Neural circuits

We are using molecular genetic techniques to study the function of neural circuits in Drosophila. We want to understand how the brain works. How does information processing in neural circuits generate complex animal behaviour? As a model system, we focus on the fly’s mating behaviours. These behaviours are robust, adaptive, and particularly amenable to genetic analysis.

A major goal for neuroscience is to understand how information processing in neural circuits guides behavioural decisions. How, at any given moment, does an animal decide what to do? Somehow, the brain selects the best course of action by integrating information from multiple sources – sensory input, internal physiological states, and individual experience. We would like to find out how the brain does this.

As a model, we have chosen to study the sex life of the fruit fly Drosophila melanogaster. During mating, flies make decisions that are critical for their reproductive success, and hence their evolutionary fitness. Upon encountering another fly, the male estimates his chances of success and decides if it is worth investing time and energy in courtship. Whether or not mating actually occurs is a matter of female choice, based on how she assesses of her suitor’s quality, as well as her own readiness to mate. These are complex decisions made by complex brains, but working with flies has the great advantage that genetic tools can be used to identify and manipulate the relevant neurons and circuits in the brain. With these tools, it should be possible to establish causal relationships linking cellular biochemistry, circuit function, and animal behaviour. 

The male brain

Figure 1 (Click to view legend)

Remarkably, the different mating behaviour of male and female flies can largely be explained by the sex-specific splicing of a single gene – fruitless (fru). If females are forced to express male-specific fruM transcripts, they behave like males. Conversely, males that lack fruM behave like females.

Figure 2 (Click to view legend)

fru is expressed in some 2000 neurons, distributed in clusters throughout the nervous system (Fig. 1). The activity of these neurons is essential for courtship behaviour. We are currently developing methods to gain genetic access to distinct subsets of fru neurons, so that we can study the anatomy and physiology of the fru circuit at single-cell resolution (Fig. 2). We would like to know if and how each of type of fru neuron contributes to courtship, what types of signal each neuron processes, and how and to what extent sexually dimorphic processing in these neurons leads to the distinct behaviours of males and females.

Figure 3 (Click to view legend)

One important class of fru+ neurons are the olfactory receptor neurons (ORNs) that detect pheromones. We have recently found that one subclass of fru+ ORNs expresses the odorant receptor Or67d and responds to a male sex pheromone. These neurons connect to second-order olfactory neurons in the antennal lobe of the brain (called DA1 projection neurons) (Fig. 3). The neurons are also fru+, and appear to make sexually dimorphic connections in higher brain centers. This may be a critical site for sex-specific processing of pheromone signals.

 

 

The female brain

The female decides whether to accept or reject the male based in part on her perception of his courtship song and pheromones. The biggest factor in the female’s decision, however, is her own mating status. Virgin females are generally receptive to courting males, whereas females that have recently mated are not. This difference can largely be attributed to a small peptide, called the sex peptide (SP), that is present in the first male’s seminal fluid. If females mate to males that lack SP, they remain receptive to other males. Conversely, direct injection of SP into virgin females renders them unreceptive. But how and where does SP act in the female to modulate her mating decision?

By screening our transgenic RNAi library, we have recently identified a molecular receptor for SP, a G-protein coupled receptor we call SPR (sex peptide receptor). SPR is broadly expressed in the nervous system, but we find that it is specifically required in a small subset of fru+ sensory neurons that innervate the reproductive tract and project axons to various regions in the central nervous system. Our ongoing efforts are aimed at understanding how SP modulates the function of these neurons, and how this in turn impacts the functioning of circuits in the brain that assess male courtship signals and decide whether or not to allow mating.
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