Pub Date : 2024-09-19DOI: 10.1101/2024.09.17.613591
Michael J Bennington, Ashlee S Liao, Ravesh Sukhnandan, Bidisha Kundu, Stephen M Rogers, Jeffrey P Gill, Jeffrey M McManus, Gregory P Sutton, Hillel J Chiel, Victoria A Webster-Wood
To understand how behaviors arise in animals, it is necessary to investigate both the neural circuits and the biomechanics of the periphery. A tractable model system for studying multifunctional control is the feeding apparatus of the marine mollusk Aplysia californica. Previous in silico and in roboto models have investigated how the nervous and muscular systems interact in this system. However, these models are still limited in their ability to match in vivo data both qualitatively and quantitatively. We introduce a new neuromechanical model of Aplysia feeding that combines a modified version of a previously developed neural model with a novel biomechanical model that better reflects the anatomy and kinematics of Aplysia feeding. The model was calibrated using a combination of previously measured biomechanical parameters and hand-tuning to behavioral data. Using this model, simulation feeding experiments were conducted, and the resulting behavioral metrics were compared to animal data. The model successfully produces three key behaviors seen in Aplysia and demonstrates a good quantitative agreement with biting and swallowing behaviors. Additional work is needed to match rejection behavior quantitatively and to reflect qualitative observations related to the relative contributions of two key muscles, the hinge and I3. Future improvements will focus on incorporating the effects of deformable 3D structures in the simulated buccal mass.
{"title":"Incorporating buccal mass planar mechanics and anatomical features improves neuromechanical modeling of Aplysia feeding behavior","authors":"Michael J Bennington, Ashlee S Liao, Ravesh Sukhnandan, Bidisha Kundu, Stephen M Rogers, Jeffrey P Gill, Jeffrey M McManus, Gregory P Sutton, Hillel J Chiel, Victoria A Webster-Wood","doi":"10.1101/2024.09.17.613591","DOIUrl":"https://doi.org/10.1101/2024.09.17.613591","url":null,"abstract":"To understand how behaviors arise in animals, it is necessary to investigate both the neural circuits and the biomechanics of the periphery. A tractable model system for studying multifunctional control is the feeding apparatus of the marine mollusk Aplysia californica. Previous in silico and in roboto models have investigated how the nervous and muscular systems interact in this system. However, these models are still limited in their ability to match in vivo data both qualitatively and quantitatively. We introduce a new neuromechanical model of Aplysia feeding that combines a modified version of a previously developed neural model with a novel biomechanical model that better reflects the anatomy and kinematics of Aplysia feeding. The model was calibrated using a combination of previously measured biomechanical parameters and hand-tuning to behavioral data. Using this model, simulation feeding experiments were conducted, and the resulting behavioral metrics were compared to animal data. The model successfully produces three key behaviors seen in Aplysia and demonstrates a good quantitative agreement with biting and swallowing behaviors. Additional work is needed to match rejection behavior quantitatively and to reflect qualitative observations related to the relative contributions of two key muscles, the hinge and I3. Future improvements will focus on incorporating the effects of deformable 3D structures in the simulated buccal mass.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250202","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 : 2024-09-19DOI: 10.1101/2024.09.17.613581
Ninette Simonian, Micah Alan Johnson, Caitlin Lynch, Geena Wang, Velu Kumaravel, Taylor Kuhn, Felix Schoeller, Nicco Reggente
Background Virtual reality (VR) and immersive technologies offer benefits in anxiety reduction and mood enhancement. This study examines the effectiveness of rain stimuli and guided breathwork delivered through MindGym, a novel reflective chamber, and a traditional VR headset. Methods Physiological measures, cognitive, and trait and state assessments were collected for 126 participants, randomly assigned to VR (Breathwork), VR (Rain), MindGym (Breathwork), or MindGym (Rain) conditions. Results Significant improvements in cognitive performance, anxiety, and mood were observed across all groups, with an 11.67% reduction in anxiety (STAI). Breathwork conditions showed a greater decrease in breath rate compared to Rain. MODTAS, DPES, and Immersion positively moderated experiences of Awe and Ego Dissolution. Openness interacted with stimuli type, with higher openness associated with greater anxiety reduction in Breathwork conditions. No significant differences were found between MindGym and VR in effectiveness or immersion. Conclusions MindGym and VR demonstrated promise as acute anxiolytics, with MindGym-generated content maintaining effectiveness when translated to VR. This highlights MindGym's potential as a versatile content creation platform for immersive, anxiety-reducing experiences. Individual differences moderated treatment responses, suggesting opportunities for personalized interventions. Future research should explore complex MindGym experiences and adaptation to various delivery systems for accessible, effective anxiety management tools.
