Abstract
Recognizing that diverse morphologies of neurons are reminiscent of structures of branched polymers, we put forward a principled and systematic way of classifying neurons that employs the ideas of polymer physics. In particular, we use 3D coordinates of individual neurons, which are accessible in recent neuron reconstruction datasets from electron microscope images. We numerically calculate the form factor, F(q), a Fourier transform of the distance distribution of particles comprising an object of interest, which is routinely measured in scattering experiments to quantitatively characterize the structure of materials. For a polymer-like object consisting of n monomers spanning over a length scale of r, F(q) scales with the wavenumber \(q(=2\pi /r)\) as \(F(q)\sim q^{-\mathcal {D}}\) at an intermediate range of q, where \(\mathcal {D}\) is the fractal dimension or the inverse scaling exponent (\(\mathcal {D}=\nu ^{-1}\)) characterizing the geometrical feature (\(r\sim n^{\nu }\)) of the object. F(q) can be used to describe a neuron morphology in terms of its size (\(R_n\)) and the extent of branching quantified by \(\mathcal {D}\). By defining the distance between F(q)s as a measure of similarity between two neuronal morphologies, we tackle the neuron classification problem. In comparison with other existing classification methods for neuronal morphologies, our F(q)-based classification rests solely on 3D coordinates of neurons with no prior knowledge of morphological features. When applied to publicly available neuron datasets from three different organisms, our method not only complements other methods but also offers a physical picture of how the dendritic and axonal branches of an individual neuron fill the space of dense neural networks inside the brain.










Similar content being viewed by others
Data Availability
Python scripts used for this manuscript and the complete neuron morphologies in each cluster for the C. elegans nervous system, Drosophila PNs, and mouse V1 neuron are available at https://github.com/kirichoi/FqClustering.
References
Andrews, D.G. (2019). A new method for measuring the size of nematodes using image processing. Biology Methods and Protocols, 4, bpz020.
Aso, Y., Hattori, D., Yu, Y., Johnston, R. M., Iyer, N. A., Ngo, T. -T., et al. (2014). The neuronal architecture of the mushroom body provides a logic for associative learning. eLife, 3,
Bak, J. H., Jang, S. J., & Hyeon, C. (2018). Implications for human odor sensing revealed from the statistics of odorant-receptor interactions. PLoS Computational Biology, 14, e1006175.
Baker, F. B. (1974). Stability of two hierarchical grouping techniques case i: Sensitivity to data errors. Journal of the American Statistical Association, 69, 440–445.
Bale, H. D., & Schmidt, P. W. (1984). Small-angle x-ray-scattering investigation of submicroscopic porosity with fractal properties. Physical Review Letters, 53, 596.
Bates, A. S., Schlegel, P., Roberts, R. J., Drummond, N., Tamimi, I. F., Turnbull, R., Zhao, X., Marin, E. C., Popovici, P. D., Dhawan, S., et al. (2020). Complete connectomic reconstruction of olfactory projection neurons in the fly brain. Current Biology, 30, 3183–3199.
Buccino, A. P., Ness, T. V., Einevoll, G. T., Cauwenberghs, G., & Häfliger, P. D. (2018). A deep learning approach for the classification of neuronal cell types. In 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) (pp. 999–1002). IEEE.
Buck, L., & Axel, R. (1991). A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell, 65, 175–187.
Butcher, N. J., Friedrich, A. B., Lu, Z., Tanimoto, H., & Meinertzhagen, I. A. (2012). Different classes of input and output neurons reveal new features in microglomeruli of the adult Drosophila mushroom body calyx. The Journal of Comparative Neurology, 520, 2185–2201.
Caserta, F., Eldred, W., Fernandez, E., Hausman, R., Stanford, L., Bulderev, S., Schwarzer, S., & Stanley, H. (1995). Determination of fractal dimension of physiologically characterized neurons in two and three dimensions. Journal of Neuroscience Methods, 56, 133–144.
Chaikin, P. M., Lubensky, T. C., & Witten, T. A. (1995). Principles of condensed matter physics (Vol. 10). Cambridge University Press; Cambridge.
Chatterjee, N., & Sinha, S. (2007). Understanding the mind of a worm: Hierarchical network structure underlying nervous system function in C. elegans. Progress in Brain Research, 168, 145–153.
