@misc{15385,
abstract = {Relevant information about the data can be found in the 'Readme_Data.txt' file.
A previous version of the publication can be found on BioRxiv: https://www.biorxiv.org/content/10.1101/2022.10.11.511691v4
and published in Plos Biology (2024)},
author = {Burnett, Laura and Koppensteiner, Peter and Symonova, Olga and Masson, Tomas and Vega Zuniga, Tomas A and Contreras, Ximena and Rülicke, Thomas and Shigemoto, Ryuichi and Novarino, Gaia and Jösch, Maximilian A},
keywords = {ASD, periaqueductal gray, perception, behavior, potassium channels},
publisher = {Institute of Science and Technology Austria},
title = {{Shared behavioural impairments in visual perception and place avoidance across different autism models are driven by periaqueductal grey hypoexcitability in Setd5 haploinsufficient mice}},
doi = {10.15479/AT:ISTA:15385},
year = {2024},
}
@article{17091,
abstract = {DNA sequences are connected to genes and functions in the developing and adult brain},
author = {Novarino, Gaia and Bock, Christoph},
issn = {1095-9203},
journal = {Science},
number = {6698},
pages = {860--861},
publisher = {AAAS},
title = {{Mapping the brain’s gene-regulatory maze}},
doi = {10.1126/science.adp4663},
volume = {384},
year = {2024},
}
@article{17142,
abstract = {Despite the diverse genetic origins of autism spectrum disorders (ASDs), affected individuals share strikingly similar and correlated behavioural traits that include perceptual and sensory processing challenges. Notably, the severity of these sensory symptoms is often predictive of the expression of other autistic traits. However, the origin of these perceptual deficits remains largely elusive. Here, we show a recurrent impairment in visual threat perception that is similarly impaired in 3 independent mouse models of ASD with different molecular aetiologies. Interestingly, this deficit is associated with reduced avoidance of threatening environments—a nonperceptual trait. Focusing on a common cause of ASDs, the Setd5 gene mutation, we define the molecular mechanism. We show that the perceptual impairment is caused by a potassium channel (Kv1)-mediated hypoexcitability in a subcortical node essential for the initiation of escape responses, the dorsal periaqueductal grey (dPAG). Targeted pharmacological Kv1 blockade rescued both perceptual and place avoidance deficits, causally linking seemingly unrelated trait deficits to the dPAG. Furthermore, we show that different molecular mechanisms converge on similar behavioural phenotypes by demonstrating that the autism models Cul3 and Ptchd1, despite having similar behavioural phenotypes, differ in their functional and molecular alteration. Our findings reveal a link between rapid perception controlled by subcortical pathways and appropriate learned interactions with the environment and define a nondevelopmental source of such deficits in ASD.},
author = {Burnett, Laura and Koppensteiner, Peter and Symonova, Olga and Masson, Tomas and Vega Zuniga, Tomas A and Contreras, Ximena and Rülicke, Thomas and Shigemoto, Ryuichi and Novarino, Gaia and Jösch, Maximilian A},
issn = {1545-7885},
journal = {PLoS Biology},
publisher = {Public Library of Science},
title = {{Shared behavioural impairments in visual perception and place avoidance across different autism models are driven by periaqueductal grey hypoexcitability in Setd5 haploinsufficient mice}},
doi = {10.1371/journal.pbio.3002668},
volume = {22},
year = {2024},
}
@article{18779,
abstract = {Unsupervised segmentation in biological and non-biological images is only partially resolved. Segmentation either requires arbitrary thresholds or large teaching datasets. Here, we propose a spatial autocorrelation method based on Local Moran’s I coefficient to differentiate signal, background, and noise in any type of image. The method, originally described for geoinformatics, does not require a predefined intensity threshold or teaching algorithm for image segmentation and allows quantitative comparison of samples obtained in different conditions. It utilizes relative intensity as well as spatial information of neighboring elements to select spatially contiguous groups of pixels. We demonstrate that Moran’s method outperforms threshold-based method in both artificially generated as well as in natural images especially when background noise is substantial. This superior performance can be attributed to the exclusion of false positive pixels resulting from isolated, high intensity pixels in high noise conditions. To test the method’s power in real situation, we used high power confocal images of the somatosensory thalamus immunostained for Kv4.2 and Kv4.3 (A-type) voltage-gated potassium channels in mice. Moran’s method identified high-intensity Kv4.2 and Kv4.3 ion channel clusters in the thalamic neuropil. Spatial distribution of these clusters displayed strong correlation with large sensory axon terminals of subcortical origin. The unique association of the special presynaptic terminals and a postsynaptic voltage-gated ion channel cluster was confirmed with electron microscopy. These data demonstrate that Moran’s method is a rapid, simple image segmentation method optimal for variable and high noise conditions.},