{"title":"Contrasting Cognitive, Behavioral, and Physiological Responses to Breathwork vs. Naturalistic Stimuli in Reflective Chamber and VR Headset Environments","authors":"Ninette Simonian, Micah Alan Johnson, Caitlin Lynch, Geena Wang, Velu Kumaravel, Taylor Kuhn, Felix Schoeller, Nicco Reggente","doi":"10.1101/2024.09.17.613581","DOIUrl":"https://doi.org/10.1101/2024.09.17.613581","url":null,"abstract":"Background Virtual reality (VR) and immersive technologies offer benefits in anxiety reduction and mood enhancement. This study examines the effectiveness of rain stimuli and guided breathwork delivered through MindGym, a novel reflective chamber, and a traditional VR headset.\u0000Methods\u0000Physiological measures, cognitive, and trait and state assessments were collected for 126 participants, randomly assigned to VR (Breathwork), VR (Rain), MindGym (Breathwork), or MindGym (Rain) conditions.\u0000Results Significant improvements in cognitive performance, anxiety, and mood were observed across all groups, with an 11.67% reduction in anxiety (STAI). Breathwork conditions showed a greater decrease in breath rate compared to Rain. MODTAS, DPES, and Immersion positively moderated experiences of Awe and Ego Dissolution. Openness interacted with stimuli type, with higher openness associated with greater anxiety reduction in Breathwork conditions. No significant differences were found between MindGym and VR in effectiveness or immersion.\u0000Conclusions MindGym and VR demonstrated promise as acute anxiolytics, with MindGym-generated content maintaining effectiveness when translated to VR. This highlights MindGym's potential as a versatile content creation platform for immersive, anxiety-reducing experiences. Individual differences moderated treatment responses, suggesting opportunities for personalized interventions. Future research should explore complex MindGym experiences and adaptation to various delivery systems for accessible, effective anxiety management tools.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250157","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 : 2024-09-19DOI: 10.1101/2024.09.02.610815
Keith B Hengen, Woodrow L Shew
Brains face selective pressure to optimize computation, broadly defined. This optimization is achieved by myriad mechanisms and processes that influence the brain's computational state. These include development, plasticity, homeostasis, and more. Despite enormous variability over time and between individuals, do these diverse mechanisms converge on the same set-point? Is there a universal computational optimum around which the healthy brain tunes itself? The criticality hypothesis posits such a unified computational set-point. Criticality is a special dynamical brain state, defined by internally-generated multi-scale, marginally-stable dynamics which maximize many features of information processing. The first experimental support for this hypothesis emerged two decades ago, and evidence has accumulated at an accelerating pace, despite a contentious history. Here, we lay out the logic of criticality as a general computational end-point and systematically review experimental evidence for the hypothesis. We perform a meta-analysis of 143 datasets from manuscripts published between 2003 and 2024. To our surprise, we find that a long-standing controversy in the field is the product of a simple methodological choice that has no bearing on underlying dynamics. Our results suggest that a new generation of research can leverage the concept of criticality---as a unifying principle of brain function--to accelerate our understanding of behavior, cognition, and disease.
