Pub Date : 2024-09-12DOI: 10.1101/2024.09.08.611846
Guangnan Tian, Thomas Ka Chung Lam, Gewei Yan, Yingzhu He, Biswadeep Khan, Jianan Qu, Julie Lee Semmelhack
Most animals with two eyes combine the inputs to achieve binocular vision, which can serve numerous functions, and is particularly useful in hunting prey. However, the mechanisms by which visual information from the two eyes are combined remain largely unknown. To address this question, we identified the binocular neurons that respond to prey in zebrafish (bino-PRNs). These neurons respond specifically to prey, and their activity is enhanced during hunting. To explore the relationship between bino-PRNs and hunting, we optogenetically induced hunting and found that the bino-PRNs receive excitatory input during hunting. To determine the role of the bino-PRNs in behavior, we optogenetically activated them, and found that they promote forward prey capture swims. Our results support a model where bino-PRNs integrate sensory information from the two eyes with hunting state information to drive approach toward prey in the binocular zone.
{"title":"Integration of binocular vision and motor state to promote prey pursuit","authors":"Guangnan Tian, Thomas Ka Chung Lam, Gewei Yan, Yingzhu He, Biswadeep Khan, Jianan Qu, Julie Lee Semmelhack","doi":"10.1101/2024.09.08.611846","DOIUrl":"https://doi.org/10.1101/2024.09.08.611846","url":null,"abstract":"Most animals with two eyes combine the inputs to achieve binocular vision, which can serve numerous functions, and is particularly useful in hunting prey. However, the mechanisms by which visual information from the two eyes are combined remain largely unknown. To address this question, we identified the binocular neurons that respond to prey in zebrafish (bino-PRNs). These neurons respond specifically to prey, and their activity is enhanced during hunting. To explore the relationship between bino-PRNs and hunting, we optogenetically induced hunting and found that the bino-PRNs receive excitatory input during hunting. To determine the role of the bino-PRNs in behavior, we optogenetically activated them, and found that they promote forward prey capture swims. Our results support a model where bino-PRNs integrate sensory information from the two eyes with hunting state information to drive approach toward prey in the binocular zone.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.08.611942
Shruti D Marathe, Nixon M Abraham
Pheromone signaling is pivotal in driving social and reproductive behaviors of rodents. Learning and memorizing the pheromone locations involve olfactory subsystems. To study the neural basis of this behavior, we trained female heterozygous knockouts of GluA2 (AMPAR subunit) and NR1 (NMDAR subunit), targeting GAD65 interneuron population, in a pheromone place preference learning assay. We observed memory loss of pheromone locations on early and late recall periods, pointing towards the possible role of ionotropic glutamate receptors (iGluRs), and thereby the synaptic inhibition in pheromone location learning. Correlated changes were observed in the expression levels of activity-regulated cytoskeletal (Arc) protein, which is critical for memory consolidation, in the associated brain areas. Further, to probe the involvement of main olfactory bulb (MOB) and accessory olfactory bulb (AOB) in pheromone location learning, we knocked out NR1 and GluA2 from MOB and/or AOB neuronal circuits by stereotaxic injection of Cre-dependent AAV5 viral particles. Perturbing the inhibitory circuits of MOB and AOB & AOB-alone resulted in the loss of pheromone location memory. These results confirm the role of iGluRs and the synaptic inhibition exerted by the interneuron network of AOB in regulating learning and memory of pheromone locations.
