Tracking Neurons During Development to Understand How Neural Circuits Form

Post by Sarah Hill

What's the science?

Neurons never act alone, but instead, organize into coordinated cellular ensembles or 'circuits' to direct behaviors. Linking how newborn neurons are arranged into coordinated networks during development has previously been limited by available technologies, leaving an incomplete picture of how neural circuits are formed. However, recent advances in imaging and computational methods have offered insight into this process. This week in Cell, Wan and colleagues present a new imaging framework for tracking neurons from cell birth to emergence of synchronized global activity, shedding new light on how neural circuits assemble during development.                

How did they do it?

The authors developed an imaging method based on light-sheet fluorescence microscopy to simultaneously track the identities, lineages, migration, and activation of newborn neurons, and demonstrated the approach in the zebrafish spinal cord. First, they imaged a whole zebrafish embryo using cell-type-specific markers to identify neuron types, trace cell lineages, and monitor neuronal movements. They then performed functional imaging of the embryos to record neuronal activation during circuit formation. Additional experiments were carried out to establish how ensembles of neurons become coordinated in their activation along with multiple segments of the spinal cord, as well as how synchronized activity on the left and right sides of the spinal cord is established. Using the imaging data, they pieced together how early spinal cord neurons assemble into a fully functional circuit.        

What did they find?

Through this new imaging method, the authors successfully reconstructed an assembly of the spinal cord circuit at the single-cell level. Using the zebrafish as a model, they identified three key stages in spinal cord circuit development. First, nascent motor neurons (cells that execute motor movements) pair up with other neurons in the same spinal segment to form local ensembles of synchronized activity. In stage II, the local ensembles merge based on size into a globally synchronized ensemble that spans multiple segments. Local spinal microcircuits continue to merge until only two neural ensembles remain, on the left and right sides of the spinal cord. In stage III, alternating left-right activation is synchronized by commissural interneurons (cells that project to the opposite side of the spinal cord) recruited into the global ensembles relatively late in the process.   

What's the impact?

This is the first study to trace the development of a neural circuit at the single-cell level, from neuronal birth to emergence of a functional circuit. Importantly, the imaging framework proposed in this study can be readily translated to neural circuits beyond the spinal cord and all computational methods are open-source. 

Wan et al. Single-Cell Reconstruction of Emerging Population Activity in an Entire Developing Circuit. Cell (2019). Access the original scientific publication here.