A biologically inspired repair mechanism for neuronal reconstructions with a focus on human dendrites

Abstract

Investigating and modelling the functionality of human neurons remains challenging due to the technical limitations, resulting in scarce and incomplete 3D anatomical reconstructions. Here we used a morphological modelling approach based on optimal wiring to repair the parts of a dendritic morphology that were lost due to incomplete tissue samples. In Drosophila, where dendritic regrowth has been studied experimentally using laser ablation, we found that modelling the regrowth reproduced a bimodal distribution between regeneration of cut branches and invasion by neighbouring branches. Interestingly, our repair model followed growth rules similar to those for the generation of a new dendritic tree. To generalise the repair algorithm from Drosophila to mammalian neurons, we artificially sectioned reconstructed dendrites from mouse and human hippocampal pyramidal cell morphologies, and showed that the regrown dendrites were morphologically similar to the original ones. Furthermore, we were able to restore their electrophysiological functionality, as evidenced by the recovery of their firing behaviour. Importantly, we show that such repairs also apply to other neuron types including hippocampal granule cells and cerebellar Purkinje cells. We then extrapolated the repair to incomplete human CA1 pyramidal neurons, where the anatomical boundaries of the particular brain areas innervated by the neurons in question were known. Interestingly, the repair of incomplete human dendrites helped to simulate the recently observed increased synaptic thresholds for dendritic NMDA spikes in human versus mouse dendrites. To make the repair tool available to the neuroscience community, we have developed an intuitive and simple graphical user interface (GUI), which is available in the TREES Toolbox (www.treestoolbox.org). In briefWe use morphological modelling inspired by the regeneration of various artificially cut neuron types and repair incomplete human and nonhuman neuronal dendritic reconstructions. Author summaryReconstructing neuronal dendrites by drawing their 3D branching structures in the computer has proven to be crucial for interpreting the flow of electrical signals and therefore the computations that dendrites implement on their inputs. These reconstructions are tedious and prone to disruptive limitations imposed by experimental procedures. In recent years, complementary computational procedures have emerged that reproduce the fine details of morphology in theoretical models. These models allow, for example, to populate large-scale neural networks and to study structure-function relationships. In this work we use a morphological model based on optimised wiring for signal conduction and material cost to repair faulty reconstructions, in particular those of human hippocampal dendrites, which are rare and precious but often cut due to technical limitations. Interestingly, we find that our synthetic repair mechanism reproduces the two distinct modes of repair observed in real dendrites: regeneration from the severed branch and invasion from neighbouring branches. Our model therefore provides both a useful tool for single-cell electrophysiological simulations and a useful theoretical concept for studying the biology of dendrite repair. HighlightsO_LIOptimal wiring-based growth algorithm replicates regrowth of artificially cut dendrites C_LIO_LIThe growth algorithm repairs cut dendrites in incomplete reconstructions C_LIO_LIThe algorithm works for diverse neuron types in multiple species C_LIO_LIThe repair of morphology restores original electrophysiology C_LIO_LIThe repair of morphology supports simulations of high synaptic thresholds for NMDA spikes in human dendrites C_LIO_LIThe repair tool with user interface is available in the TREES Toolbox C_LI