{"title":"Synaptic inhibition in the accessory olfactory bulb regulates pheromone location learning and memory","authors":"Shruti D Marathe, Nixon M Abraham","doi":"10.1101/2024.09.08.611942","DOIUrl":"https://doi.org/10.1101/2024.09.08.611942","url":null,"abstract":"Pheromone signaling is pivotal in driving social and reproductive behaviors of rodents. Learning and memorizing the pheromone locations involve olfactory subsystems. To study the neural basis of this behavior, we trained female heterozygous knockouts of GluA2 (AMPAR subunit) and NR1 (NMDAR subunit), targeting GAD65 interneuron population, in a pheromone place preference learning assay. We observed memory loss of pheromone locations on early and late recall periods, pointing towards the possible role of ionotropic glutamate receptors (iGluRs), and thereby the synaptic inhibition in pheromone location learning. Correlated changes were observed in the expression levels of activity-regulated cytoskeletal (Arc) protein, which is critical for memory consolidation, in the associated brain areas. Further, to probe the involvement of main olfactory bulb (MOB) and accessory olfactory bulb (AOB) in pheromone location learning, we knocked out NR1 and GluA2 from MOB and/or AOB neuronal circuits by stereotaxic injection of Cre-dependent AAV5 viral particles. Perturbing the inhibitory circuits of MOB and AOB & AOB-alone resulted in the loss of pheromone location memory. These results confirm the role of iGluRs and the synaptic inhibition exerted by the interneuron network of AOB in regulating learning and memory of pheromone locations.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.06.611755
Santiago Ojea Ramos, Candela Medina, Maria del Carmen Krwczyk, Julieta Millan, Arturo Romano, Maria Veronica Baez, Francisco Urbano, Mariano Martin Boccia, Mariana Feld
Extensive research has focused on extracellular-signal regulated kinase 1/2 (ERK) phosphorylation in different memory and plasticity models. However, the precise mechanism by which ERK activity leads to memory stabilization and restabilization remains largely elusive, and little is known about the role of ERK 1/2 dimerization in those processes. ERK dimerization is critical for the binding and activation of extranuclear targets, some of which have been strongly associated with these processes. Here we report for the first time that ERK2 dimerization occurs in the context of the rodent nervous system and plays a critical role in plasticity and memory processes. ERK2 dimerization was blocked by DEL-22379 (DEL), a recently developed specific ERK dimerization inhibitor in mice hippocampus in vivo. Moreover, DEL impaired high frequency stimulation-induced long-term potentiation in acute hippocampal slices. However, inhibitory avoidance (IA) memory reactivation induced a significant decrease of ERK2 dimerization in hippocampi from weak IA-trained mice. Noteworthily, intrahippocampal infusion of the inhibitor after memory reactivation had a surprising bidirectional effect: while it blocked reconsolidation of a strong IA memory, the opposite effect was observed on reconsolidation of a weak IA memory, resulting in its enhancement. Although more research is needed, these initial findings suggest a relevant role of ERK dimerization in plasticity and memory.
{"title":"Role of ERK2 dimerization in synaptic plasticity and memory","authors":"Santiago Ojea Ramos, Candela Medina, Maria del Carmen Krwczyk, Julieta Millan, Arturo Romano, Maria Veronica Baez, Francisco Urbano, Mariano Martin Boccia, Mariana Feld","doi":"10.1101/2024.09.06.611755","DOIUrl":"https://doi.org/10.1101/2024.09.06.611755","url":null,"abstract":"Extensive research has focused on extracellular-signal regulated kinase 1/2 (ERK) phosphorylation in different memory and plasticity models. However, the precise mechanism by which ERK activity leads to memory stabilization and restabilization remains largely elusive, and little is known about the role of ERK 1/2 dimerization in those processes. ERK dimerization is critical for the binding and activation of extranuclear targets, some of which have been strongly associated with these processes. Here we report for the first time that ERK2 dimerization occurs in the context of the rodent nervous system and plays a critical role in plasticity and memory