author = {Dávid, Csaba and Giber, Kristóf and Szigeti, Margit Katalin and Köllő, Mihály and Nusser, Zoltan and Acsady, Laszlo},
issn = {2050-084X},
journal = {eLife},
publisher = {eLife Sciences Publications},
title = {{A novel image segmentation method based on spatial autocorrelation identifies A-type potassium channel clusters in the thalamus}},
doi = {10.7554/elife.89361},
volume = {12},
year = {2024},
}
@article{19446,
abstract = {This Comment explores new approaches to enrich large-scale population data, including incorporating macro-environmental and digital health measures.},
author = {Nees, Frauke and Renner, Paul and Holz, Nathalie E. and Polemiti, Elli and Siehl, Sebastian and Hese, Sören and Schepanski, Kerstin and Schumann, Gunter and Walter, Henrik and Heinz, Andreas and Ralser, Markus and Twardziok, Sven and Vaidya, Nilakshi and Bernas, Antoine and Serin, Emin and Jentsch, Marcel and Hitchen, Esther and Kebir, Hedi and Lett, Tristram A. and Roy, Jean Charles and Eils, Roland and Taron, Ulrike Helene and Schütz, Tatjana and Banks, Jamie and Banaschewski, Tobias and Jansone, Karina and Christmann, Nina and Meyer-Lindenberg, Andreas and Tost, Heike and Holz, Nathalie and Schwarz, Emanuel and Stringaris, Argyris and Neidhart, Maja and Seefried, Beke and Aden, Rieke and Andreassen, Ole A. and Westlye, Lars T. and Van Der Meer, Dennis and Fernandez, Sara and Kjelkenes, Rikka and Ask, Helga and Rapp, Michael and Tschorn, Mira and Böttger, Sarah Jane and Marquand, Andre and Novarino, Gaia and Marr, Lena and Slater, Mel and Viapiana, Guillem Feixas and Orosa, Francisco Eiroa and Gallego, Jaime and Pastor, Alvaro and Forstner, Andreas J. and Hoffmann, Per and Nöthen, Markus M. and Claus, Isabelle and Miller, Abigail and Mathey, Carina M. and Heilmann-Heimbach, Stefanie and Sommer, Peter and Patraskaki, Myrto and Wilbertz, Johannes and Schmitt, Karen and Jirsa, Viktor and Petkoski, Spase and Pitel, Séverine and Otten, Lisa and Athanasiadis, Anastasios Polykarpos and Pearmund, Charlie and Spanlang, Bernhard and Alvarez, Elena and Sanchez, Mavi and Giner, Arantxa and Jia, Tianye and Gong, Yanting and Xia, Yunman and Chang, Xiao and Calhoun, Vince and Liu, Jingyu and Schwalber, Ameli and Thompson, Paul and Clinton, Nicholas and Desrivières, Sylvane and Young, Allan H. and Stahl, Bernd and Ogoh, George},
issn = {2731-6076},
journal = {Nature Mental Health},
number = {10},
pages = {1124--1127},
publisher = {Springer Nature},
title = {{Large-scale population data enrichment in mental health research}},
doi = {10.1038/s44220-024-00316-z},
volume = {2},
year = {2024},
}
@article{20039,
abstract = {This Comment presents a high-level protocol for data harmonization within large cohorts, in which it postulates four main steps including (1) expert review, (2) pre-statistical harmonization, (3) statistical harmonization, and (4) validation.},
author = {Neidhart, Maja and Kjelkenes, Rikka and Jansone, Karina and Rehák Bučková, Barbora and Holz, Nathalie and Nees, Frauke and Walter, Henrik and Schumann, Gunter and Rapp, Michael A. and Banaschewski, Tobias and Schwarz, Emanuel and Marquand, Andre and Ogoh, George and Stahl, Bernd and Young, Allan H. and Desrivières, Sylvane and Clinton, Nicholas and Thompson, Paul and Schwalber, Ameli and Liu, Jingyu and Calhoun, Vince and Chang, Xiao and Xia, Yunman and Gong, Yanting and Jia, Tianye and Renner, Paul and Hese, Sören and Giner, Arantxa and Sanchez, Mavi and Alvarez, Elena and Spanlang, Bernhard and Pearmund, Charlie and Athanasiadis, Anastasios Polykarpos and Otten, Lisa and Pitel, Séverine and Petkoski, Spase and Jirsa, Viktor and Schmitt, Karen and Wilbertz, Johannes and Patraskaki, Myrto and Sommer, Peter and Heilmann-Heimbach, Stefanie and Mathey, Carina M. and Miller, Abigail and Claus, Isabelle and Nöthen, Markus M. and Hoffmann, Per and Forstner, Andreas J. and Pastor, Alvaro and Gallego, Jaime and Orosa, Francisco Eiroa and Viapiana, Guillem Feixas and