Chatzigeorgiou, M., Yoo, S., Watson, J. D., Lee, W. -H., Spencer, W. C., Kindt, K. S., Hwang, S. W., Miller, D. M., III., Treinin, M., Driscoll, M., et al. (2010). Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in c. elegans nociceptors. Nature neuroscience, 13, 861–868.
Cho, J. Y., & Sternberg, P. W. (2014). Multilevel modulation of a sensory motor circuit during c. elegans sleep and arousal. Cell, 156, 249–260.
Choi, K., Kim, W. K., & Hyeon, C. (2022). Olfactory responses of drosophila are encoded in the organization of projection neurons. bioRxiv.
Couto, A., Alenius, M., & Dickson, B. J. (2005). Molecular, anatomical, and functional organization of the Drosophila olfactory system. Current Biology, 15, 1535–1547.
Daoud, M., Cotton, J. P., Farnoux, B., Jannink, G., Sarma, G., Benoit, H., Duplessix, R., Picot, C., & de Gennes, P. G. (1975). Solutions of flexible polymers. Neutron Experiments and Interpretation. Macromolecules, 8, 804.
Daoud, M., & Jannink, G. (1976). Temperature-concentration diagram of polymer solutions. Journal of Physics, 37, 973–979.
Daoud, M., & Joanny, J. (1981). Conformation of branched polymers. Journal of Physics, 42, 1359–1371.
De Gennes, P. -G. (1979). Scaling concepts in polymer physics. Cornell University Press.
Debye, P., Anderson, H., Jr., & Brumberger, H. (1957). Scattering by an inhomogeneous solid. II. The correlation function and its application. Journal of Applied Physics, 28, 679–683.
de Vries, S. E., Lecoq, J. A., Buice, M. A., Groblewski, P. A., Ocker, G. K., Oliver, M., Feng, D., Cain, N., Ledochowitsch, P., Millman, D., et al. (2020). A large-scale standardized physiological survey reveals functional organization of the mouse visual cortex. Nature Neuroscience, 23, 138–151.
Díaz-Balzac, C. A., Rahman, M., Lázaro-Peña, M. I., Hernandez, L. A. M., Salzberg, Y., Aguirre-Chen, C., Kaprielian, Z., & Bülow, H. E. (2016). Muscle-and skin-derived cues jointly orchestrate patterning of somatosensory dendrites. Current Biology, 26, 2379–2387.
Doi, M., Edwards, S. F., & Edwards, S. F. (1988). The theory of polymer dynamics (Vol. 73). Oxford University Press.
Duplantier, B. (1987). Geometry of polymer chains near the theta-point and dimensional regularization. The Journal of Chemical Physics, 86, 4233–4244.
Felleman, D. J., & Van Essen, D. C. (1991). Distributed hierarchical processing in the primate cerebral cortex. Cerebral Cortex (New York, NY: 1991), 1, 1–47.
Gao, Q., Yuan, B., & Chess, A. (2000). Convergent projections of drosophila olfactory neurons to specific glomeruli in the antennal lobe. Nature Neuroscience, 3, 780–785.
Glickfeld, L. L., Andermann, M. L., Bonin, V., & Reid, R. C. (2013). Cortico-cortical projections in mouse visual cortex are functionally target specific. Nature Neuroscience, 16, 219–226.
Gouwens, N. W., Sorensen, S. A., Berg, J., Lee, C., Jarsky, T., Ting, J., Sunkin, S. M., Feng, D., Anastassiou, C. A., Barkan, E., et al. (2019). Classification of electrophysiological and morphological neuron types in the mouse visual cortex. Nature Neuroscience, 22, 1182–1195.
Grosberg, A. Y., Khokhlov, A. R., Stanley, H. E., Mallinckrodt, A. J., & McKay, S. (1995). Statistical physics of macromolecules. Computers in Physics, 9, 171–172.
Gruntman, E., & Turner, G. C. (2013). Integration of the olfactory code across dendritic claws of single mushroom body neurons. Nature Neuroscience, 16, 1821–1829.
Han, Y., Kebschull, J. M., Campbell, R. A., Cowan, D., Imhof, F., Zador, A. M., & Mrsic-Flogel, T. D. (2018). The logic of single-cell projections from visual cortex. Nature, 556, 51–56.
Harris, J. A., Mihalas, S., Hirokawa, K. E., Whitesell, J. D., Choi, H., Bernard, A., Bohn, P., Caldejon, S., Casal, L., Cho, A., et al. (2019). Hierarchical organization of cortical and thalamic connectivity. Nature, 575, 195–202.
