Sensory transduction begins with electrical signals in primary sensory cells. Before these signals can be used to direct behavioral choices, they must be re-formatted, or transformed. This is the job of the brain's sensory processing circuits. Sensory transformations occur progressively, as information moves from primary sense organs toward motor planning regions. Our research is aimed at understanding the fundamental principles governing these transformations, their mechanisms, and their functions.
The Drosophila Antennal Lobe as a Model for Sensory Processing
The brain is generally studied either at the level of individual neurons and synapses or at the level of neural systems. We want to bridge the gap between these levels of explanation. This is most feasible in a brain that contains a small number of neurons, where each neuron (or type of neuron) is easily identifiable, where it is possible to make both intra- and extracellular recordings from identified neurons in an awake organism, and where genetic tools permit very specific in vivo manipulations of cellular and circuit properties. We use the fruit fly Drosophila melanogaster as a model organism because it meets all these criteria.
Probably the most experimentally tractable region in the Drosophila brain is the antennal lobe, and thus much of our research has focused on this region. The antennal lobe is the first brain region in the olfactory system, analogous to the mammalian olfactory bulb. It receives input from a well-characterized population of olfactory receptor neurons (ORNs), and its anatomy is highly organized: all the ORNs that express the same odorant receptor gene project their axons to the same compartment (or glomerulus). In total, there are about 50 glomeruli in the antennal lobe, each corresponding to a unique odorant receptor gene. ORNs make excitatory synapses with second-order neurons called projection neurons (PNs). Each PN receives direct ORN input from just a single glomerulus, and lateral input from other glomeruli via local interneurons. The orderly anatomy of this circuit, and the ability to label identified neurons within the circuit with green fluorescent protein (GFP), make it a useful model for studying sensory processing.
Selective Amplification of Weak Signals
The first step in olfactory processing occurs when odor molecules bind receptors on ORNs. Each odor typically activates multiple ORN types, and this generates a characteristic pattern of electrical activity in the ORN population. In a recent series of experiments, we made recordings from ORNs and PNs corresponding to the same glomeruli, and characterized how they respond to odors. We found that when an odor drives weak signals in an ORN (low firing rates), those signals are strongly amplified in postsynaptic PNs. By contrast, strong ORN signals (high firing rates) are not amplified to the same degree. Selective amplification of weak signals is potentially useful because it tends to protect these signals from noise contamination at later stages of sensory processing. Moreover, selective amplification of weak signals is useful for "decoding" neural spike trains in higher brain regions: a computational model of antennal lobe processing suggests that this transformation makes it easier for downstream neurons to respond selectively to a weak stimulus.
We next investigated the mechanisms of selective amplification. We showed that the amplification of weak firing rates is due to the unusual strength of the ORN-PN synapse, together with the fact that many ORNs converge upon each PN. There are two reasons why strong signals are not amplified in the same way that weak signals are. First, the ORN-PN synapse shows pronounced short-term depression at high firing rates. Second, there is an intrinsic ceiling on how fast PNs can fire. Thus, this transformation reflects nonlinear features of ORN-PN synapses and of PNs themselves.
The Role of Crosstalk Between Processing Channels
Because each odor typically activates ORN input to multiple glomeruli, the odor response of a PN could in principle reflect both direct input from its cognate ORNs and lateral input from other glomeruli via local neurons (LNs). We therefore became interested in the mechanisms and functions of crosstalk between glomeruli.
To see how PN odor responses change when lateral input to a glomerulus is removed, we took advantage of the fact that a few glomeruli exclusively receive input from ORNs in a minor olfactory organ, the maxillary palps, whereas most glomeruli exclusively receive input from ORNs in the antennae. We first characterized the responses of a genetically labeled PN postsynaptic to a palp glomerulus, and we then repeated these measurements in flies where the antennae had been removed. Removing the antennae does not affect the direct ORN input to palp glomeruli, but it removes most input to the rest of the circuit. The odor responses of palp PNs were disinhibited when the antennae were removed. This suggests that the net effect of lateral input is inhibitory. Next, we performed the reverse experiment: instead of removing lateral input to a glomerulus, we instead removed direct input to a glomerulus. We accomplished this by covering the palps with a plastic shield, thereby preventing odors from binding receptors on palp ORNs. In this situation, we saw that odor stimulation of the antennae suppressed spontaneous activity in palp PNs. This is consistent with the idea that lateral input is predominantly inhibitory. We went on to show that lateral inhibition reflects the release of the inhibitory neurotransmitter GABA from LNs. GABA binds to receptors on ORN axon terminals, thereby diminishing the strength of ORN-PN synapses.
In other experiments, we discovered that there are also excitatory lateral connections acting in parallel with inhibitory lateral connections. This was unexpected, since it had been previously thought that all antennal lobe LNs release the inhibitory neurotransmitter GABA. Lateral excitatory connections are broad and are recruited by weak levels of ORN input to the circuit. We therefore speculate that the importance of lateral excitation may be greatest when stimuli are weak. Lateral excitation may serve to transiently boost the excitability of the circuit, thereby promoting detection of weak odor stimuli.