TY - GEN AB - The development, evolution, and function of the vertebrate central nervous system (CNS) can be best studied using diverse model organisms. Amphibians, with their unique phylogenetic position at the transition between aquatic and terrestrial lifestyles, are valuable for understanding the origin and evolution of the tetrapod brain and spinal cord. Their metamorphic developmental transitions and unique regenerative abilities also facilitate the discovery of mechanisms for neural circuit remodeling and replacement. The genetic toolkit for amphibians, however, remains limited, with only a few species having sequenced genomes and a small number of transgenic lines available. In mammals, recombinant adeno-associated viral vectors (AAVs) have become a powerful alternative to genome modification for visualizing and perturbing the nervous system. AAVs are DNA viruses that enable neuronal transduction in both developing and adult animals with low toxicity and spatial, temporal, and cell-type specificity. However, AAVs have never been shown to transduce amphibian cells efficiently. To bridge this gap, we established a simple, scalable, and robust strategy to screen AAV serotypes in three distantly-related amphibian species: the frogs Xenopus laevis and Pelophylax bedriagae, and the salamander Pleurodeles waltl, in both developing larval tadpoles and post-metamorphic animals. For each species, we successfully identified at least two AAV serotypes capable of infecting the CNS; however, no pan-amphibian serotype was identified, indicating rapid evolution of AAV tropism. In addition, we developed an AAV-based strategy that targets isochronic cohorts of developing neurons – a critical tool for parsing neural circuit assembly. Finally, to enable visualization and manipulation of neural circuits, we identified AAV variants for retrograde tracing of neuronal projections in adult animals. Our findings expand the toolkit for amphibians to include AAVs, establish a generalizable workflow for AAV screening in non-canonical research organisms, generate testable hypotheses for the evolution of AAV tropism, and lay the foundation for modern cross-species comparisons of vertebrate CNS development, function, and evolution. AU - Jaeger, Eliza C.B. AU - Vijatovic, David AU - Deryckere, Astrid AU - Zorin, Nikol AU - Nguyen, Akemi L. AU - Ivanian, Georgiy AU - Woych, Jamie AU - Arnold, Rebecca C AU - Ortega Gurrola, Alonso AU - Shvartsman, Arik AU - Barbieri, Francesca AU - Toma, Florina-Alexandra AU - Gorbsky, Gary J. AU - Horb, Marko E. AU - Cline, Hollis T. AU - Shay, Timothy F. AU - Kelley, Darcy B. AU - Yamaguchi, Ayako AU - Shein-Idelson, Mark AU - Tosches, Maria Antonietta AU - Sweeney, Lora Beatrice Jaeger ID - 15016 T2 - bioRxiv TI - Adeno-associated viral tools to trace neural development and connectivity across amphibians ER - TY - JOUR AB - 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. AU - Schumann, Gunter AU - Andreassen, Ole A. AU - Banaschewski, Tobias AU - Calhoun, Vince D. AU - Clinton, Nicholas AU - Desrivieres, Sylvane AU - Brandlistuen, Ragnhild Eek AU - Feng, Jianfeng AU - Hese, Soeren AU - Hitchen, Esther AU - Hoffmann, Per AU - Jia, Tianye AU - Jirsa, Viktor AU - Marquand, Andre F. AU - Nees, Frauke AU - Nöthen, Markus M. AU - Novarino, Gaia AU - Polemiti, Elli AU - Ralser, Markus AU - Rapp, Michael AU - Schepanski, Kerstin AU - Schikowski, Tamara AU - Slater, Mel AU - Sommer, Peter AU - Stahl, Bernd Carsten AU - Thompson, Paul M. AU - Twardziok, Sven AU - Van Der Meer, Dennis AU - Walter, Henrik AU - Westlye, Lars ID - 14443 IS - 10 JF - JAMA Psychiatry TI - Addressing global environmental challenges to mental health using population neuroscience: A review VL - 80 ER - TY - JOUR AB - 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. AU - Xu, Jiayuan AU - Liu, Nana AU - Polemiti, Elli AU - Garcia-Mondragon, Liliana AU - Tang, Jie AU - Liu, Xiaoxuan AU - Lett, Tristram AU - Yu, Le AU - Nöthen, Markus M. AU - Feng, Jianfeng AU - Yu, Chunshui AU - Marquand, Andre AU - Schumann, Gunter AU - Walter, Henrik AU - Heinz, Andreas AU - Ralser, Markus AU - Twardziok, Sven AU - Vaidya, Nilakshi AU - Serin, Emin AU - Jentsch, Marcel AU - Hitchen, Esther AU - Eils, Roland AU - Taron, Ulrike Helene AU - Schütz, Tatjana AU - Schepanski, Kerstin