Heimbeck, G., Bugnon, V., Gendre, N., Keller, A., & Stocker, R. F. (2001). A central neural circuit for experience-independent olfactory and courtship behavior in drosophila melanogaster. Proceedings of the National Academy of Sciences, 98, 15336–15341.
Heisenberg, M. (2003). Mushroom body memoir: From maps to models. Nature Reviews. Neuroscience, 4, 266–275.
Hübener, M. (2003). Mouse visual cortex. Current Opinion in Neurobiology, 13, 413–420.
Jarrell, T. A., Wang, Y., Bloniarz, A. E., Brittin, C. A., Xu, M., Thomson, J. N., Albertson, D. G., Hall, D. H., & Emmons, S. W. (2012). The connectome of a decision-making neural network. Science, 337, 437–444.
Jeanne, J. M., Fişek, M., & Wilson, R. I. (2018). The organization of projections from olfactory glomeruli onto higher-order neurons. Neuron, 98, 1198–1213.
Jefferis, G. S., Potter, C. J., Chan, A. M., Marin, E. C., Rohlfing, T., Maurer, C. R., Jr., & Luo, L. (2007). Comprehensive maps of Drosophila higher olfactory centers: Spatially segregated fruit and pheromone representation. Cell, 128, 1187–1203.
Ji, W., Gămănuţ, R., Bista, P., D’Souza, R. D., Wang, Q., & Burkhalter, A. (2015). Modularity in the organization of mouse primary visual cortex. Neuron, 87, 632–643.
Kandel, E. R., Schwartz, J. H., Jessell, T. M., Seigelbaum, S. A., & Hudspeth, A. J. (Eds.) (2013). Principles of Neural Science (5th ed.). McGraw Hill.
Langfelder, P., Zhang, B., & Horvath, S. (2008). Defining clusters from a hierarchical cluster tree: the Dynamic Tree Cut package for R. Bioinformatics, 24, 719–720.
Laturnus, S., Kobak, D., & Berens, P. (2020). A systematic evaluation of interneuron morphology representations for cell type discrimination. Neuroinformatics, 18, 591–609.
Liao, M., Liang, X., & Howard, J. (2021). The narrowing of dendrite branches across nodes follows a well-defined scaling law (p. 118). National Academy of Sciences: Proceeddings.
Liu, L., & Hyeon, C. (2016). Contact statistics highlight distinct organizing principles of proteins and RNA. Biophysical Journal, 110, 2320–2327.
Liu, L., Pincus, P. A., & Hyeon, C. (2019). Compressing Θ-chain in slit geometry. Nano Letters, 19, 5667–5673.
Lu, Y., Carin, L., Coifman, R., Shain, W., & Roysam, B. (2015). Quantitative arbor analytics: Unsupervised harmonic co-clustering of populations of brain cell arbors based on l-measure. Neuroinformatics, 13, 47–63.
Maguire, S. M., Clark, C. M., Nunnari, J., Pirri, J. K., & Alkema, M. J. (2011). The c. elegans touch response facilitates escape from predacious fungi. Current Biology, 21, 1326–1330.
Mainen, Z. F., & Sejnowski, T. J. (1996). Influence of dendritic structure on firing pattern in model neocortical neurons. Nature, 382, 363–366.
Malnic, B., Hirono, J., Sato, T., & Buck, L. B. (1999). Combinatorial receptor codes for odors. Cell, 96, 713–723.
Mihaljević, B., Larrañaga, P., Benavides-Piccione, R., Hill, S., DeFelipe, J., & Bielza, C. (2018). Towards a supervised classification of neocortical interneuron morphologies. BMC Bioinformatics, 19, 1–22.
Mohammadi, A., Byrne Rodgers, J., Kotera, I., & Ryu, W. S. (2013). Behavioral response of caenorhabditis elegansto localized thermal stimuli. BMC Neuroscience, 14, 1–12.
Moyle, M. W., Barnes, K. M., Kuchroo, M., Gonopolskiy, A., Duncan, L. H., Sengupta, T., Shao, L., Guo, M., Santella, A., Christensen, R., et al. (2021). Structural and developmental principles of neuropil assembly in C. elegans. Nature, 591, 99–104.
