robust development of neural circuits

For additional discussion, please see the full article in Current Biology, and check out our interview on the node.

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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.


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Facial motor neurons (shown in green) normally migrate from their birthplace in rhombomere 4 (R4) to their final settling locations in rhombomeres 5-7.  However, specific mutations can disrupt that migration - leaving facial motor neurons stuck in the wrong place.

Can these mis-positioned motor neurons still incorporate into functional neural circuits?


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Facial motor neurons drive two groups of muscles:  several muscles on the ventral surface of the buccal cavity (left) ... 

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... and additional muscles over the operculum (the flap covering the opening to the gills).  These muscles are involved in suction feeding and respiration.


Whole cell recording from a facial motor neuron (orange trace) during simultaneous recording of motor activity in the tail (white trace).

In wild type larvae, facial motor neurons exhibit two patterns of respiratory activity:  infrequent bursts associated with attempted whole-body movements (shown in the box), and additional rhythmic bursts (~0.5-2Hz).  

Whole cell recording from facial motor neuron (orange trace) during simultaneous recording of motor activity in the tail (white trace). 

Surprisingly, the radically mis-positioned facial motor neurons in migration mutants also exhibit both rhythmic and body movement-associated bursting respiratory activity - suggesting that normal positioning might not be absolutely necessary for circuit development.  In other words, premotor neurons from rhythmic respiratory networks may still target facial motor neurons - even though those facial motor neurons are in the wrong place.


 Orange traces represent the rotational movement of the operculum (shown in the above right inset), tracked from a video recorded at 20 frames per sec.  Note the respiratory pattern: rhythmic movements (~0.5-2Hz), followed by a large movement correlated with an attempted struggle or swim (arrows), followed by a pause before the pattern repeats.

Orange traces represent the rotational movement of the operculum (shown in the above right inset), tracked from a video recorded at 20 frames per sec.  Note the respiratory pattern: rhythmic movements (~0.5-2Hz), followed by a large movement correlated with an attempted struggle or swim (arrows), followed by a pause before the pattern repeats.

Indeed, rhythmic respiratory movements of the operculum (shown in orange) are still executed in migration mutant zebrafish - with a similar temporal pattern to that observed in wild type fish. Again, this strongly suggests that facial motor neuron function is robust to positional disruption.


what's next?

We still don't completely understand the rules that determine how neurons target each other to establish synaptic connections.  We do know that some neurons search for their partners in a specific location in the brain, and that moving the partners around can severely disrupt that process and cause functional abnormalities in the animal.  Indeed, it makes sense to use neuronal positioning to guide synaptic connectivity, since many neuronal populations are reliably located in the same region of the brain across individuals.

However, in this case, facial motor neurons seem to retain at least some of their functional output when they are dramatically re-positioned, suggesting that at least some of their synaptic partners can still find them.  I'd like to understand how this robust function is achieved, and probe for more subtle defects in the mutant circuit that might be not apparent from spontaneous respiratory activity alone (and might leave the respiratory network vulnerable to specific behavioral challenges).


WHY does this matter?

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.