AU - Banks, Jamie AU - Banaschewski, Tobias AU - Jansone, Karina AU - Christmann, Nina AU - Meyer-Lindenberg, Andreas AU - Tost, Heike AU - Holz, Nathalie AU - Schwarz, Emanuel AU - Stringaris, Argyris AU - Neidhart, Maja AU - Nees, Frauke AU - Siehl, Sebastian AU - A. Andreassen, Ole AU - T. Westlye, Lars AU - Van Der Meer, Dennis AU - Fernandez, Sara AU - Kjelkenes, Rikka AU - Ask, Helga AU - Rapp, Michael AU - Tschorn, Mira AU - Böttger, Sarah Jane AU - Novarino, Gaia AU - Marr, Lena AU - Slater, Mel AU - Viapiana, Guillem Feixas AU - Orosa, Francisco Eiroa AU - Gallego, Jaime AU - Pastor, Alvaro AU - Forstner, Andreas AU - Hoffmann, Per AU - M. Nöthen, Markus AU - J. Forstner, Andreas AU - Claus, Isabelle AU - Miller, Abbi AU - Heilmann-Heimbach, Stefanie AU - Sommer, Peter AU - Boye, Mona AU - Wilbertz, Johannes AU - Schmitt, Karen AU - Jirsa, Viktor AU - Petkoski, Spase AU - Pitel, Séverine AU - Otten, Lisa AU - Athanasiadis, Anastasios Polykarpos AU - Pearmund, Charlie AU - Spanlang, Bernhard AU - Alvarez, Elena AU - Sanchez, Mavi AU - Giner, Arantxa AU - Hese, Sören AU - Renner, Paul AU - Jia, Tianye AU - Gong, Yanting AU - Xia, Yunman AU - Chang, Xiao AU - Calhoun, Vince AU - Liu, Jingyu AU - Thompson, Paul AU - Clinton, Nicholas AU - Desrivieres, Sylvane AU - H. Young, Allan AU - Stahl, Bernd AU - Ogoh, George ID - 13168 JF - Nature Medicine SN - 1078-8956 TI - Effects of urban living environments on mental health in adults VL - 29 ER - TY - JOUR AU - Narzisi, Antonio AU - Halladay, Alycia AU - Masi, Gabriele AU - Novarino, Gaia AU - Lord, Catherine ID - 14455 JF - Frontiers in Psychiatry TI - Tempering expectations: Considerations on the current state of stem cells therapy for autism treatment VL - 14 ER - TY - JOUR AB - 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. AU - Velicky, Philipp AU - Miguel Villalba, Eder AU - Michalska, Julia M AU - Lyudchik, Julia AU - Wei, Donglai AU - Lin, Zudi AU - Watson, Jake AU - Troidl, Jakob AU - Beyer, Johanna AU - Ben Simon, Yoav AU - Sommer, Christoph M AU - Jahr, Wiebke AU - Cenameri, Alban AU - Broichhagen, Johannes AU - Grant, Seth G.N. AU - Jonas, Peter M AU - Novarino, Gaia AU - Pfister, Hanspeter AU - Bickel, Bernd AU - Danzl, Johann G ID - 13267 JF - Nature Methods SN - 1548-7091 TI - Dense 4D nanoscale reconstruction of living brain tissue VL - 20 ER - TY - THES AB - 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. AU - Knaus, Lisa ID - 13107 SN - 2663 - 337X TI - The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival ER - TY - JOUR AB - 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. AU - Knaus, Lisa AU - Basilico, Bernadette AU - Malzl, Daniel AU - Gerykova Bujalkova, Maria AU - Smogavec, Mateja AU - Schwarz, Lena A. AU - Gorkiewicz, Sarah AU - Amberg, Nicole AU - Pauler, Florian AU - Knittl-Frank, Christian AU - Tassinari, Marianna AU - Maulide, Nuno AU - Rülicke, Thomas AU - Menche, Jörg AU - Hippenmeyer, Simon AU - Novarino, Gaia ID - 12802 IS - 9 JF - Cell KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0092-8674 TI - Large neutral amino acid levels tune perinatal neuronal excitability and survival VL - 186 ER - TY - DATA AB - 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. AU - Danzl, Johann G ID - 13126 TI - Research data for the publication "Imaging brain tissue architecture across millimeter to nanometer scales" ER - TY - JOUR AB - 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. AU - Michalska, Julia M AU - Lyudchik, Julia AU - Velicky, Philipp AU - Korinkova, Hana AU - Watson, Jake AU - Cenameri, Alban AU - Sommer, Christoph M AU - Amberg, Nicole AU - Venturino, Alessandro AU - Roessler, Karl AU - Czech, Thomas AU - Höftberger, Romana AU - Siegert, Sandra AU - Novarino, Gaia AU - Jonas, Peter M AU - Danzl, Johann G ID - 14257 JF - Nature Biotechnology SN - 1087-0156 TI - Imaging brain tissue architecture across millimeter to nanometer scales ER - TY - JOUR AB - 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. AU - Basilico, Bernadette AU - Ferrucci, Laura AU - Khan, Azka AU - Di Angelantonio, Silvia AU - Ragozzino, Davide AU - Reverte, Ingrid ID - 12140 JF - Frontiers in Cellular Neuroscience KW - Cellular and Molecular Neuroscience SN - 1662-5102 TI - What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior VL - 16 ER -