Oh, S. W., Harris, J. A., Ng, L., Winslow, B., Cain, N., Mihalas, S., Wang, Q., Lau, C., Kuan, L., Henry, A. M., et al. (2014). A mesoscale connectome of the mouse brain. Nature, 508, 207–214.
Resulaj, A. (2021). Projections of the mouse primary visual cortex (p. 15). Neural Circuits: Front.
Ristanović, D., Nedeljkov, V., Stefanović, B., Milošević, N., Grgurević, M., & Štulić, V. (2002). Fractal and nonfractal analysis of cell images: Comparison and application to neuronal dendritic arborization. Biological Cybernetics, 87, 278–288.
Ristanović, D., Stefanović, B. D., & Puškaš, N. (2014). Fractal analysis of dendrite morphology using modified box-counting method. Neuroscience Research, 84, 64–67.
Rosenberg, A., & Hirschberg, J. (2007). V-measure: a conditional entropy-based external cluster evaluation measure. In Proceedings of the 2007 joint conference on empirical methods in natural language processing and computational natural language learning (EMNLP-CoNLL) (pp. 410–420).
Rubinstein, M., Colby, R. H., et al. (2003). Polymer physics (Vol. 23). New York: Oxford University Press.
Salzberg, Y., Díaz-Balzac, C. A., Ramirez-Suarez, N. J., Attreed, M., Tecle, E., Desbois, M., Kaprielian, Z., & Bülow, H. E. (2013). Skin-derived cues control arborization of sensory dendrites in Caenorhabditis elegans. Cell, 155, 308–320.
Sarma, G. P., Lee, C. W., Portegys, T., Ghayoomie, V., Jacobs, T., Alicea, B., Cantarelli, M., Currie, M., Gerkin, R. C., Gingell, S., et al. (2018). OpenWorm: overview and recent advances in integrative biological simulation of Caenorhabditis elegans. Philosophical Transactions of the Royal Society B, 373, 20170382.
Scheffer, L. K., Xu, C. S., Januszewski, M., Lu, Z., Takemura, S. -Y., Hayworth, K. J., Huang, G. B., Shinomiya, K., Maitlin-Shepard, J., Berg, S., et al. (2020). A connectome and analysis of the adult Drosophila central brain. eLife, 9,
Schultzhaus, J. N., Saleem, S., Iftikhar, H., & Carney, G. E. (2017). The role of the Drosophila lateral horn in olfactory information processing and behavioral response. Journal of Insect Physiology, 98, 29–37.
Scorcioni, R., Polavaram, S., & Ascoli, G. A. (2008). L-measure: a web-accessible tool for the analysis, comparison and search of digital reconstructions of neuronal morphologies. Nature Protocols, 3, 866–876.
Seki, Y., Rybak, J., Wicher, D., Sachse, S., & Hansson, B. S. (2010). Physiological and morphological characterization of local interneurons in the Drosophila antennal lobe. Journal of Neurophysiology, 104, 1007–1019.
Smith, J. H., Rowland, C., Harland, B., Moslehi, S., Montgomery, R., Schobert, K., Watterson, W., Dalrymple-Alford, J., & Taylor, R. (2021). How neurons exploit fractal geometry to optimize their network connectivity. Scientific Reports, 11, 1–13.
Smith, T., Jr, Lange, G., & Marks, W. B. (1996). Fractal methods and results in cellular morphology-dimensions, lacunarity and multifractals. Journal of Neuroscience Methods, 69, 123–136.
Stauffer, D., & Aharony, A. (2018). Introduction to percolation theory. Taylor & Francis.
Strehl, A., & Ghosh, J. (2002). Cluster ensembles-a knowledge reuse framework for combining multiple partitions. Journal of Machine Learning Research, 3, 583–617.
Tsalik, E. L., & Hobert, O. (2003). Functional mapping of neurons that control locomotory behavior in Caenorhabditis elegans. Journal of Neurobiology, 56, 178–197.
Tsiola, A., Hamzei-Sichani, F., Peterlin, Z., & Yuste, R. (2003). Quantitative morphologic classification of layer 5 neurons from mouse primary visual cortex. The Journal of Comparative Neurology, 461, 415–428.
Uylings, H. B., & VanPelt, J. (2002). Measures for quantifying dendritic arborizations. Network: Computation in Neural Systems, 13, 397.
van Elburg, R. A., & van Ooyen, A. (2010). Impact of dendritic size and dendritic topology on burst firing in pyramidal cells. PLoS Computational Biology, 6, e1000781.