processes. ERK2 dimerization was blocked by DEL-22379 (DEL), a recently developed specific ERK dimerization inhibitor in mice hippocampus in vivo. Moreover, DEL impaired high frequency stimulation-induced long-term potentiation in acute hippocampal slices. However, inhibitory avoidance (IA) memory reactivation induced a significant decrease of ERK2 dimerization in hippocampi from weak IA-trained mice. Noteworthily, intrahippocampal infusion of the inhibitor after memory reactivation had a surprising bidirectional effect: while it blocked reconsolidation of a strong IA memory, the opposite effect was observed on reconsolidation of a weak IA memory, resulting in its enhancement.\u0000Although more research is needed, these initial findings suggest a relevant role of ERK dimerization in plasticity and memory.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.06.611733
Max Horrocks, Jennifer L Mohn, Santiago Jaramillo
Psychedelics are known to induce profound perceptual distortions, yet the neural mechanisms underlying these effects, particularly within the auditory system, remain poorly understood. In this study, we investigated the effects of the psychedelic compound 2,5-Dimethoxy-4-iodoamphetamine (DOI), a serotonin 2A receptor agonist, on the activity of neurons in the auditory cortex of awake mice. We examined whether DOI administration alters sound-frequency tuning, variability in neural responses, and deviance detection (a neural process reflecting the balance between top-down and bottom-up processing). Our results show that while DOI does not alter the frequency selectivity of auditory cortical neurons in a consistent manner, it increases trial-by-trial variability in responses and consistently diminishes the neural distinction between expected (standard) and unexpected (oddball) stimuli. This reduction in deviance detection was primarily driven by a decrease in the response to oddball sounds, suggesting that DOI dampens the auditory cortex's sensitivity to unexpected events. These findings provide insights into how psychedelics disrupt sensory processing and shed light on the neural mechanisms underlying the altered perception of auditory stimuli observed in the psychedelic state.
众所周知，迷幻药会诱发严重的知觉失真，但这些影响（尤其是在听觉系统中）的神经机制仍然鲜为人知。在这项研究中，我们研究了迷幻化合物 2,5-二甲氧基-4-碘苯丙胺（DOI）（一种血清素 2A 受体激动剂）对清醒小鼠听觉皮层神经元活动的影响。我们研究了服用 DOI 是否会改变声频调谐、神经反应的变异性和偏差检测（一种反映自上而下和自下而上处理之间平衡的神经过程）。我们的研究结果表明，虽然 DOI 不会以一致的方式改变听觉皮层神经元的频率选择性，但它会增加每次试验的反应变异性，并持续减少预期刺激（标准）和意外刺激（奇异刺激）之间的神经区分。这种偏差检测的降低主要是由对怪声反应的降低所驱动的，这表明 DOI 会抑制听觉皮层对意外事件的敏感性。这些发现为迷幻药如何扰乱感官处理提供了见解，并阐明了在迷幻状态下观察到的听觉刺激感知改变的神经机制。
{"title":"The serotonergic psychedelic DOI impairs deviance detection in the auditory cortex","authors":"Max Horrocks, Jennifer L Mohn, Santiago Jaramillo","doi":"10.1101/2024.09.06.611733","DOIUrl":"https://doi.org/10.1101/2024.09.06.611733","url":null,"abstract":"Psychedelics are known to induce profound perceptual distortions, yet the neural mechanisms underlying these effects, particularly within the auditory system, remain poorly understood. In this study, we investigated the effects of the psychedelic compound 2,5-Dimethoxy-4-iodoamphetamine (DOI), a serotonin 2A receptor agonist, on the activity of neurons in the auditory cortex of awake mice. We examined whether DOI administration alters sound-frequency tuning, variability in neural responses, and deviance detection (a neural process reflecting the balance between top-down and bottom-up processing). Our results show that while DOI does not alter the frequency selectivity of auditory cortical neurons in a consistent manner, it increases trial-by-trial variability in responses and consistently diminishes the neural distinction between expected (standard) and unexpected (oddball) stimuli. This reduction in deviance detection was primarily driven by a decrease in the response to oddball sounds, suggesting that DOI dampens the auditory cortex's sensitivity to unexpected events. These findings provide insights into how psychedelics disrupt sensory processing and shed light on the neural mechanisms underlying the altered perception of auditory stimuli observed in the psychedelic state.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.06.18.599524
Johannes Wetekam, Nell Gotta, Luciana Lopez-Jury, Julio Hechavarria, Manfred Koessl
