Znamenskiy & Kullmann | Mapping human neocortical circuits with high-throughput molecular connectomics

This position is in partnership with Dimitri Kullmann
Professor of Neurology, UCL Queen Square Institute of Neurology
Znamenskiy & Kullmann | Mapping human neocortical circuits with high-throughput molecular connectomics
Deadline for applications has passed.

Key information

Applications closed
15 November 2023, 12:00 GMT
Information
Posted 02 October 2023

Research topics

Human Biology & Physiology Neurosciences
Background texture taken from the lab imagery.

A PhD project for the 2024 doctoral clinical fellows programme with Petr Znamenskiy (primary supervisor, Crick) and Dimitri Kullmann (UCL)

Project background and description

The Znamenskiy lab studies the organisation of neural circuits in the neocortex. We aim to understand how organisation of synaptic connections of individual neurons gives rise to the computations they perform[1, 2]. This project will aim to develop a new method for high-throughput reconstruction of synaptic connectivity in the human neocortex to identify circuit abnormalities associated with neurological disorders.

Conventional methods for measuring synaptic connectivity are extremely laborious – ongoing large-scale connectomics projects aiming to map connectivity in a small volume of cortical tissue have so far required 10s of person-years of effort. Adding to the challenge, recent transcriptomic studies have catalogued the molecular diversity of cortical neurons, revealing that they can be classified into ~100 molecular subtypes[3, 4]. These transcriptomic subclasses may follow different rules in selecting their synaptic partners and therefore play different roles in computations performed by neocortical circuits.

To accelerate progress in this field, we have recently developed a new circuit tracing method, relying on rabies viruses expressing molecular barcodes, that will make it possible for a single experimenter to rapidly trace thousands of synaptic connections in a matter of weeks (manuscript in preparation). Briefly, our approach relies on the ability of rabies virus to spread between synaptically connected neurons[5]. When individual neurons are infected with rabies viruses expressing unique RNA “barcodes”, they transmit their barcodes to their presynaptic inputs. Therefore, synaptic connections can be identified by matching barcode sequences between pre- and post-synaptic neurons.

The project would aim to adapt this approach to the human cortex using organotypic slices cultures from tissue resected during neurosurgery. In collaboration with Harry Bulstrode, a neurosurgeon at the University of Cambridge, it will aim to translate our viral tools to human cortex slices. Systematically profiling the organization of synaptic connections in individual patient samples will provide a powerful new method for identification of circuit abnormalities in neurological disorders and help design cell-type targeted gene therapies.

The partner institution for this project is UCL.

References:

1.    Kim, M. H., Znamenskiy, P., Iacaruso, M. F. and Mrsic-Flogel, T. D. (2018)
    Segregated Subnetworks of Intracortical Projection Neurons in Primary Visual Cortex. Neuron 100: 1313-1321 e1316.
2.    Znamenskiy, P., Kim, M.-H., Muir, D. R., Iacaruso, M. F., Hofer, S. B. and Mrsic-Flogel, T. D. (2018)
    Functional selectivity and specific connectivity of inhibitory neurons in primary visual cortex. bioRxiv: 294835.
3.    Tasic, B., Yao, Z., Graybuck, L. T., Smith, K. A., Nguyen, T. N., Bertagnolli, D., . . . Zeng, H. (2018)
    Shared and distinct transcriptomic cell types across neocortical areas. Nature 563: 72-78.
4.    Yao, Z., van Velthoven, C. T. J., Nguyen, T. N., Goldy, J., Sedeno-Cortes, A. E., Baftizadeh, F., . . . Zeng, H. (2021) A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell 184: 3222-3241 e3226.
5.    Wickersham, I. R., Lyon, D. C., Barnard, R. J., Mori, T., Finke, S., Conzelmann, K. K., . . . Callaway, E. M. (2007) Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 53: 639-647.