Trends in Neurosciences
ReviewCracking neural circuits in a tiny brain: new approaches for understanding the neural circuitry of Drosophila
Section snippets
What is circuit cracking?
The Oxford English Dictionary defines to crack as ‘to puzzle out, make out, solve, discuss.’ To completely solve a neural circuit would require
- (i)
describing a behavior whose neural circuit mechanisms we seek to understand,
- (ii)
identifying which neurons are involved,
- (iii)
determining what drives activity in each type of neuron and how these signals are transformed through the circuit,
- (iv)
discovering the cellular, synaptic and circuit mechanisms underlying these neural transformations
- (v)
understanding why these neural
Why the fly?
Cracking every neural circuit in every species would be impossible and pointless. But a detailed comparison of several circuits in different species should help reveal what features of neural circuits are fundamental and which are specializations. Many (although not all) neuroscientists believe that some neural circuits in Drosophila are worth including in this research program.
The most obvious reason is the power of the Drosophila genetic toolbox. Mouse neurogenetic tools are beginning to
Defining the behavioral task
Circuit cracking generally begins with an observable behavior that we seek to understand. Classical Drosophila behavioral paradigms were designed to screen many flies simultaneously for profound defects, with the goal of isolating new genetic variants. But neuroscientists are increasingly interested in fly behavior for its own sake, rather than simply viewing it as a tool for isolating mutations [3].
Several recent behavioral studies have expanded our notion of the fly's cognitive ability. For
What neurons are involved?
We have little notion of what neurons are involved in many fly behaviors. For example, we have no idea which neurons mediate somatosensory, gustatory or auditory behavior (except primary sensory cells and motorneurons). Although we know where the axons of the relevant primary sensory cells project, this does not make it trivial to find their postsynaptic targets. This is because the fly brain and thoracic ganglion are small (∼200 microns) relative to the size of an individual fly neuron (which
Assigning function to neurons
Once neurons have been genetically identified, we face the challenge of understanding how information is represented by neural activity in this circuit, and how this activity reflects the computations being performed. Until recently, it was considered impossible to monitor neural signals in the Drosophila central nervous system in vivo. As a result, most studies have sought to reveal circuit function by inactivating or stimulating neurons of interest – that is, testing whether neurons are
Mechanisms of circuit processing
The next step is to uncover the synaptic and cellular mechanisms underlying sensorimotor transformations. This means mapping synaptic connectivity and investigating the functional properties of these connections.
The gold standard for demonstrating a synaptic connection is to directly visualize both pre- and postsynaptic specializations with electron microscopy. Systematic ultrastructural studies of the Drosophila brain are currently underway in several laboratories, but full 3D reconstructions
Mathematical models of circuits and behavior
The final output of even small circuits represents a complex interplay between circuit elements. Mathematical models can help reveal the logic of circuit operation by organizing anatomical and neurophysiological data, and can guide experimental studies by providing testable predications about both neural activity and behavior. So far, Drosophila has inspired few modeling efforts, but studies in other relatively simple animals suggest ways in which these techniques might be useful. For example,
Limitations of the model organism
The virtues of Drosophila as a model for systems neuroscience are easy to grasp. However, the limitations of this model organism receive less public attention. Some of these limitations might be swept aside by future breakthroughs, but others might be intrinsic to the fly.
One problem is that the small size of the Drosophila brain will make it extremely challenging to perform electrophysiological measurements in the behaving fly. Functional imaging might offer a solution to this problem, but
Acknowledgements
The Wilson laboratory is supported by grants from the NIH (1R01DC008174-01), a Pew Scholar Award, a McKnight Scholar Award, a Sloan Foundation Research Fellowship and Beckman Young Investigator Award (to R.I.W.).
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