Slater, Mel and Marr, Lena and Novarino, Gaia and Böttger, Sarah Jane and Tschorn, Mira and Rapp, Michael and Ask, Helga and Fernandez, Sara and Van Der Meer, Dennis and Westlye, Lars T. and Andreassen, Ole A. and Aden, Rieke and Seefried, Beke and Siehl, Sebastian and Nees, Frauke and Stringaris, Argyris and Tost, Heike and Meyer-Lindenberg, Andreas and Christmann, Nina and Banks, Jamie and Schepanski, Kerstin and Schütz, Tatjana and Taron, Ulrike Helene and Eils, Roland and Roy, Jean Charles and Lett, Tristram A. and Kebir, Hedi and Polemiti, Elli and Hitchen, Esther and Jentsch, Marcel and Serin, Emin and Bernas, Antoine and Vaidya, Nilakshi and Twardziok, Sven and Ralser, Markus and Heinz, Andreas},
issn = {2731-6076},
journal = {Nature Mental Health},
number = {10},
pages = {1134--1137},
publisher = {Springer Nature},
title = {{A protocol for data harmonization in large cohorts}},
doi = {10.1038/s44220-024-00315-0},
volume = {2},
year = {2024},
}
@article{20156,
abstract = {Integrative analyses that incorporate different levels of ‘-omics’ data represent a powerful tool for deciphering the biological mechanisms that underlie environmental influences on mental health and disease. This Comment highlights various aspects of such multi-omics approaches, using the example of the EU-funded environMENTAL project.},
author = {Desrivières, Sylvane and Miller, Abigail and Mathey, Carina M. and Yu, Xinyang and Chen, Di and Agunbiade, Kofoworola and Heilmann-Heimbach, Stefanie and Forstner, Andreas J. and Schumann, Gunter and Hoffmann, Per and Nöthen, Markus M. and Ogoh, George and Stahl, Bernd and Young, Allan H. and Clinton, Nicholas and Thompson, Paul and Schwalber, Ameli and Liu, Jingyu and Calhoun, Vince and Chang, Xiao and Xia, Yunman and Gong, Yanting and Jia, Tianye and Renner, Paul and Hese, Sören and Giner, Arantxa and Sanchez, Mavi and Alvarez, Elena and Spanlang, Bernhard and Pearmund, Charlie and Athanasiadis, Anastasios Polykarpos and Otten, Lisa and Pitel, Séverine and Petkoski, Spase and Jirsa, Viktor and Schmitt, Karen and Wilbertz, Johannes and Patraskaki, Myrto and Sommer, Peter and Claus, Isabelle and Pastor, Alvaro and Gallego, Jaime and Orosa, Francisco Eiroa and Viapiana, Guillem Feixas and Slater, Mel and Marr, Lena and Novarino, Gaia and Marquand, Andre and Böttger, Sarah Jane and Tschorn, Mira and Rapp, Michael and Ask, Helga and Kjelkenes, Rikka and Fernandez, Sara and Van Der Meer, Dennis and Westlye, Lars T. and Andreassen, Ole A. and Aden, Rieke and Seefried, Beke and Siehl, Sebastian and Nees, Frauke and Neidhart, Maja and Stringaris, Argyris and Schwarz, Emanuel and Holz, Nathalie and Tost, Heike and Meyer-Lindenberg, Andreas and Christmann, Nina and Jansone, Karina and Banaschewski, Tobias and Banks, Jamie and Schepanski, Kerstin and Schütz, Tatjana and Taron, Ulrike Helene and Eils, Roland and Roy, Jean Charles and Lett, Tristram A. and Kebir, Hedi and Polemiti, Elli and Hitchen, Esther and Jentsch, Marcel and Serin, Emin and Bernas, Antoine and Vaidya, Nilakshi and Twardziok, Sven and Ralser, Markus and Heinz, Andreas and Walter, Henrik},
issn = {2731-6076},
journal = {Nature Mental Health},
number = {10},
pages = {1131--1133},
publisher = {Springer Nature},
title = {{Multi-omics analyses of the environMENTAL project provide insights into mental health and disease}},
doi = {10.1038/s44220-024-00317-y},
volume = {2},
year = {2024},
}
@article{20157,
abstract = {The focus of much of contemporary research ethics is on compliance with established protocols. However, large data-driven neuroscience research raises new ethical concerns that have no agreed-upon solution. Here we reflect on these challenges and propose better integration of public and patient involvement in this evolving landscape.},
author = {Stahl, Bernd and Ogoh, George and Schumann, Gunter and Walter, Henrik and Stahl, Bernd and Young, Allan H. and Desrivières, Sylvane and Clinton, Nicholas and Thompson, Paul and Schwalber, Ameli and Liu, Jingyu and Calhoun, Vince and Chang, Xiao and Xia, Yunman and Gong, Yanting and Jia, Tianye and Renner, Paul and Hese, Sören and Giner, Arantxa and Sanchez, Mavi and Alvarez, Elena and Spanlang, Bernhard and Pearmund, Charlie and Athanasiadis, Anastasios Polykarpos and Otten, Lisa and Pitel, Séverine and Petkoski, Spase and Jirsa, Viktor and Schmitt, Karen and Wilbertz, Johannes and Patraskaki, Myrto and Sommer, Peter and Heilmann-Heimbach, Stefanie and Mathey, Carina M. and Miller, Abigail and Claus, Isabelle and Nöthen, Markus M. and Hoffmann, Per and Forstner, Andreas J. and Pastor, Alvaro and