-01DOI: 10.1371/journal.pbio.3002865
Jiyeon Hwang, Junichi Okada, Li Liu, Jeffrey E Pessin, Gary J Schwartz, Young-Hwan Jo
Hepatic lipid metabolism is regulated by the autonomic nervous system of the liver, with the sympathetic innervation being extensively studied, while the parasympathetic efferent innervation is less understood despite its potential importance. In this study, we investigate the consequences of disrupted brain-liver communication on hepatic lipid metabolism in mice exposed to obesogenic conditions. We found that a subset of hepatocytes and cholangiocytes are innervated by parasympathetic nerve terminals originating from the dorsal motor nucleus of the vagus. The elimination of the brain-liver axis by deleting parasympathetic cholinergic neurons innervating the liver prevents hepatic steatosis and promotes browning of inguinal white adipose tissue (ingWAT). The loss of liver-innervating cholinergic neurons increases hepatic Cyp7b1 expression and fasting serum bile acid levels. Furthermore, knockdown of the G protein-coupled bile acid receptor 1 gene in ingWAT reverses the beneficial effects of the loss of liver-innervating cholinergic neurons, leading to the reappearance of hepatic steatosis. Deleting liver-innervating cholinergic neurons has a small but significant effect on body weight, which is accompanied by an increase in energy expenditure. Taken together, these data suggest that targeting the parasympathetic cholinergic innervation of the liver is a potential therapeutic approach for enhancing hepatic lipid metabolism in obesity and diabetes.
{"title":"The development of hepatic steatosis depends on the presence of liver-innervating parasympathetic cholinergic neurons in mice fed a high-fat diet.","authors":"Jiyeon Hwang, Junichi Okada, Li Liu, Jeffrey E Pessin, Gary J Schwartz, Young-Hwan Jo","doi":"10.1371/journal.pbio.3002865","DOIUrl":"10.1371/journal.pbio.3002865","url":null,"abstract":"<p><p>Hepatic lipid metabolism is regulated by the autonomic nervous system of the liver, with the sympathetic innervation being extensively studied, while the parasympathetic efferent innervation is less understood despite its potential importance. In this study, we investigate the consequences of disrupted brain-liver communication on hepatic lipid metabolism in mice exposed to obesogenic conditions. We found that a subset of hepatocytes and cholangiocytes are innervated by parasympathetic nerve terminals originating from the dorsal motor nucleus of the vagus. The elimination of the brain-liver axis by deleting parasympathetic cholinergic neurons innervating the liver prevents hepatic steatosis and promotes browning of inguinal white adipose tissue (ingWAT). The loss of liver-innervating cholinergic neurons increases hepatic Cyp7b1 expression and fasting serum bile acid levels. Furthermore, knockdown of the G protein-coupled bile acid receptor 1 gene in ingWAT reverses the beneficial effects of the loss of liver-innervating cholinergic neurons, leading to the reappearance of hepatic steatosis. Deleting liver-innervating cholinergic neurons has a small but significant effect on body weight, which is accompanied by an increase in energy expenditure. Taken together, these data suggest that targeting the parasympathetic cholinergic innervation of the liver is a potential therapeutic approach for enhancing hepatic lipid metabolism in obesity and diabetes.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22eCollection Date: 2024-10-01DOI: 10.1371/journal.pbio.3002853
Yasir Malik, Yavuz Kulaberoglu, Shajahan Anver, Sara Javidnia, Gillian Borland, Rene Rivera, Stephen Cranwell, Danel Medelbekova, Tatiana Svermova, Jackie Thomson, Susan Broughton, Tobias von der Haar, Colin Selman, Jennifer M A Tullet, Nazif Alic
tRNAs are evolutionarily ancient molecular decoders essential for protein translation. In eukaryotes, tRNAs and other short, noncoding RNAs are transcribed by RNA polymerase (Pol) III, an enzyme that promotes ageing in yeast, worms, and flies. Here, we show that a partial reduction in Pol III activity specifically disrupts tRNA levels. This effect is conserved across worms, flies, and mice, where computational models indicate that it impacts mRNA decoding. In all 3 species, reduced Pol III activity increases proteostatic resilience. In worms, it activates the unfolded protein response (UPR) and direct disruption of tRNA metabolism is sufficient to recapitulate this. In flies, decreasing Pol III's transcriptional initiation on tRNA genes by a loss-of-function in the TFIIIC transcription factor robustly extends lifespan, improves proteostatic resilience and recapitulates the broad-spectrum benefits to late-life health seen following partial Pol III inhibition. We provide evidence that a partial reduction in Pol III activity impacts translation, quantitatively or qualitatively, in both worms and flies, indicating a potential mode of action. Our work demonstrates a conserved and previously unappreciated role of tRNAs in animal ageing.