Auditory deviance detection, the neural process by which unexpected stimuli are identified within repetitive acoustic environments, is crucial for survival. While this phenomenon has been extensively studied in the cortex, recent evidence indicates that it also occurs in subcortical regions, including the inferior colliculus (IC). However, compared to animal studies, research on subcortical deviance detection in humans is often constrained by methodological limitations, leaving several important questions unanswered. This study aims to overcome some of these limitations by employing auditory brainstem responses (ABRs) to investigate the earliest neural correlates of deviance detection in humans, with a focus on the IC. We presented healthy participants with low- and high-frequency chirps in an oddball paradigm and observed significant deviance detection effects in the ABR, specifically when low-frequency chirps were used as deviants within a context of high-frequency standards. These effects manifested as larger and faster ABRs to deviant stimuli, with the strongest responses occurring at higher stimulation rates. Our findings suggest that the human IC exhibits rapid, stimulus-specific deviance detection with differential modulation of response amplitude and latency. The data indicate that the temporal dynamics of novelty detection in humans align well with the data reported in animals, helping to bridge the gap between animal and human research. By uncovering previously unknown characteristics of subcortical deviance detection in humans, this study highlights the value of ABR recordings with excellent temporal resolution in investigating subcortical deviance detection processes.
听觉偏差检测是在重复的声学环境中识别意外刺激的神经过程，对于生存至关重要。虽然这种现象已在大脑皮层得到广泛研究，但最近的证据表明，它也发生在皮层下区域，包括下丘（IC）。然而，与动物研究相比，有关人类皮层下偏差检测的研究往往受到方法论限制，导致一些重要问题悬而未决。本研究旨在通过使用听觉脑干反应（ABRs）来研究人类偏差检测的最早神经相关性，重点是 IC，从而克服其中的一些局限性。我们在一个怪人范例中向健康参与者展示了低频和高频鸣叫，并在 ABR 中观察到了显著的偏差检测效应，特别是当低频鸣叫被用作高频标准背景下的偏差时。这些效应表现为对偏差刺激的 ABR 更大、更快，刺激频率越高，反应越强烈。我们的研究结果表明，人类集成电路表现出快速、刺激特异性的偏差检测，并对反应幅度和延迟进行不同的调节。这些数据表明，人类新奇事物检测的时间动态与动物报告的数据非常吻合，有助于缩小动物和人类研究之间的差距。通过揭示人类皮层下偏差检测以前未知的特征，这项研究强调了时间分辨率极高的 ABR 记录在研究皮层下偏差检测过程中的价值。
{"title":"Rapid and Stimulus-Specific Deviance Detection in the Human Inferior Colliculus","authors":"Johannes Wetekam, Nell Gotta, Luciana Lopez-Jury, Julio Hechavarria, Manfred Koessl","doi":"10.1101/2024.06.18.599524","DOIUrl":"https://doi.org/10.1101/2024.06.18.599524","url":null,"abstract":"Auditory deviance detection, the neural process by which unexpected stimuli are identified within repetitive acoustic environments, is crucial for survival. While this phenomenon has been extensively studied in the cortex, recent evidence indicates that it also occurs in subcortical regions, including the inferior colliculus (IC). However, compared to animal studies, research on subcortical deviance detection in humans is often constrained by methodological limitations, leaving several important questions unanswered. This study aims to overcome some of these limitations by employing auditory brainstem responses (ABRs) to investigate the earliest neural correlates of deviance detection in humans, with a focus on the IC. We presented healthy participants with low- and high-frequency chirps in an oddball paradigm and observed significant deviance detection effects in the ABR, specifically when low-frequency chirps were used as deviants within a context of high-frequency standards. These effects manifested as larger and faster ABRs to deviant stimuli, with the strongest responses occurring at higher stimulation rates. Our findings suggest that the human IC exhibits rapid, stimulus-specific deviance detection with differential modulation of response amplitude and latency. The data indicate that the temporal dynamics of novelty detection in humans align well with the data reported in animals, helping to bridge the gap between animal and human research. By uncovering previously unknown characteristics of subcortical deviance detection in humans, this study highlights the value of ABR recordings with excellent temporal resolution in investigating subcortical deviance detection processes.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.11.612349
Hannah L Stone, Jamie L Mitchell, Mia Fuentes-Jimenez, Jasmine E Tran, Jason D Yeatman, Maya Yablonski