Gallego, Jaime and Orosa, Francisco Eiroa and Viapiana, Guillem Feixas and Slater, Mel and Marr, Lena and Novarino, Gaia and Marquand, Andre and Böttger, Sarah Jane and Tschorn, Mira and Rapp, Michael and Ask, Helga and Kjelkenes, Rikka and Fernandez, Sara and Van Der Meer, Dennis and Westlye, Lars T. and Andreassen, Ole A. and Aden, Rieke and Seefried, Beke and Siehl, Sebastian and Nees, Frauke and Neidhart, Maja and Stringaris, Argyris and Schwarz, Emanuel and Holz, Nathalie and Tost, Heike and Meyer-Lindenberg, Andreas and Christmann, Nina and Jansone, Karina and Banaschewski, Tobias and Banks, Jamie and Schepanski, Kerstin and Schütz, Tatjana and Taron, Ulrike Helene and Eils, Roland and Roy, Jean Charles and Lett, Tristram A. and Kebir, Hedi and Polemiti, Elli and Hitchen, Esther and Jentsch, Marcel and Serin, Emin and Bernas, Antoine and Vaidya, Nilakshi and Twardziok, Sven and Ralser, Markus and Heinz, Andreas and Walter, Henrik},
issn = {2731-6076},
journal = {Nature Mental Health},
number = {10},
publisher = {Springer Nature},
title = {{Rethinking ethics in interdisciplinary and big data-driven neuroscience projects}},
doi = {10.1038/s44220-024-00320-3},
volume = {2},
year = {2024},
}
@article{17331,
abstract = {Amyloidosis are a group of diseases in which soluble proteins aggregate and deposit in fibrillar conformation extracellularly in tissues. The effectiveness of therapeutic strategies depends on the specific protein involved, being crucial to accurately determine its nature. Moreover, following the diagnosis, the search for the mutation within relatives allows the clinical advice. Here we report the precise diagnosis and explored the possible reasons of the structural pathogenicity for a renal amyloidosis related to a fibrinogen Aα-chain variant. Whole-exome sequencing and GATK calling pipeline were leveraged to characterize the protein variant present in a patient with kidney failure. Bioinformatics strategies were applied to suggest potential explanations of the variants aggregation. Our pipeline allowed the identification of a single-point variant of fibrinogen Aα-chain, which opened the possibility of curative transplantation. In silico structural analysis suggested that the pathogenicity of the variant may be attributed to a heightened susceptibility to yield a peptide prone to deposit as an oligomer with a β-sheet structure. Exploiting the comprehensive coverage of whole-genome sequencing, we managed to fill a vacant stage in the diagnosis of hereditary amyloidosis and to stimulate the advancement in biomedicine.},
author = {Cattaneo, Elizabeth R and Gisonno, Romina A and Abba, Martín C and Santana, Marianela and Rosú, Silvana A and Nucifora, Elsa and Aguirre, María A and Giordani, María C and Tricerri, M. Alejandra and Ramella, Nahuel A},
issn = {1097-0134},
journal = {Proteins: Structure, Function and Bioinformatics},
number = {12},
pages = {1366--1374},
publisher = {Wiley},
title = {{Hereditary amyloidosis: Insights into a fibrinogen A variant protein}},
doi = {10.1002/prot.26732},
volume = {92},
year = {2024},
}
@unpublished{18677,
abstract = {The information-processing capability of the brain’s cellular network depends on the physical wiring pattern between neurons and their molecular and functional characteristics. Mapping neurons and resolving their individual synaptic connections can be achieved by volumetric imaging at nanoscale resolution with dense cellular labeling. Light microscopy is uniquely positioned to visualize specific molecules but dense, synapse-level circuit reconstruction by light microscopy has been out of reach due to limitations in resolution, contrast, and volumetric imaging capability. Here we developed light-microscopy based connectomics (LICONN). We integrated specifically engineered hydrogel embedding and expansion with comprehensive deep-learning based segmentation and analysis of connectivity, thus directly incorporating molecular information in synapse-level brain tissue reconstructions. LICONN will allow synapse-level brain tissue phenotyping in biological experiments in a readily adoptable manner.},
author = {Tavakoli, Mojtaba and Lyudchik, Julia and Januszewski, Michał and Vistunou, Vitali and Agudelo Duenas, Nathalie and Vorlaufer, Jakob and Sommer, Christoph M and Kreuzinger, Caroline and Oliveira, Bárbara and Cenameri, Alban and Novarino, Gaia and Jain, Viren and Danzl, Johann G},
booktitle = {bioRxiv},
title = {{Light-microscopy based dense connectomic reconstruction of mammalian brain tissue}},
doi = {10.1101/2024.03.01.582884},
year = {2024},
}
@article{12802,