tRNA 是蛋白质翻译所必需的古老分子解码器。在真核生物中,tRNA 和其他短的非编码 RNA 由 RNA 聚合酶(Pol)III 转录,这种酶促进了酵母、蠕虫和苍蝇的老化。在这里,我们发现 Pol III 活性的部分降低会特异性地破坏 tRNA 水平。这种效应在蠕虫、苍蝇和小鼠中是一致的,计算模型表明它影响了 mRNA 的解码。在所有 3 个物种中,Pol III 活性的降低都会增加蛋白静态复原力。在蠕虫中,它激活了未折叠蛋白反应(UPR),而直接破坏 tRNA 代谢足以重现这种情况。在苍蝇中,通过 TFIIIC 转录因子的功能缺失来减少 Pol III 对 tRNA 基因的转录启动,可以有力地延长寿命、提高蛋白质恢复能力,并再现了部分抑制 Pol III 后对晚年健康的广泛益处。我们提供的证据表明,部分降低 Pol III 活性会对蠕虫和苍蝇的翻译产生定量或定性影响,这表明了一种潜在的作用模式。我们的工作证明了 tRNA 在动物衰老过程中的作用是一致的,而且是以前未曾认识到的。
{"title":"Disruption of tRNA biogenesis enhances proteostatic resilience, improves later-life health, and promotes longevity.","authors":"Yasir Malik, Yavuz Kulaberoglu, Shajahan Anver, Sara Javidnia, Gillian Borland, Rene Rivera, Stephen Cranwell, Danel Medelbekova, Tatiana Svermova, Jackie Thomson, Susan Broughton, Tobias von der Haar, Colin Selman, Jennifer M A Tullet, Nazif Alic","doi":"10.1371/journal.pbio.3002853","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002853","url":null,"abstract":"<p><p>tRNAs are evolutionarily ancient molecular decoders essential for protein translation. In eukaryotes, tRNAs and other short, noncoding RNAs are transcribed by RNA polymerase (Pol) III, an enzyme that promotes ageing in yeast, worms, and flies. Here, we show that a partial reduction in Pol III activity specifically disrupts tRNA levels. This effect is conserved across worms, flies, and mice, where computational models indicate that it impacts mRNA decoding. In all 3 species, reduced Pol III activity increases proteostatic resilience. In worms, it activates the unfolded protein response (UPR) and direct disruption of tRNA metabolism is sufficient to recapitulate this. In flies, decreasing Pol III's transcriptional initiation on tRNA genes by a loss-of-function in the TFIIIC transcription factor robustly extends lifespan, improves proteostatic resilience and recapitulates the broad-spectrum benefits to late-life health seen following partial Pol III inhibition. We provide evidence that a partial reduction in Pol III activity impacts translation, quantitatively or qualitatively, in both worms and flies, indicating a potential mode of action. Our work demonstrates a conserved and previously unappreciated role of tRNAs in animal ageing.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22eCollection Date: 2024-10-01DOI: 10.1371/journal.pbio.3002610
Lin Cai, Takeshi Arimitsu, Naomi Shinohara, Takao Takahashi, Yoko Hakuno, Masahiro Hata, Ei-Ichi Hoshino, Stuart K Watson, Simon W Townsend, Jutta L Mueller, Yasuyo Minagawa
Pre-babbling infants can track nonadjacent dependencies (NADs) in the auditory domain. While this forms a crucial prerequisite for language acquisition, the neurodevelopmental origins of this ability remain unknown. We applied functional near-infrared spectroscopy in neonates and 6- to 7-month-old infants to investigate the neural substrate supporting NAD learning and detection using tone sequences in an artificial grammar learning paradigm. Detection of NADs was indicated by left prefrontal activation in neonates while by left supramarginal gyrus (SMG), superior temporal gyrus (STG), and inferior frontal gyrus activation in 6- to 7-month-olds. Functional connectivity analyses further indicated that the neonate activation pattern during the test phase benefited from a brain network consisting of prefrontal regions, left SMG and STG during the rest and learning phases. These findings suggest a left-hemispheric learning-related functional brain network may emerge at birth and serve as the foundation for the later engagement of these regions for NAD detection, thus, providing a neural basis for language acquisition.
咿呀学语前的婴儿可以在听觉领域追踪非相邻依存关系(NAD)。虽然这构成了语言习得的重要前提,但这种能力的神经发育起源仍然未知。我们在新生儿和 6 到 7 个月大的婴儿身上应用了功能性近红外光谱技术,在人工语法学习范式中使用音调序列来研究支持 NAD 学习和检测的神经基质。新生儿的左前额叶激活显示了对 NAD 的检测,而 6 到 7 个月大的婴儿的左侧边际上回(SMG)、颞上回(STG)和额下回激活显示了对 NAD 的检测。功能连接分析进一步表明,新生儿在测试阶段的激活模式在休息和学习阶段受益于由前额叶区、左侧SMG和STG组成的大脑网络。这些研究结果表明,与学习相关的左半球脑功能网络可能在新生儿出生时就已出现,并为这些区域日后参与NAD检测奠定了基础,从而为语言习得提供了神经基础。
{"title":"Functional reorganization of brain regions supporting artificial grammar learning across the first half year of life.","authors":"Lin Cai, Takeshi Arimitsu, Naomi Shinohara, Takao Takahashi, Yoko Hakuno, Masahiro Hata, Ei-Ichi Hoshino, Stuart K Watson, Simon W Townsend, Jutta L Mueller, Yasuyo Minagawa","doi":"10.1371/journal.pbio.3002610","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002610","url":null,"abstract":"<p><p>Pre-babbling infants can track nonadjacent dependencies (NADs) in the auditory domain. While this forms a crucial prerequisite for language acquisition, the neurodevelopmental origins of this ability remain unknown. We applied functional near-infrared spectroscopy in neonates and 6- to 7-month-old infants to investigate the neural substrate supporting NAD learning and detection using tone sequences in an artificial grammar learning paradigm. Detection of NADs was indicated by left prefrontal activation in neonates while by left supramarginal gyrus (SMG), superior temporal gyrus (STG), and inferior frontal gyrus activation in 6- to 7-month-olds. Functional connectivity analyses further indicated that the neonate activation pattern during the test phase benefited from a brain network consisting of prefrontal regions, left SMG and STG during the rest and learning phases. These findings suggest a left-hemispheric learning-related functional brain network may emerge at birth and serve as the foundation for the later engagement of these regions for NAD detection, thus, providing a neural basis for language acquisition.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}