Research

How do brain circuits assemble so precisely during development?

Please watch this 3-minute animated video that summarizes the research interests and goals of the Dombrovski lab.

How does the brain translate what we see into what we do? Every action we take, from catching a ball to avoiding danger, relies on precise connections between neurons.
Dr. Mark Dombrovski at the University of Colorado Boulder explores how these neural circuits form, linking the genetic and molecular building blocks of the brain to behaviours.

Why Drosophila visual system?

The Drosophila visual system is an ideal model for uncovering general principles of neural wiring. Its circuits are highly stereotyped and hardwired, with many neuronal types whose roles and connectivity are already well defined. Several complete electron microscopy (EM)-based connectomes and two developmental single-cell transcriptomic atlases provide amazing structural and molecular data that we can use to investigate how these circuits are assembled. Combined with powerful genetic tools, this system lets us connect molecular identity to synaptic specificity and function with exceptionalclarity.

Specifically, we focus on a process called visuomotor transformation, where visual stimuli get converted into precise body movements.
In the fly, this transformation occurs between Visual Projection Neurons (VPN, 50+ cell types) that detect features and Descending Neurons (DN, 200+ cell types) that control motor programs.
We seek to understand the molecular logic of VPN-DN synaptic connectivity.

Our Research directions

• How does each neuron know which wiring molecules to express, when, and at what levels?

We focus on the transcriptional and developmental logic that gives each cell type its unique synaptic specificity.

• Where do recognition proteins actually go inside neurons?
• How do they target specific dendrites, axons, or synapses?

We build genetic and imaging tools to visualize these molecules and identify their interaction partners.

• Can a single gene misexpression change wiring rules?
• Can a neuron require when its normal partner is absent?

We use controlled misexpression and perturbations to test whether predicted recognition molecules are sufficient to reroute connectivity.

In the long-term, we aim to uncover the general principles that let neurons recognize the right partners and assemble functional circuits. By combining genetics, connectomics, and transcriptomics, we hope to build predictive models of synaptic specificity, and use them to understand when wiring rules are fixed, when they are flexible, and how they change during development, experience, or recovery from injury.

Approaches and Techniques we use

We use single-cell RNA-sequencing to understand what genes different cell types express at particular developmental stages, and how these gene expression programs are affected upon targeted genetic perturbations (Perturb-scRNAseq) and other manipulations.

We currently collaborate with the labs of Gwyneth Card at Columbia University,
Katie von Reyn at Drexel University, and
Mark Frye at UCLA to test and validate our molecular models using behavioral assays, in vivo calcium imaging and electrophysiology. We are looking forward to develop some of these amazing techniques in our own lab soon.

We use single-molecule fluorescent RNA in situ hybridization (smFISH) coupled with expansion microscopy to directly visualize and measure gene expression within individual neurons.

The heart and soul of our lab. We take advantage of the amazing molecular genetics toolkit available for the fly, enabling us to manipulate virtually any given neuron in the brain. This allows to address cell-type-specific molecular mechanisms of brain wiring with an unprecedented level of specificity and resolution.