{"title":"Is criticality a unified set-point of brain function?","authors":"Keith B Hengen, Woodrow L Shew","doi":"10.1101/2024.09.02.610815","DOIUrl":"https://doi.org/10.1101/2024.09.02.610815","url":null,"abstract":"Brains face selective pressure to optimize computation, broadly defined. This optimization is achieved by myriad mechanisms and processes that influence the brain's computational state. These include development, plasticity, homeostasis, and more. Despite enormous variability over time and between individuals, do these diverse mechanisms converge on the same set-point? Is there a universal computational optimum around which the healthy brain tunes itself? The criticality hypothesis posits such a unified computational set-point. Criticality is a special dynamical brain state, defined by internally-generated multi-scale, marginally-stable dynamics which maximize many features of information processing. The first experimental support for this hypothesis emerged two decades ago, and evidence has accumulated at an accelerating pace, despite a contentious history. Here, we lay out the logic of criticality as a general computational end-point and systematically review experimental evidence for the hypothesis. We perform a meta-analysis of 143 datasets from manuscripts published between 2003 and 2024. To our surprise, we find that a long-standing controversy in the field is the product of a simple methodological choice that has no bearing on underlying dynamics. Our results suggest that a new generation of research can leverage the concept of criticality---as a unifying principle of brain function--to accelerate our understanding of behavior, cognition, and disease.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250225","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 : 2024-09-19DOI: 10.1101/2024.09.17.613603
Yukako Yamane, Yuzhe Li, Keita Matsumoto, Ryota Kanai, Miles Desforges, Carlos Enrique Gutierrez, Kenji Doya
Advancements in calcium indicators and optical techniques have made optical neural recording a common tool in neuroscience. As the volume of optical neural recording data grows, streamlining the data analysis pipelines for image preprocessing, signal extraction, and subsequent neural activity analyses becomes essential. There are a number of challenges in optical neural data analysis. 1) The quality of original and processed data needs to be carefully examined at each step. 2) As there are numerous image preprocessing, cell extraction, and activity analysis algorithms, each with pros and cons, experimenters need to implement or install them to compare and select optimal methods and parameters for each step of processing. 3) To ensure the reproducibility of the research, each analysis step needs to be recorded in a systematic way. 4) For data sharing and meta-analyses, adoption of standard data formats and processing protocols is required. To address these challenges, we developed Optical Neuroimage Studio (OptiNiSt) (https://github.com/oist/optinist), a framework for intuitively creating calcium data analysis pipelines that are scalable, extendable, and reproducible. OptiNiSt includes the following features. 1) Researchers can easily create analysis pipelines by selecting multiple processing modules, tuning their parameters, and visualizing the results at each step through a graphic user interface in a web browser. 2) In addition to common analytical tools that are pre-installed, new analysis algorithms in Python can be easily added. 3) Once a processing pipeline is designed, the entire workflow with its modules and parameters are stored in a YAML file, which makes the pipeline reproducible and deployable on high-performance computing clusters. 4) OptiNiSt can read image data in a variety of file formats and store the analysis results in NWB (Neurodata Without Borders), a standard data format for data sharing. We expect that this framework will be helpful in standardizing optical neural data analysis protocols.