abstract = {Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.},
author = {Knaus, Lisa and Basilico, Bernadette and Malzl, Daniel and Gerykova Bujalkova, Maria and Smogavec, Mateja and Schwarz, Lena A. and Gorkiewicz, Sarah and Amberg, Nicole and Pauler, Florian and Knittl-Frank, Christian and Tassinari, Marianna and Maulide, Nuno and Rülicke, Thomas and Menche, Jörg and Hippenmeyer, Simon and Novarino, Gaia},
issn = {0092-8674},
journal = {Cell},
keywords = {General Biochemistry, Genetics and Molecular Biology},
number = {9},
pages = {1950--1967.e25},
publisher = {Elsevier},
title = {{Large neutral amino acid levels tune perinatal neuronal excitability and survival}},
doi = {10.1016/j.cell.2023.02.037},
volume = {186},
year = {2023},
}
@phdthesis{13107,
abstract = {Within the human body, the brain exhibits the highest rate of energy consumption amongst all organs, with the majority of generated ATP being utilized to sustain neuronal activity. Therefore, the metabolism of the mature cerebral cortex is geared towards preserving metabolic homeostasis whilst generating significant amounts of energy. This requires a precise interplay between diverse metabolic pathways, spanning from a tissue-wide scale to the level of individual neurons. Disturbances to this delicate metabolic equilibrium, such as those resulting from maternal malnutrition
or mutations affecting metabolic enzymes, often result in neuropathological variants of neurodevelopment. For instance, mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), have been associated with autism and microcephaly. However, despite recent progress in the field, the extent of metabolic restructuring that occurs within the developing brain and the corresponding alterations in nutrient demands during various critical periods remain largely unknown. To investigate this, we performed metabolomic profiling of the murine cerebral cortex to characterize the metabolic state of the forebrain at different developmental stages. We found that the developing cortex undergoes substantial metabolic reprogramming, with specific sets of metabolites displaying stage-specific changes. According to our observations, we determined a distinct temporal period in postnatal development during which the cortex displays heightened reliance on LNAAs. Hence, using a conditional knock-out mouse model, we deleted Slc7a5 in neural cells, allowing us to monitor the impact of a perturbed neuronal metabolic state across multiple developmental stages of corticogenesis. We found that manipulating the levels of essential LNAAs in cortical neurons in vivo affects one particular perinatal developmental period critical for cortical network refinement. Abnormally low intracellular LNAA levels result in cell-autonomous alterations in neuronal lipid metabolism, excitability, and survival during this particular time window. Although most of the effects of Slc7a5 deletion on neuronal physiology are transient, derailment of these processes during this brief but crucial window leads to long-term circuit dysfunction in mice. In conclusion, out data indicate that the cerebral cortex undergoes significant metabolic reorganization during development. This process involves the intricate integration of multiple metabolic pathways to ensure optimal neuronal function throughout different developmental stages. Our findings offer a paradigm for understanding how neurons synchronize the expression of nutrient-related genes with their activity to allow proper brain maturation. Further, our results demonstrate that disruptions in these precisely calibrated metabolic processes during critical periods of brain development may result in neuropathological outcomes in mice and in humans.},
author = {Knaus, Lisa},
issn = {2663-337X},
pages = {147},
publisher = {Institute of Science and Technology Austria},
title = {{The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival}},
doi = {10.15479/at:ista:13107},
year = {2023},
}
@misc{13126,
abstract = {Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here, we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanometer synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS uses fixation-compatible extracellular labeling and optical imaging, including stimulated emission depletion or expansion microscopy, to comprehensively delineate cellular structures. It enables three-dimensional reconstruction of single synapses and mapping of synaptic connectivity by identification and analysis of putative synaptic cleft regions. Applying CATS to the mouse hippocampal mossy fiber circuitry, we reconstructed and quantified the synaptic input and output structure of identified neurons. We furthermore demonstrate applicability to clinically derived human tissue samples, including formalin-fixed paraffin-embedded routine diagnostic specimens, for visualizing the cellular architecture of brain tissue in health and disease.},
