Circuit Development and Robustness - Project Overview

 

Imagine that I'm giving you a set of instructions for navigating through a busy city to a specific target.  I could direct you to a specific location:  take the expressway headed north, get off at exit 25.  Or I could direct you to a specific landmark or cue:  take the expressway headed north, look for the big blue building with the flashing green sign.  Either strategy would work fine, as long as your target stays at exit 25, stays blue, and keeps up its flashing green sign.

However, if something changes, these strategies will fail in different ways.  If the target moves to a different exit, the first set will fail - but the second set will still work.  Conversely, if the target changes color or takes down its sign, the second set will fail - but the first will still work.  In other words, each strategy is robust to some changes and sensitive to others.

What does this have to do with neurons?

During development, new neurons also have to navigate their way through a busy environment to a specific target:  a presynaptic neuron extends its axonal process to find postsynaptic targets - often other neurons with whom it will form functional neural circuits.  

Just as I could deploy different strategies to guide you through a busy city, the developing nervous system can deploy different strategies to guide a specific presynaptic axon to a postsynaptic target.  For example, some neurons send their axons to a specific location in the developing brain; others use cell surface molecules (signs) to recognize their targets.  And although multiple strategies might work equally well for a particular synapse - in normal animals, with unchanging conditions - these strategies will fail in different ways in response to perturbations.  Each will be robust to some changes and sensitive to others.

My goal is to learn more about how different synaptic targeting strategies are deployed across the nervous system, and how patterns in deployment impact the structure and function of neural circuits.

Why is this important?

The relationship between robustness and sensitivity to change for a specific set of synapses will determine whether and how those synapses become dysfunctional (and cause disease) in response to gene mutations, developmental disruptions, and abrupt environmental change.  Thus, patterns of synaptic targeting strategy deployment across the nervous system will shape the landscape of developmental disorders.

These factors will also shape the landscape of survivable variation between individuals within a population - how much a specific neural circuit can vary without causing a disastrous change in behavior.  Survivable variants provide an opportunity for neural circuit evolution in response to selective pressures.  The specific synaptic targeting strategy deployed by a given neural circuit will help to shape its evolutionary trajectory, by facilitating variation along certain parameters while constraining variation along other parameters.