{"title":"Optical Neuroimage Studio (OptiNiSt): intuitive, scalable, extendable framework for optical neuroimage data analysis","authors":"Yukako Yamane, Yuzhe Li, Keita Matsumoto, Ryota Kanai, Miles Desforges, Carlos Enrique Gutierrez, Kenji Doya","doi":"10.1101/2024.09.17.613603","DOIUrl":"https://doi.org/10.1101/2024.09.17.613603","url":null,"abstract":"Advancements in calcium indicators and optical techniques have made optical neural recording a common tool in neuroscience. As the volume of optical neural recording data grows, streamlining the data analysis pipelines for image preprocessing, signal extraction, and subsequent neural activity analyses becomes essential. There are a number of challenges in optical neural data analysis. 1) The quality of original and processed data needs to be carefully examined at each step. 2) As there are numerous image preprocessing, cell extraction, and activity analysis algorithms, each with pros and cons, experimenters need to implement or install them to compare and select optimal methods and parameters for each step of processing. 3) To ensure the reproducibility of the research, each analysis step needs to be recorded in a systematic way. 4) For data sharing and meta-analyses, adoption of standard data formats and processing protocols is required. To address these challenges, we developed Optical Neuroimage Studio (OptiNiSt) (https://github.com/oist/optinist), a framework for intuitively creating calcium data analysis pipelines that are scalable, extendable, and reproducible. OptiNiSt includes the following features. 1) Researchers can easily create analysis pipelines by selecting multiple processing modules, tuning their parameters, and visualizing the results at each step through a graphic user interface in a web browser. 2) In addition to common analytical tools that are pre-installed, new analysis algorithms in Python can be easily added. 3) Once a processing pipeline is designed, the entire workflow with its modules and parameters are stored in a YAML file, which makes the pipeline reproducible and deployable on high-performance computing clusters. 4) OptiNiSt can read image data in a variety of file formats and store the analysis results in NWB (Neurodata Without Borders), a standard data format for data sharing. We expect that this framework will be helpful in standardizing optical neural data analysis protocols.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250160","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 : 2024-09-19DOI: 10.1101/2024.09.18.613653
Jonathan W VanRyzin, Kathryn J Reissner
Social behaviors are critical for survival and fitness of a species, and maladaptive social behaviors are frequently associated with neurodevelopmental and psychiatric disorders. As such, the neural circuits and cellular mechanisms driving social behaviors inform critical processes contributing to both health and disease. In particular, the nucleus accumbens (NAc) is a key hub for the integration of both social and non-social information required for successful social interactions and reward motivated behaviors. While astrocytes within the NAc have a recognized role in modulating neural activity, their influence over social behavior is yet undefined. To address this question, we manipulated NAc astrocyte signaling and determined effects on social interactions. NAc core astrocytes bidirectionally influenced social behavior in rats; agonism of astrocyte-specific hM3D(Gq) DREADD receptors increased social interaction time in the social interaction test and increased social preference in the 3-chamber test. Conversely, decreasing intracellular calcium signaling in astrocytes with viral expression of hPMCA reduced both social interaction and social preference in these tests. These results suggest that NAc astrocytes actively participate in the regulation of social behavior and highlight a putative role for astrocytes in disorders characterized by social dysfunction.
{"title":"Nucleus accumbens astrocytes bidirectionally modulate social behavior","authors":"Jonathan W VanRyzin, Kathryn J Reissner","doi":"10.1101/2024.09.18.613653","DOIUrl":"https://doi.org/10.1101/2024.09.18.613653","url":null,"abstract":"Social behaviors are critical for survival and fitness of a species, and maladaptive social behaviors are frequently associated with neurodevelopmental and psychiatric disorders. As such, the neural circuits and cellular mechanisms driving social behaviors inform critical processes contributing to both health and disease. In particular, the nucleus accumbens (NAc) is a key hub for the integration of both social and non-social information required for successful social interactions and reward motivated behaviors. While astrocytes within the NAc have a recognized role in modulating neural activity, their influence over social behavior is yet undefined. To address this question, we manipulated NAc astrocyte signaling and determined effects on social interactions. NAc core astrocytes bidirectionally influenced social behavior in rats; agonism of astrocyte-specific hM3D(Gq) DREADD receptors increased social interaction time in the social interaction test and increased social preference in the 3-chamber test. Conversely, decreasing intracellular calcium signaling in astrocytes with viral expression of hPMCA reduced both social interaction and social preference in these tests. These results suggest that NAc astrocytes actively participate in the regulation of social behavior and highlight a putative role for astrocytes in disorders characterized by social dysfunction.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250200","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 : 2024-09-19DOI: 10.1101/2024.09.18.613666
Nguyet Le, Sherine Awad, Isabella Palazzo, Thanh Hoang, Seth Blackshaw
Retinal Muller glia in cold-blooded vertebrates can reprogram into neurogenic progenitors to replace neurons lost to injury, but mammals lack this ability. While recent studies have shown that transgenic overexpression of neurogenic bHLH factors and glial-specific disruption of NFI family transcription factors and Notch signaling induce neurogenic competence in mammalian Muller glia, induction of neurogenesis in wildtype glia has thus far proven elusive. Here we report that viral overexpression of the pluripotency factor Oct4 (Pou5f1) induces transdifferentiation of wildtype mouse Muller glia into bipolar neurons, and stimulates this process synergistically in parallel with Notch loss of function. Single cell multiomic analysis shows that Oct4 overexpression leads to widespread changes in gene expression and chromatin accessibility, inducing activity of both the neurogenic transcription factor Rfx4 and the Yamanaka factors Sox2 and Klf4. This study demonstrates that viral overexpression of Oct4 induces neurogenic competence in wildtype retinal Muller glia, identifying mechanisms that could be used in cell-based therapies for treating retinal dystrophies.
