Revealing the wiring rules of neural circuit assembly with spatiotemporally resolved molecular connectomics

Introduction

The human genome contains several thousand genes that play a key role in the development of the brain’s connectome, a precise assembly of neural connections with billions of neurons and trillions of synapses.

Research Question

How is genomic information translated into synapse-specific connectivity underlying behavior and cognition? Answering this fundamental question will provide important insights about the principles underlying nervous system development and is relevant for neurodevelopmental disorders such as autism.

Current Limitations

However, current approaches to measure neuronal connectivity have intrinsic limitations that prevent combined analysis of connected neurons and their gene expression profiles at a scale that matches the complexity of the mammalian nervous system.

Proposed Approach

Here I propose to develop a novel approach for massively parallel neural circuit tracing with barcoded rabies virus and 3D intact-tissue RNA-sequencing. This will permit a comprehensive understanding of neural network architecture via the large-scale measurement of molecular, cellular, and circuit-level mechanisms in the mouse brain.

Advantages of the New Method

Compared to current efforts that require vast scientific resources to map synaptic connectivity among a few cells or small tissue volumes, my approach will enable routine measurements of connections among thousands of single neurons with molecular detail.

Methodology

Based on my expertise in in vivo barcoding, I will conduct a longitudinal study to reveal the wiring rules underlying the spatiotemporal development of neural circuits from diverse neuron types in the mouse prefrontal cortex, a brain region that plays a key role in cognition.

Cross-Sectional Analysis

I will follow a cross-sectional approach to unravel the effects of distinct mutations on neuronal wiring in the prefrontal cortex in two mouse models of autism (Cntnap2-/-, Syngap1+/-).

Expected Outcomes

My work will provide an innovative experimental platform and offer mechanistic insights into the developmental algorithms that the genome uses to encode the connectome.