author = {Danzl, Johann G},
publisher = {Institute of Science and Technology Austria},
title = {{Research data for the publication "Imaging brain tissue architecture across millimeter to nanometer scales"}},
doi = {10.15479/AT:ISTA:13126},
year = {2023},
}
@article{13168,
abstract = {Urban-living individuals are exposed to many environmental factors that may combine and interact to influence mental health. While individual factors of an urban environment have been investigated in isolation, no attempt has been made to model how complex, real-life exposure to living in the city relates to brain and mental health, and how this is moderated by genetic factors. Using the data of 156,075 participants from the UK Biobank, we carried out sparse canonical correlation analyses to investigate the relationships between urban environments and psychiatric symptoms. We found an environmental profile of social deprivation, air pollution, street network and urban land-use density that was positively correlated with an affective symptom group (r = 0.22, Pperm < 0.001), mediated by brain volume differences consistent with reward processing, and moderated by genes enriched for stress response, including CRHR1, explaining 2.01% of the variance in brain volume differences. Protective factors such as greenness and generous destination accessibility were negatively correlated with an anxiety symptom group (r = 0.10, Pperm < 0.001), mediated by brain regions necessary for emotion regulation and moderated by EXD3, explaining 1.65% of the variance. The third urban environmental profile was correlated with an emotional instability symptom group (r = 0.03, Pperm < 0.001). Our findings suggest that different environmental profiles of urban living may influence specific psychiatric symptom groups through distinct neurobiological pathways.},
author = {Xu, Jiayuan and Liu, Nana and Polemiti, Elli and Garcia-Mondragon, Liliana and Tang, Jie and Liu, Xiaoxuan and Lett, Tristram and Yu, Le and Nöthen, Markus M. and Feng, Jianfeng and Yu, Chunshui and Marquand, Andre and Schumann, Gunter and Walter, Henrik and Heinz, Andreas and Ralser, Markus and Twardziok, Sven and Vaidya, Nilakshi and Serin, Emin and Jentsch, Marcel and Hitchen, Esther and Eils, Roland and Taron, Ulrike Helene and Schütz, Tatjana and Schepanski, Kerstin and Banks, Jamie and Banaschewski, Tobias and Jansone, Karina and Christmann, Nina and Meyer-Lindenberg, Andreas and Tost, Heike and Holz, Nathalie and Schwarz, Emanuel and Stringaris, Argyris and Neidhart, Maja and Nees, Frauke and Siehl, Sebastian and A. Andreassen, Ole and T. Westlye, Lars and Van Der Meer, Dennis and Fernandez, Sara and Kjelkenes, Rikka and Ask, Helga and Rapp, Michael and Tschorn, Mira and Böttger, Sarah Jane and Novarino, Gaia and Marr, Lena and Slater, Mel and Viapiana, Guillem Feixas and Orosa, Francisco Eiroa and Gallego, Jaime and Pastor, Alvaro and Forstner, Andreas and Hoffmann, Per and M. Nöthen, Markus and J. Forstner, Andreas and Claus, Isabelle and Miller, Abbi and Heilmann-Heimbach, Stefanie and Sommer, Peter and Boye, Mona and Wilbertz, Johannes and Schmitt, Karen and Jirsa, Viktor and Petkoski, Spase and Pitel, Séverine and Otten, Lisa and Athanasiadis, Anastasios Polykarpos and Pearmund, Charlie and Spanlang, Bernhard and Alvarez, Elena and Sanchez, Mavi and Giner, Arantxa and Hese, Sören and Renner, Paul and Jia, Tianye and Gong, Yanting and Xia, Yunman and Chang, Xiao and Calhoun, Vince and Liu, Jingyu and Thompson, Paul and Clinton, Nicholas and Desrivieres, Sylvane and H. Young, Allan and Stahl, Bernd and Ogoh, George},
issn = {1546-170X},
journal = {Nature Medicine},
pages = {1456--1467},
publisher = {Springer Nature},
title = {{Effects of urban living environments on mental health in adults}},
doi = {10.1038/s41591-023-02365-w},
volume = {29},
year = {2023},
}
@article{14443,
abstract = {Importance Climate change, pollution, urbanization, socioeconomic inequality, and psychosocial effects of the COVID-19 pandemic have caused massive changes in environmental conditions that affect brain health during the life span, both on a population level as well as on the level of the individual. How these environmental factors influence the brain, behavior, and mental illness is not well known.