{"title":"Viral-mediated Oct4 overexpression and inhibition of Notch signaling synergistically induce neurogenic competence in mammalian Muller glia.","authors":"Nguyet Le, Sherine Awad, Isabella Palazzo, Thanh Hoang, Seth Blackshaw","doi":"10.1101/2024.09.18.613666","DOIUrl":"https://doi.org/10.1101/2024.09.18.613666","url":null,"abstract":"Retinal Muller glia in cold-blooded vertebrates can reprogram into neurogenic progenitors to replace neurons lost to injury, but mammals lack this ability. While recent studies have shown that transgenic overexpression of neurogenic bHLH factors and glial-specific disruption of NFI family transcription factors and Notch signaling induce neurogenic competence in mammalian Muller glia, induction of neurogenesis in wildtype glia has thus far proven elusive. Here we report that viral overexpression of the pluripotency factor Oct4 (Pou5f1) induces transdifferentiation of wildtype mouse Muller glia into bipolar neurons, and stimulates this process synergistically in parallel with Notch loss of function. Single cell multiomic analysis shows that Oct4 overexpression leads to widespread changes in gene expression and chromatin accessibility, inducing activity of both the neurogenic transcription factor Rfx4 and the Yamanaka factors Sox2 and Klf4. This study demonstrates that viral overexpression of Oct4 induces neurogenic competence in wildtype retinal Muller glia, identifying mechanisms that could be used in cell-based therapies for treating retinal dystrophies.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250201","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 : 2024-09-19DOI: 10.1101/2024.09.18.613685
Hyukmin Kim, Harun Noristiani, Jinbin Zhai, Meredith Manire, Shuxin Li, Jian Zhong, Young-Jin Son
Primary sensory axons fail to regenerate into the spinal cord following dorsal root injury leading to permanent sensory deficits. Re-entry is prevented at the dorsal root entry zone (DREZ), the CNS-PNS interface. Current approaches for promoting DR regeneration across the DREZ have had some success, but sustained, long-distance regeneration, particularly of large-diameter myelinated axons, still remains a formidable challenge. We have previously shown that induced expression of constitutively active B-RAF (kaBRAF) enhanced the regenerative competence of injured DRG neurons in adult mice. In this study, we investigated whether robust intraspinal regeneration can be achieved after a cervical DR injury by selective expression of kaBRAF alone or in combination with deletion of the myelin-associated inhibitors or neuron-intrinsic growth suppressors (PTEN or SOCS3). We found that kaBRAF promoted some axon regeneration across the DREZ but did not produce significant functional recovery by two months. Supplementary deletion of Nogo, MAG, and OMgp only modestly improved kaBRAF-induced regeneration. Deletion of PTEN or SOCS3 individually or in combination failed to promote any growth across the DREZ. In marked contrast, simultaneous deletion of PTEN, but not SOCS3, dramatically enhanced kaBRAF-mediated regeneration enabling many more axons to penetrate the DREZ and grow deep into the spinal cord. This study shows that dual activation of BRAF-MEK-ERK and PI3K-Akt-mTOR signaling is an effective strategy to stimulate robust intraspinal DR regeneration.