Van Ooyen, A., Duijnhouwer, J., Remme, M. W., & van Pelt, J. (2002). The effect of dendritic topology on firing patterns in model neurons. Network: Computation in neural systems, 13, 311.
Varshney, L. R., Chen, B. L., Paniagua, E., Hall, D. H., & Chklovskii, D. B. (2011). Structural properties of the Caenorhabditis elegans neuronal network. PLoS Computational Biology, 7, e1001066.
Vasmer, D., Pooryasin, A., Riemensperger, T., & Fiala, A. (2014). Induction of aversive learning through thermogenetic activation of Kenyon cell ensembles in Drosophila. Frontiers in Behavioral Neuroscience, 8, 174.
Vasques, X., Vanel, L., Villette, G., & Cif, L. (2016). Morphological neuron classification using machine learning. Frontiers in Neuroanatomy, 10, 102.
Wakabayashi, T., Kitagawa, I., & Shingai, R. (2004). Neurons regulating the duration of forward locomotion in caenorhabditis elegans. Neuroscience Research, 50, 103–111.
Wang, Q., Sporns, O., & Burkhalter, A. (2012). Network analysis of corticocortical connections reveals ventral and dorsal processing streams in mouse visual cortex. The Journal of Neuroscience, 32, 4386–4399.
Way, J. C., & Chalfie, M. (1989). The mec-3 gene of Caenorhabditis elegans requires its own product for maintained expression and is expressed in three neuronal cell types. Genes & Development, 3, 1823–1833.
Wen, Q., Stepanyants, A., Elston, G. N., Grosberg, A. Y., & Chklovskii, D. B. (2009). Maximization of the connectivity repertoire as a statistical principle governing the shapes of dendritic arbors. Proceedings of the National Academy of Sciences, 106, 12536–12541.
White, J. (1985). Neuronal connectivity in Caenorhabditis elegans. Trends in Neurosciences, 8, 277–283.
White, J. G., Southgate, E., Thomson, J. N., Brenner, S., et al. (1986). The structure of the nervous system of the nematode Caenorhabditis elegans. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 314, 1–340.
Wong, P.-Z., & Bray, A. J. (1988). Porod scattering from fractal surfaces. Physical Review Letters, 60, 1344.
Woo, J., Choi, K., Kim, S. H., Han, K., & Choi, M. (2022). The structural aspects of neural dynamics and information flow. Frontiers in Bioscience-Landmark, 27.
y Cajal, S. R. (1911). Histologie du système nerveux de l’homme & des vertébrés: Cervelet, cerveau moyen, rétine, couche optique, corps strié, écorce cérébrale générale & régionale, grand sympathique (Vol. 2). A. Maloine.
Zeng, H., & Sanes, J. R. (2017). Neuronal cell-type classification: challenges, opportunities and the path forward. Nature Reviews Neuroscience, 18, 530–546.
Zhang, T., Zeng, Y., Zhang, Y., Zhang, X., Shi, M., Tang, L., Zhang, D., & Xu, B. (2021). Neuron type classification in rat brain based on integrative convolutional and tree-based recurrent neural networks. Scientific Reports, 11, 1–14.
Zheng, Z., Lauritzen, J. S., Perlman, E., Robinson, C. G., Nichols, M., Milkie, D., Torrens, O., Price, J., Fisher, C. B., Sharifi, N., et al. (2018). A complete electron microscopy volume of the brain of adult Drosophila melanogaster. Cell, 174, 730–743.
Zimm, B. H., & Stockmayer, W. H. (1949). The dimensions of chain molecules containing branches and rings. The Journal of Chemical Physics, 17, 1301–1314.
Acknowledgements
We thank the Center for Advanced Computation in KIAS for providing computing resources.
Funding
This study was supported by KIAS Individual Grants CG077002 (K.C.), CG076002 (W.K.K.), and CG035003 (C.H.).
Author information
Authors and Affiliations
Contributions
K.C., W.K.K. and C.H. wrote the main manuscript text and K.C. prepared figures. All authors reviewed the manuscript.
Corresponding author
Ethics declarations
Ethics Approval
Not applicable.
Consent to Participate
Not applicable.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Choi, K., Kim, W.K. & Hyeon, C. Polymer Physics-Based Classification of Neurons. Neuroinform 21, 177–193 (2023). https://doi.org/10.1007/s12021-022-09605-3
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12021-022-09605-3