Observations A research strategy enabling population neuroscience to contribute to identify brain mechanisms underlying environment-related mental illness by leveraging innovative enrichment tools for data federation, geospatial observation, climate and pollution measures, digital health, and novel data integration techniques is described. This strategy can inform innovative treatments that target causal cognitive and molecular mechanisms of mental illness related to the environment. An example is presented of the environMENTAL Project that is leveraging federated cohort data of over 1.5 million European citizens and patients enriched with deep phenotyping data from large-scale behavioral neuroimaging cohorts to identify brain mechanisms related to environmental adversity underlying symptoms of depression, anxiety, stress, and substance misuse.
Conclusions and Relevance This research will lead to the development of objective biomarkers and evidence-based interventions that will significantly improve outcomes of environment-related mental illness.},
author = {Schumann, Gunter and Andreassen, Ole A. and Banaschewski, Tobias and Calhoun, Vince D. and Clinton, Nicholas and Desrivieres, Sylvane and Brandlistuen, Ragnhild Eek and Feng, Jianfeng and Hese, Soeren and Hitchen, Esther and Hoffmann, Per and Jia, Tianye and Jirsa, Viktor and Marquand, Andre F. and Nees, Frauke and Nöthen, Markus M. and Novarino, Gaia and Polemiti, Elli and Ralser, Markus and Rapp, Michael and Schepanski, Kerstin and Schikowski, Tamara and Slater, Mel and Sommer, Peter and Stahl, Bernd Carsten and Thompson, Paul M. and Twardziok, Sven and Van Der Meer, Dennis and Walter, Henrik and Westlye, Lars},
issn = {2168-6238},
journal = {JAMA Psychiatry},
number = {10},
pages = {1066--1074},
publisher = {American Medical Association},
title = {{Addressing global environmental challenges to mental health using population neuroscience: A review}},
doi = {10.1001/jamapsychiatry.2023.2996},
volume = {80},
year = {2023},
}
@article{14455,
author = {Narzisi, Antonio and Halladay, Alycia and Masi, Gabriele and Novarino, Gaia and Lord, Catherine},
issn = {1664-0640},
journal = {Frontiers in Psychiatry},
publisher = {Frontiers},
title = {{Tempering expectations: Considerations on the current state of stem cells therapy for autism treatment}},
doi = {10.3389/fpsyt.2023.1287879},
volume = {14},
year = {2023},
}
@article{13267,
abstract = {Three-dimensional (3D) reconstruction of living brain tissue down to an individual synapse level would create opportunities for decoding the dynamics and structure–function relationships of the brain’s complex and dense information processing network; however, this has been hindered by insufficient 3D resolution, inadequate signal-to-noise ratio and prohibitive light burden in optical imaging, whereas electron microscopy is inherently static. Here we solved these challenges by developing an integrated optical/machine-learning technology, LIONESS (live information-optimized nanoscopy enabling saturated segmentation). This leverages optical modifications to stimulated emission depletion microscopy in comprehensively, extracellularly labeled tissue and previous information on sample structure via machine learning to simultaneously achieve isotropic super-resolution, high signal-to-noise ratio and compatibility with living tissue. This allows dense deep-learning-based instance segmentation and 3D reconstruction at a synapse level, incorporating molecular, activity and morphodynamic information. LIONESS opens up avenues for studying the dynamic functional (nano-)architecture of living brain tissue.},
author = {Velicky, Philipp and Miguel Villalba, Eder and Michalska, Julia M and Lyudchik, Julia and Wei, Donglai and Lin, Zudi and Watson, Jake and Troidl, Jakob and Beyer, Johanna and Ben Simon, Yoav and Sommer, Christoph M and Jahr, Wiebke and Cenameri, Alban and Broichhagen, Johannes and Grant, Seth G.N. and Jonas, Peter M and Novarino, Gaia and Pfister, Hanspeter and Bickel, Bernd and Danzl, Johann G},
issn = {1548-7105},
journal = {Nature Methods},
pages = {1256--1265},
publisher = {Springer Nature},
title = {{Dense 4D nanoscale reconstruction of living brain tissue}},
doi = {10.1038/s41592-023-01936-6},
volume = {20},
year = {2023},
}
@article{10818,
abstract = {Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1−/− mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses.},