{"title":"Deleting PTEN, but not SOCS3 or myelin inhibitors, robustly boosts BRAF-elicited intraspinal regeneration of peripheral sensory axons","authors":"Hyukmin Kim, Harun Noristiani, Jinbin Zhai, Meredith Manire, Shuxin Li, Jian Zhong, Young-Jin Son","doi":"10.1101/2024.09.18.613685","DOIUrl":"https://doi.org/10.1101/2024.09.18.613685","url":null,"abstract":"Primary sensory axons fail to regenerate into the spinal cord following dorsal root injury leading to permanent sensory deficits. Re-entry is prevented at the dorsal root entry zone (DREZ), the CNS-PNS interface. Current approaches for promoting DR regeneration across the DREZ have had some success, but sustained, long-distance regeneration, particularly of large-diameter myelinated axons, still remains a formidable challenge. We have previously shown that induced expression of constitutively active B-RAF (kaBRAF) enhanced the regenerative competence of injured DRG neurons in adult mice. In this study, we investigated whether robust intraspinal regeneration can be achieved after a cervical DR injury by selective expression of kaBRAF alone or in combination with deletion of the myelin-associated inhibitors or neuron-intrinsic growth suppressors (PTEN or SOCS3). We found that kaBRAF promoted some axon regeneration across the DREZ but did not produce significant functional recovery by two months. Supplementary deletion of Nogo, MAG, and OMgp only modestly improved kaBRAF-induced regeneration. Deletion of PTEN or SOCS3 individually or in combination failed to promote any growth across the DREZ. In marked contrast, simultaneous deletion of PTEN, but not SOCS3, dramatically enhanced kaBRAF-mediated regeneration enabling many more axons to penetrate the DREZ and grow deep into the spinal cord. This study shows that dual activation of BRAF-MEK-ERK and PI3K-Akt-mTOR signaling is an effective strategy to stimulate robust intraspinal DR regeneration.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250163","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 : 2024-09-19DOI: 10.1101/2024.09.18.613669
Gina Picchiarelli, Anne Wienand, Salim Megat, Amr Aly, Marije Been, Nibha Mishra, Saskia Hutten, Erin Sternburg, Pierre Cauchy, Stephane Dieterle, Marica Catinozzi, Valerie Demais, Laura Tzeplaeff, Annemarie Huebers, Dagmar Zeuschner, Angela Rosenbohm, Albert C Ludolph, Anne-Laurence Boutillier, Tobias Boeckers, Dorothee Dormann, Maria Demestre, Chantal Sellier, Clotilde Lagier-Tourenne, Erik Storkebaum, Luc Dupuis
FUS is an RNA binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show that ALS-associated FUS mutations lead to ultrastructural defects in muscle of FUS-ALS patients, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionary-conserved cell autonomous function of FUS in muscle development. Mechanistically, FUS is required for transcription of MEF2 dependent genes, binds to the promoter of genes bound by ETS transcription factors in particular ETV5 and co-activates transcription of MEF2 dependent genes with ETV5. FUS phase separates with ETV5 and MEF2A, and MEF2A binding to FUS is potentiated by ETV5. Last, Etv5 haploinsufficiency exacerbates muscle weakness in a mouse model of FUS-ALS. These findings establish FUS as an essential protein for skeletal muscle structure through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.