Inferior frontal cortex (IFC) is a critical region for reading and language. This part of the cortex is highly heterogeneous in its structural and functional organization and shows high variability across individuals. Despite decades of research, the relationship between specific IFC regions and reading skill remains unclear. To shed light on the function of IFC in reading, we aim to (1) characterize the functional landscape of text-selective responses in the IFC, while accounting for interindividual variability; and (2) examine how text-selective regions in the IFC relate to reading proficiency. To this end, children with a wide range of reading ability (N=66; age 7-14 years, 34 female, 32 male) completed functional MRI scans while performing two tasks on text and non-text visual stimuli. Importantly, both tasks do not explicitly require reading, and can be performed on all visual stimuli. This design allows us to tease apart stimulus-driven responses from task-driven responses and examine where in the IFC task and stimulus interact. We were able to identify three anatomically-distinct, text-selective clusters of activation in the IFC, in the inferior frontal sulcus (IFS), and dorsal and ventral precentral gyrus (PrG). These three regions showed a strong task effect that was highly specific to text. Furthermore, text-selectivity in the IFS and dorsal PrG was associated with reading proficiency, such that better readers showed higher selectivity to text. These findings suggest that text-selective regions in the IFC are sensitive to both stimulus and task, and highlight the importance of this region for proficient reading.
{"title":"Anatomically distinct regions in the inferior frontal cortex are modulated by task and reading skill","authors":"Hannah L Stone, Jamie L Mitchell, Mia Fuentes-Jimenez, Jasmine E Tran, Jason D Yeatman, Maya Yablonski","doi":"10.1101/2024.09.11.612349","DOIUrl":"https://doi.org/10.1101/2024.09.11.612349","url":null,"abstract":"Inferior frontal cortex (IFC) is a critical region for reading and language. This part of the cortex is highly heterogeneous in its structural and functional organization and shows high variability across individuals. Despite decades of research, the relationship between specific IFC regions and reading skill remains unclear. To shed light on the function of IFC in reading, we aim to (1) characterize the functional landscape of text-selective responses in the IFC, while accounting for interindividual variability; and (2) examine how text-selective regions in the IFC relate to reading proficiency. To this end, children with a wide range of reading ability (N=66; age 7-14 years, 34 female, 32 male) completed functional MRI scans while performing two tasks on text and non-text visual stimuli. Importantly, both tasks do not explicitly require reading, and can be performed on all visual stimuli. This design allows us to tease apart stimulus-driven responses from task-driven responses and examine where in the IFC task and stimulus interact. We were able to identify three anatomically-distinct, text-selective clusters of activation in the IFC, in the inferior frontal sulcus (IFS), and dorsal and ventral precentral gyrus (PrG). These three regions showed a strong task effect that was highly specific to text. Furthermore, text-selectivity in the IFS and dorsal PrG was associated with reading proficiency, such that better readers showed higher selectivity to text. These findings suggest that text-selective regions in the IFC are sensitive to both stimulus and task, and highlight the importance of this region for proficient reading.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.09.612106
Alicia R. Lane, Noah E. Scher, Shatabdi Bhattacharjee, Stephanie A. Zlatic, Anne M. Roberts, Avanti Gokhale, Kaela S. Singleton, Duc M. Duong, Mike McKenna, William L. Liu, Alina Baiju, Felix G Rivera Moctezuma, Tommy Tran, Atit Patel, Lauren B. Clayton, Michael J. Petris, Levi B. Wood, Anupam Patgiri, Alysia D. Vrailas-Mortimer, Daniel N. Cox, Blaine R. Roberts, Erica Werner, Victor Faundez