author = {Basilico, Bernadette and Ferrucci, Laura and Ratano, Patrizia and Golia, Maria T. and Grimaldi, Alfonso and Rosito, Maria and Ferretti, Valentina and Reverte, Ingrid and Sanchini, Caterina and Marrone, Maria C. and Giubettini, Maria and De Turris, Valeria and Salerno, Debora and Garofalo, Stefano and St‐Pierre, Marie‐Kim and Carrier, Micael and Renzi, Massimiliano and Pagani, Francesca and Modi, Brijesh and Raspa, Marcello and Scavizzi, Ferdinando and Gross, Cornelius T. and Marinelli, Silvia and Tremblay, Marie‐Ève and Caprioli, Daniele and Maggi, Laura and Limatola, Cristina and Di Angelantonio, Silvia and Ragozzino, Davide},
issn = {1098-1136},
journal = {Glia},
keywords = {Cellular and Molecular Neuroscience, Neurology},
number = {1},
pages = {173--195},
publisher = {Wiley},
title = {{Microglia control glutamatergic synapses in the adult mouse hippocampus}},
doi = {10.1002/glia.24101},
volume = {70},
year = {2022},
}
@article{12140,
abstract = {Microglia are dynamic cells, constantly surveying their surroundings and interacting with neurons and synapses. Indeed, a wealth of knowledge has revealed a critical role of microglia in modulating synaptic transmission and plasticity in the developing brain. In the past decade, novel pharmacological and genetic strategies have allowed the acute removal of microglia, opening the possibility to explore and understand the role of microglia also in the adult brain. In this review, we summarized and discussed the contribution of microglia depletion strategies to the current understanding of the role of microglia on synaptic function, learning and memory, and behavior both in physiological and pathological conditions. We first described the available microglia depletion methods highlighting their main strengths and weaknesses. We then reviewed the impact of microglia depletion on structural and functional synaptic plasticity. Next, we focused our analysis on the effects of microglia depletion on behavior, including general locomotor activity, sensory perception, motor function, sociability, learning and memory both in healthy animals and animal models of disease. Finally, we integrated the findings from the reviewed studies and discussed the emerging roles of microglia on the maintenance of synaptic function, learning, memory strength and forgetfulness, and the implications of microglia depletion in models of brain disease.},
author = {Basilico, Bernadette and Ferrucci, Laura and Khan, Azka and Di Angelantonio, Silvia and Ragozzino, Davide and Reverte, Ingrid},
issn = {1662-5102},
journal = {Frontiers in Cellular Neuroscience},
keywords = {Cellular and Molecular Neuroscience},
publisher = {Frontiers Media},
title = {{What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior}},
doi = {10.3389/fncel.2022.1022431},
volume = {16},
year = {2022},
}
@article{12174,
abstract = {Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease.
Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs.
Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes.
ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.},
author = {Guerrini, Renzo and Mei, Davide and Szigeti, Margit Katalin and Pepe, Sara and Koenig, Mary Kay and Von Allmen, Gretchen and Cho, Megan T and McDonald, Kimberly and Baker, Janice and Bhambhani, Vikas and Powis, Zöe and Rodan, Lance and Nabbout, Rima and Barcia, Giulia and Rosenfeld, Jill A and Bacino, Carlos A and Mignot, Cyril and Power, Lillian H and Harris, Catharine J and Marjanovic, Dragan and Møller, Rikke S and Hammer, Trine B and Keski Filppula, Riikka and Vieira, Päivi and Hildebrandt, Clara and Sacharow, Stephanie and Maragliano, Luca and Benfenati, Fabio and Lachlan, Katherine and Benneche, Andreas and Petit, Florence and de Sainte Agathe, Jean Madeleine and Hallinan, Barbara and Si, Yue and Wentzensen, Ingrid M and Zou, Fanggeng and Narayanan, Vinodh and Matsumoto, Naomichi and Boncristiano, Alessandra and la Marca, Giancarlo and Kato, Mitsuhiro and Anderson, Kristin and Barba, Carmen and Sturiale, Luisa and Garozzo, Domenico and Bei, Roberto and Masuelli, Laura and Conti, Valerio and Novarino, Gaia and Fassio, Anna},
issn = {1460-2156},
journal = {Brain},
keywords = {Neurology (clinical)},
number = {8},
pages = {2687--2703},
publisher = {Oxford University Press},
title = {{Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis}},
doi = {10.1093/brain/awac145},
volume = {145},
year = {2022},
}