{"title":"FUS controls muscle differentiation and structure through LLPS mediated recruitment of MEF2 and ETV5","authors":"Gina Picchiarelli, Anne Wienand, Salim Megat, Amr Aly, Marije Been, Nibha Mishra, Saskia Hutten, Erin Sternburg, Pierre Cauchy, Stephane Dieterle, Marica Catinozzi, Valerie Demais, Laura Tzeplaeff, Annemarie Huebers, Dagmar Zeuschner, Angela Rosenbohm, Albert C Ludolph, Anne-Laurence Boutillier, Tobias Boeckers, Dorothee Dormann, Maria Demestre, Chantal Sellier, Clotilde Lagier-Tourenne, Erik Storkebaum, Luc Dupuis","doi":"10.1101/2024.09.18.613669","DOIUrl":"https://doi.org/10.1101/2024.09.18.613669","url":null,"abstract":"FUS is an RNA binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show that ALS-associated FUS mutations lead to ultrastructural defects in muscle of FUS-ALS patients, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionary-conserved cell autonomous function of FUS in muscle development. Mechanistically, FUS is required for transcription of MEF2 dependent genes, binds to the promoter of genes bound by ETS transcription factors in particular ETV5 and co-activates transcription of MEF2 dependent genes with ETV5. FUS phase separates with ETV5 and MEF2A, and MEF2A binding to FUS is potentiated by ETV5. Last, Etv5 haploinsufficiency exacerbates muscle weakness in a mouse model of FUS-ALS. These findings establish FUS as an essential protein for skeletal muscle structure through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250155","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 : 2024-09-19DOI: 10.1101/2024.09.18.613794
Piplu Bhuiyan, Wenjia Zhang, Ge Liang, Bailin Jiang, Robert Vera, Rebecca Chae, Kyulee Kim, Lauren St. Louis, Ying Wang, Jia Liu, Huafeng Wei
This study compares the changes in lithium concentrations in the brain and blood following the administration of intranasal or oral lithium chloride (LiCl) dissolved in either Ryanodex Formulation Vehicle (RFV) or water, as well as the therapeutic effectiveness and side effects of intranasal versus oral lithium chloride (LiCl) in RFV, and their mechanisms for inhibiting inflammation and pyroptosis in 5xFAD Alzheimers Disease (AD) mice brains. In comparison to oral LiCl in RFV, intranasal LiCl in RFV decreased lithium blood concentrations but increased brain concentrations and duration, resulting in a significantly higher brain/blood lithium concentration ratio than intranasal LiCl in water or oral LiCl in RFV in young adult mice. Intranasal LiCl in RFV robustly protects both memory loss and depressive behavior in both young and old 5xFAD mice, with no side effects or thyroid/kidney toxicity. In fact, intranasal LiCl in RFV protects against age-dependent kidney function impairment in 5xFAD mice. This lithium mediated neuroprotection was associated with its potent effects on the inhibition of InsP3R-1 Ca2+ channel receptor increase, ameliorating pathological inflammation and activation of the pyroptosis pathway, and the associated loss of synapse proteins. Intranasal LiCl in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and treat both dementia and depression with no or minimal side effects/organ toxicity, particular in AD.
{"title":"Intranasal Lithium Chloride Nanoparticles Inhibit Inflammatory Pyroptosis in Brains and Ameliorate Memory Loss and Depression Behavior in 5xFAD mice","authors":"Piplu Bhuiyan, Wenjia Zhang, Ge Liang, Bailin Jiang, Robert Vera, Rebecca Chae, Kyulee Kim, Lauren St. Louis, Ying Wang, Jia Liu, Huafeng Wei","doi":"10.1101/2024.09.18.613794","DOIUrl":"https://doi.org/10.1101/2024.09.18.613794","url":null,"abstract":"This study compares the changes in lithium concentrations in the brain and blood following the administration of intranasal or oral lithium chloride (LiCl) dissolved in either Ryanodex Formulation Vehicle (RFV) or water, as well as the therapeutic effectiveness and side effects of intranasal versus oral lithium chloride (LiCl) in RFV, and their mechanisms for inhibiting inflammation and pyroptosis in 5xFAD Alzheimers Disease (AD) mice brains. In comparison to oral LiCl in RFV, intranasal LiCl in RFV decreased lithium blood concentrations but increased brain concentrations and duration, resulting in a significantly higher brain/blood lithium concentration ratio than intranasal LiCl in water or oral LiCl in RFV in young adult mice. Intranasal LiCl in RFV robustly protects both memory loss and depressive behavior in both young and old 5xFAD mice, with no side effects or thyroid/kidney toxicity. In fact, intranasal LiCl in RFV protects against age-dependent kidney function impairment in 5xFAD mice. This lithium mediated neuroprotection was associated with its potent effects on the inhibition of InsP3R-1 Ca2+ channel receptor increase, ameliorating pathological inflammation and activation of the pyroptosis pathway, and the associated loss of synapse proteins. Intranasal LiCl in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and treat both dementia and depression with no or minimal side effects/organ toxicity, particular in AD.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250197","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 : 2024-09-19DOI: 10.1101/2024.09.18.613710