Rare inherited diseases caused by mutations in the copper transporters SLC31A1 (CTR1) or ATP7A induce copper deficiency in the brain and throughout the body, causing seizures and neurodegeneration in infancy. The mechanistic underpinnings of such neuropathology remains unclear. Here, we characterized the molecular mechanisms by which neuronal cells respond to copper depletion in multiple genetic model systems. Targeted deletion of CTR1 in neuroblastoma clonal cell lines produced copper deficiency that was associated with compromised copper-dependent Golgi and mitochondrial enzymes and a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis revealed simultaneous upregulation of mTORC1 and S6K signaling, along with reduced PERK signaling in CTR1 KO cells. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis as measured by puromycin labeling. These effects of copper depletion were corroborated by spatial transcriptomic profiling of the cerebellum of Atp7aflx/Y :: Vil1Cre/+ mice, in which copper-deficient Purkinje cells exhibited upregulated protein synthesis machinery and expression of mTORC1-S6K pathway genes. We tested whether increased activity of mTOR in copper-deficient neurons was adaptive or deleterious by genetic epistasis experiments in Drosophila. Copper deficiency dendritic phenotypes in class IV neurons are partially rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper depletion.
{"title":"Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration","authors":"Alicia R. Lane, Noah E. Scher, Shatabdi Bhattacharjee, Stephanie A. Zlatic, Anne M. Roberts, Avanti Gokhale, Kaela S. Singleton, Duc M. Duong, Mike McKenna, William L. Liu, Alina Baiju, Felix G Rivera Moctezuma, Tommy Tran, Atit Patel, Lauren B. Clayton, Michael J. Petris, Levi B. Wood, Anupam Patgiri, Alysia D. Vrailas-Mortimer, Daniel N. Cox, Blaine R. Roberts, Erica Werner, Victor Faundez","doi":"10.1101/2024.09.09.612106","DOIUrl":"https://doi.org/10.1101/2024.09.09.612106","url":null,"abstract":"Rare inherited diseases caused by mutations in the copper transporters <em>SLC31A1</em> (CTR1) or <em>ATP7A</em> induce copper deficiency in the brain and throughout the body, causing seizures and neurodegeneration in infancy. The mechanistic underpinnings of such neuropathology remains unclear. Here, we characterized the molecular mechanisms by which neuronal cells respond to copper depletion in multiple genetic model systems. Targeted deletion of CTR1 in neuroblastoma clonal cell lines produced copper deficiency that was associated with compromised copper-dependent Golgi and mitochondrial enzymes and a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis revealed simultaneous upregulation of mTORC1 and S6K signaling, along with reduced PERK signaling in CTR1 KO cells. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis as measured by puromycin labeling. These effects of copper depletion were corroborated by spatial transcriptomic profiling of the cerebellum of <em>Atp7a<sup>flx/Y</sup> :: Vil1<sup>Cre/+</sup></em> mice, in which copper-deficient Purkinje cells exhibited upregulated protein synthesis machinery and expression of mTORC1-S6K pathway genes. We tested whether increased activity of mTOR in copper-deficient neurons was adaptive or deleterious by genetic epistasis experiments in <em>Drosophila</em>. Copper deficiency dendritic phenotypes in class IV neurons are partially rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper depletion.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1101/2024.09.10.612324
Taylor J Woodward, Diana Dimen, Emily Fender Sizemore, Sarah Stockman, Fezaan Kazi, Serge Luquet, Ken Mackie, Istvan Katona, Andrea G Hohmann
The endocannabinoid (eCB) system regulates stress responsiveness and hypothalamic-pituitary-adrenal (HPA) axis activity. The enzyme N-acyl phosphatidylethanolamine phospholipase-D (NAPE-PLD) is primarily responsible for the synthesis of the endocannabinoid signaling molecule anandamide (AEA) and other structurally related lipid signaling molecules known as N-acylethanolamines (NAEs). However, little is known about how activity of this enzyme affects behavior. As AEA plays a regulatory role in stress adaptation, we hypothesized that reducing synthesis of AEA and other NAEs would dysregulate stress reactivity. To test this hypothesis, we evaluated wild type (WT) and NAPE-PLD knockout (KO) mice in behavioral assays that assess stress responsiveness and anxiety-like behavior. NAPE-PLD KO mice exhibited anxiety-like behaviors in the open field test and the light-dark box