scholarly journals A single-cell level and connectome-derived computational model of the Drosophila brain

2018 ◽  
Author(s):  
Yu-Chi Huang ◽  
Cheng-Te Wang ◽  
Ta-Shun Su ◽  
Kuo-Wei Kao ◽  
Yen-Jen Lin ◽  
...  

AbstractComputer simulations play an important role in testing hypotheses, integrating knowledge, and providing predictions of neural circuit functions. While considerable effort has been dedicated into simulating primate or rodent brains, the fruit fly (Drosophila melanogaster) is becoming a promising model animal in computational neuroscience for its small brain size, complex cognitive behavior, and abundancy of data available from genes to circuits. Moreover, several Drosophila connectome projects have generated a large number of neuronal images that account for a significant portion of the brain, making a systematic investigation of the whole brain circuit possible. Supported by FlyCircuit (http://www.flycircuit.tw), one of the largest Drosophila neuron image databases, we began a long-term project with the goal to construct a whole-brain spiking network model of the Drosophila brain. In this paper, we report the outcome of the first phase of the project. We developed the Flysim platform, which 1) identifies the polarity of each neuron arbor, 2) predicts connections between neurons, 3) translates morphology data from the database into physiology parameters for computational modeling, 4) reconstructs a brain-wide network model, which consists of 20,089 neurons and 1,044,020 synapses, and 5) performs computer simulations of the resting state. We compared the reconstructed brain network with a randomized brain network by shuffling the connections of each neuron. We found that the reconstructed brain can be easily stabilized by implementing synaptic short-term depression, while the randomized one exhibited seizure-like firing activity under the same treatment. Furthermore, the reconstructed Drosophila brain was structurally and dynamically more diverse than the randomized one and exhibited both Poisson-like and patterned firing activities. Despite being at its early stage of development, this single-cell level brain model allows us to study some of the fundamental properties of neural networks including network balance, critical behavior, long-term stability, and plasticity.

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Yu Tanouchi ◽  
Anand Pai ◽  
Heungwon Park ◽  
Shuqiang Huang ◽  
Nicolas E. Buchler ◽  
...  

2012 ◽  
Vol 84 (8) ◽  
pp. 1407-1407
Author(s):  
A. Grünberger ◽  
C. Probst ◽  
W. Wiechert ◽  
D. Kohlheyer

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e52087 ◽  
Author(s):  
Benny J. Chen ◽  
Yiqun Jiao ◽  
Ping Zhang ◽  
Albert Y. Sun ◽  
Geoffrey S. Pitt ◽  
...  

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii1-ii1
Author(s):  
Y Y Yabo ◽  
A Oudin ◽  
A Skupin ◽  
P V Nazarov ◽  
S P Niclou ◽  
...  

Abstract BACKGROUND Glioblastomas are among the most heterogeneous tumors, which hampers patient stratification and development of effective therapies. Glioblastomas create a dynamic ecosystem, where heterogeneous tumor cells interact with the tumor microenvironment to establish different niches. Upon tumor growth, Glioblastoma cells manifest remarkable plasticity and respond flexibly to selective pressures by transiting towards states favorable to the new tumor microenvitonment. How this phenotypic plasticity contributes to treatment resistance is currently less clear. The exact nature of treatment resistant, tolerant and sensitive Glioblastoma cells remains unresolved. Further studies at the single cell level are needed to reveal transient and long-term signatures of the resistant states. MATERIAL AND METHODS To investigate long-term phenotypic changes upon treatment at the single cell level we performed single cell RNA-seq (scRNA-seq) on the longitudinal patient-derived xenograft (PDOX) models derived from Glioblastoma patient tumors prior and after the standard-of-care treatment. In addition, direct treatment of PDOXs with temozolomide combined with scRNA-seq allowed revealing short-term transcriptomic changes both in tumor cells and in the mouse-derived cells forming tumor microenvironment. Advanced computational algorithms, including reference-free deconvolution methods, were applied to reveal treatment resistance signatures and master regulators of the identified treatment-resistant subpopulations. RESULTS We show that PDOX models recapitulate all the major cell types and transcriptional programs reported in Glioblastoma patient samples, providing clinically relevant models for investigating treatment resistance signatures of tumor cells and associated tumor microenvironment. Analysis of treatment naïve and treated Glioblastomas at the single cell level revealed presence of pre-existing treatment resistant states as well as newly established resistant subpopulatons. Certain transcriptomic changes are preserved long term, regardless of the lack of genetic evolution of the tumor cells. CONCLUSION Phenotypic plasticity is an important factor contributing to resistance mechanisms in Glioblastoma. Key molecular regulators of tumor cell plasticity towards treatment resistance states represent novel targets for future combinatory treatments.


2008 ◽  
Vol 48 (supplement) ◽  
pp. S109
Author(s):  
Tomoyuki Kaneko ◽  
Fumimasa Nomura ◽  
Yuki Tomoe ◽  
Ikurou Suzuki ◽  
Junko Hayashi ◽  
...  

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