Safwan K Hyder, Willian Lazarini-Lopes, Jonathan Toib, Gabrielle Williams, Alex Sukharev, Patrick A Forcelli
Engagement of the striatum (caudate/putamen) and other basal ganglia nuclei during seizures was first observed over 75 years ago. Basal ganglia output nuclei, and the substantia nigra pars reticulata, in particular, have well-established anti-seizure effects across a large array of experimental models. However, striatal control fo seizures is understudied. To address this gap, we used optogenetic approaches to activate and inactivate neurons in the dorsal striatum of Sprague-Dawley rats submitted to the gamma-butyrolactone (GBL) model of absence epilepsy, amygdala kindling model of temporal lobe epilepsy, and pilocarpine-induced Status Epilepticus (SE). All tests were performed on a within-subject basis. Animals were tested in two different light frequencies (5 Hz and 100 Hz). Open-loop (continuous light delivery) optogenetic activation of the dorsal striatal neurons robustly suppressed seizures in all models. On the other hand, optogenetic silencing of the dorsal striatal neurons increased absence seizure expression and facilitated SE onset but had no effect on kindled limbic seizures. In the GBL model, we also verified if the closed-loop strategy (light delivery in response to seizure detection) would be enough to induce antiseizure effects. On-demand light delivery in ChR2-expressing animals reduced SWD duration, while the same approach in ArchT-expressing animals increased SWD duration. These results demonstrated previously unrecognized anti-absence effects associated with striatal continuous and on-demand neuromodulation. Together, these findings document a robust, bidirectional role of the dorsal striatum in the control of seizure generation and propagation in a variety of seizure models, including focal seizure onset and generalized seizures.
{"title":"Optogenetic stimulation of dorsal striatum bidirectionally controls seizures","authors":"Safwan K Hyder, Willian Lazarini-Lopes, Jonathan Toib, Gabrielle Williams, Alex Sukharev, Patrick A Forcelli","doi":"10.1101/2024.09.18.613710","DOIUrl":"https://doi.org/10.1101/2024.09.18.613710","url":null,"abstract":"Engagement of the striatum (caudate/putamen) and other basal ganglia nuclei during seizures was first observed over 75 years ago. Basal ganglia output nuclei, and the substantia nigra pars reticulata, in particular, have well-established anti-seizure effects across a large array of experimental models. However, striatal control fo seizures is understudied. To address this gap, we used optogenetic approaches to activate and inactivate neurons in the dorsal striatum of Sprague-Dawley rats submitted to the gamma-butyrolactone (GBL) model of absence epilepsy, amygdala kindling model of temporal lobe epilepsy, and pilocarpine-induced Status Epilepticus (SE). All tests were performed on a within-subject basis. Animals were tested in two different light frequencies (5 Hz and 100 Hz). Open-loop (continuous light delivery) optogenetic activation of the dorsal striatal neurons robustly suppressed seizures in all models. On the other hand, optogenetic silencing of the dorsal striatal neurons increased absence seizure expression and facilitated SE onset but had no effect on kindled limbic seizures. In the GBL model, we also verified if the closed-loop strategy (light delivery in response to seizure detection) would be enough to induce antiseizure effects. On-demand light delivery in ChR2-expressing animals reduced SWD duration, while the same approach in ArchT-expressing animals increased SWD duration. These results demonstrated previously unrecognized anti-absence effects associated with striatal continuous and on-demand neuromodulation. Together, these findings document a robust, bidirectional role of the dorsal striatum in the control of seizure generation and propagation in a variety of seizure models, including focal seizure onset and generalized seizures.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250205","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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