test after a period of single housing. NAPE-PLD KO mice exhibited a heightened freezing response to the testing environment that was further enhanced by exposure to 2,3,5-trimethyl-3-thiazoline (TMT) predator odor. NAPE-PLD KO mice exhibited an exaggerated freezing response at baseline but blunted response to TMT when compared to WT mice. NAPE-PLD KO mice also exhibited a context-dependent dysregulation of HPA axis in response to TMT in the paraventricular hypothalamic nucleus at a neuronal level, as measured by c-Fos immunohistochemstry. Male, but not female, NAPE-PLD knockout mice showed higher levels of circulating corticosterone relative to same-sex wildtype mice in response to TMT exposure, suggesting a sexually-dimorphic dysregulation of the HPA axis at the hormonal level. Together, these findings suggest the enzymatic activity of NAPE-PLD regulates emotional resilience and recovery from both acute and sustained stress.
{"title":"Genetic deletion of NAPE-PLD induces context-dependent dysregulation of anxiety-like behaviors, stress responsiveness, and HPA-axis functionality in mice","authors":"Taylor J Woodward, Diana Dimen, Emily Fender Sizemore, Sarah Stockman, Fezaan Kazi, Serge Luquet, Ken Mackie, Istvan Katona, Andrea G Hohmann","doi":"10.1101/2024.09.10.612324","DOIUrl":"https://doi.org/10.1101/2024.09.10.612324","url":null,"abstract":"The endocannabinoid (eCB) system regulates stress responsiveness and hypothalamic-pituitary-adrenal (HPA) axis activity. The enzyme N-acyl phosphatidylethanolamine phospholipase-D (NAPE-PLD) is primarily responsible for the synthesis of the endocannabinoid signaling molecule anandamide (AEA) and other structurally related lipid signaling molecules known as N-acylethanolamines (NAEs). However, little is known about how activity of this enzyme affects behavior. As AEA plays a regulatory role in stress adaptation, we hypothesized that reducing synthesis of AEA and other NAEs would dysregulate stress reactivity. To test this hypothesis, we evaluated wild type (WT) and NAPE-PLD knockout (KO) mice in behavioral assays that assess stress responsiveness and anxiety-like behavior. NAPE-PLD KO mice exhibited anxiety-like behaviors in the open field test and the light-dark box test after a period of single housing. NAPE-PLD KO mice exhibited a heightened freezing response to the testing environment that was further enhanced by exposure to 2,3,5-trimethyl-3-thiazoline (TMT) predator odor. NAPE-PLD KO mice exhibited an exaggerated freezing response at baseline but blunted response to TMT when compared to WT mice. NAPE-PLD KO mice also exhibited a context-dependent dysregulation of HPA axis in response to TMT in the paraventricular hypothalamic nucleus at a neuronal level, as measured by c-Fos immunohistochemstry. Male, but not female, NAPE-PLD knockout mice showed higher levels of circulating corticosterone relative to same-sex wildtype mice in response to TMT exposure, suggesting a sexually-dimorphic dysregulation of the HPA axis at the hormonal level. Together, these findings suggest the enzymatic activity of NAPE-PLD regulates emotional resilience and recovery from both acute and sustained stress.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1101/2024.09.11.612475
Andres Varani, Caroline Mailhes-Hamon, Romain W Sala, Sarah Fouda, Jimena L Frontera, Clément Léna, Daniela Popa
Motor skill learning is a complex and gradual process that involves the cortex and basal ganglia, both crucial for the acquisition and long-term retention of skills. The cerebellum, which rapidly learns to adjust the movement, connects to the motor cortex and the striatum via the ventral and intralaminar thalamus respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. Using a targeted chemogenetic inhibition that preserves the motor abilities, we found that cerebellar nuclei neurons projecting to the intralaminar thalamus contribute to learning and expression, while cerebellar nuclei neurons projecting to the ventral thalamus contribute to offline consolidation. Asymptotic performance, however, required each type of neurons. Thus, our results show that cerebellar neurons belonging to two parallel cerebello-thalamic pathways play distinct, but complementary, roles functioning on different timescales and both necessary for motor skill learning.
