Real-time manipulation of neuronal activity in whole animals provides a powerful means by which the neuronal basis of behavior can be determined. Bath et al. (2014) describe a method for controlling the behavior of freely walking Drosophila using temperature. What distinguishes their work from earlier work is the method by which they deliver temperature changes. They use a tracking infrared (IR) laser that can heat the fly or even specific body parts of the fly, altering neuronal activity using a thermogenetic switch, and very rapidly affect a change in the insects’ behavior.
A few years ago optogenetics emerged as a powerful method by which neuronal activity could be controlled with high spatial and temporal resolution. The basic idea is to express light-sensitive proteins capable of stimulating neuronal activity in spatially restricted patterns, using light as a trigger. For example, channelrhodopsin is a cation channel that can be activated with light. There are a number of other light-sensitive ion channels.
You can see how that works in the accompanying video where a light-sensitive ion channel is expressed in specific muscles of the nematode, Caenorhabditis elegans. In this case green light triggers the channel in specific cells that are expressing a light-sensitive ion channel, muscles relax and the worm become longer. Turn off the green light and the worm’s muscles contract and it resumes moving.
There are temperature-actuated switches for controlling neuronal activity and behavior. In Drosophila there is a temperature sensitive allele of the shibire gene (Shits1) which has a semidominant phenotype. Shibire plays a role in synaptic vessel recycling and flies with the temperature sensitive allele expressed in cholinergic neurons show dramatic responses to temperature, depending upon which neurons are affected. Basically, nerve activity stops at an elevated temperture.
On can achieve very high spatial resolution (targeting specific neurons with high precision) using Shits1 in conjunction with the very robust collection of Gal4 driver lines available in Drosophila and UAS-regulated Shits1. Temporal resolution has been more of a challenge (achieving a short response time between applying heat and achieving a behavioral response), mainly because the environmental temperature has been modulated in the past and this limits how quickly nerves are heated and cooled.
Bath et al. (2104) achieve high temporal resolution by using an IR laser that can track moving flies in a small chamber allowing them to very precisely and rapidly warm the fly to affect Shits1 in cells specifically expressing it. They could get responses in less than a second after laser activation. Amazingly, they could program their laser tracking system to aim at the antennae, thorax or abdomen of a moving fly to allow them to achieve additional spatial resolution in identifying the roles of individual neurons in particular behaviors.
The spatially distinct expression of Shits1 using the powerful Gal4/UAS system in Drosophila to alter fly behavior was reported initially by Kitamoto (2001). Bath et al. (2014) take that method to a new level by adding a Star Wars-like laser tracking system the allows them to “zap” freely moving flies and quickly alter their neuronal activity and behavior in ways that will help them define the neural activity associated with certain behaviors. The current experiments were performed with flies moving in two dimensions, that is walking, but the authors say that their system could also work on flies moving in three dimensions, opening up a greater range of behaviors that could be dissected with this ‘mind altering’ technology.
Here’s a link to some amazing videos of the system in action.
This paper is a great example of the marriage between a powerful genetic technology for regulating gene expression in spatial well-defined ways (Gal4 enhancer-trap lines) with clever and advanced hardware.
FlyMAD: rapid thermogenetic control of neuronal activity in freely walking Drosophila
Daniel E Bath, John R Stowers, Dorothea Hörmann, Andreas Poehlmann, Barry J Dickson & Andrew D Straw
Nature Methods 11, 756–762 (2014)