{"title":"Multiple Functions of Cerebello-Thalamic Neurons in Learning and Offline Consolidation of a Motor Skill in mice.","authors":"Andres Varani, Caroline Mailhes-Hamon, Romain W Sala, Sarah Fouda, Jimena L Frontera, Clément Léna, Daniela Popa","doi":"10.1101/2024.09.11.612475","DOIUrl":"https://doi.org/10.1101/2024.09.11.612475","url":null,"abstract":"Motor skill learning is a complex and gradual process that involves the cortex and basal ganglia, both crucial for the acquisition and long-term retention of skills. The cerebellum, which rapidly learns to adjust the movement, connects to the motor cortex and the striatum via the ventral and intralaminar thalamus respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. Using a targeted chemogenetic inhibition that preserves the motor abilities, we found that cerebellar nuclei neurons projecting to the intralaminar thalamus contribute to learning and expression, while cerebellar nuclei neurons projecting to the ventral thalamus contribute to offline consolidation. Asymptotic performance, however, required each type of neurons. Thus, our results show that cerebellar neurons belonging to two parallel cerebello-thalamic pathways play distinct, but complementary, roles functioning on different timescales and both necessary for motor skill learning.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1101/2024.09.09.610935
Hanna den Bakker, Fabian Kloosterman
The hippocampus is known to encode spatial information and reactivate experienced trajectories during sharp-wave ripple events. These events are thought to be key time-points at which information about learned trajectories is transferred to the neocortex for long-term storage. It is unclear, however, how this information may be transferred and integrated in downstream cortical regions. In this study, we performed high-density probe recordings across the full depth of the medial prefrontal cortex and in the hippocampus simultaneously in rats while they were performing a task of spatial navigation. We find that neurons in the medial prefrontal cortex encode spatial information and reliably predict upcoming choice on a maze, and we find that a subset of neurons in the mPFC is modulated by hippocampal sharp-wave ripples. However, the neurons that are involved in predicting upcoming choice are not the neurons that are modulated by hippocampal sharp-wave ripples. This indicates that the integration of spatial information requires the collaboration of different specialized populations of neurons.
{"title":"Neurons in the medial prefrontal cortex that are not modulated by hippocampal sharp-wave ripples are involved in spatial tuning and signaling upcoming choice.","authors":"Hanna den Bakker, Fabian Kloosterman","doi":"10.1101/2024.09.09.610935","DOIUrl":"https://doi.org/10.1101/2024.09.09.610935","url":null,"abstract":"The hippocampus is known to encode spatial information and reactivate experienced trajectories during sharp-wave ripple events. These events are thought to be key time-points at which information about learned trajectories is transferred to the neocortex for long-term storage. It is unclear, however, how this information may be transferred and integrated in downstream cortical regions. In this study, we performed high-density probe recordings across the full depth of the medial prefrontal cortex and in the hippocampus simultaneously in rats while they were performing a task of spatial navigation. We find that neurons in the medial prefrontal cortex encode spatial information and reliably predict upcoming choice on a maze, and we find that a subset of neurons in the mPFC is modulated by hippocampal sharp-wave ripples. However, the neurons that are involved in predicting upcoming choice are not the neurons that are modulated by hippocampal sharp-wave ripples. This indicates that the integration of spatial information requires the collaboration of different specialized populations of neurons.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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