1) What does the olfactory bulb compute?
The olfactory bulb has a distinct two-layered structure; the glomerular layer - where the input signals arrive; and the mitral cell layer - from where the bulbar output exits to further higher centers in the brain. Very little is known of how these output cells process the input signals arriving from the glomeruli. How do the activity patterns of single cells or their populations encode all meaningful attributes of odor stimuli?
The fundamental step in understanding the bulb transfer function is characterization of the spatio-temporal receptive fields of these mitral cells, on a large scale basis – large number of neurons, as well as a wide variety of odorants.
To this effect, we probe neuronal responses in the two layers of the bulb both optically (large number of cells) and electrophysiologically (high temporal precision), while stimulating with a large panel of odorants (>100), as well as by precise activation of individual glomeruli using optogenetic tools.
An important test of our understanding of the bulbar circuitry lies in the ability to predictably induce or alter olfactory percepts and ultimately behavior. Optogenetic tools allow us to modulate the spatio-temporal properties of olfactory bulb inputs, systematically, and determine how precise changes in the activity of the circuit alter olfactory behaviors.
2) What principles underlie the lateral connectivity of the bulb?
Activity in the bulb is a rich mix of excitation and inhibition, via both direct inputs and feedforward and feedback connections by a wide variety of cell types. Juxta-glomerular cells are local interneurons that surround the glomeruli and send neurites within and across glomeruli. In the external plexiform layer, another class of inter-neurons, the granule cells, mediates cross talk between mitral cells via reciprocal synapses with lateral mitral cell dendrites. Both interneuron types are generic denominations for heterogeneous neuronal populations with respect to wiring, gene expression and physiological properties. Their activity is thought to be important for shaping odor responses. Despite decades of study in the slice preparation, little is known about how these inter-neurons operate in the intact circuit, in vivo, as mice probe chemical stimuli.
In collaboration with Josh Huang’s group, we are making use of genetic tools to dissect the circuit extensively, by expressing activity reporters and inducers in specific inter-neuron subpopulations.
Having done that, we plan to investigate systematically the function of distinct interneuron types and their relationships with the olfactory receptor neurons and the mitral cells while recording responses to a rich set of inputs.
3) What is the role of centrifugal input in gating bulb function depending on various ‘behavioral states’?
Olfaction is an active sense. Responses in the olfactory system are modulated not only by the stimuli, but also by the animal’s own behavior and motivational state. For instance, passive inhalation of odor under anesthesia, or free active sniffing of the environment trigger widely different patterns of neuronal activity.
We are investigating how connections in the bulbar circuit are regulated in relation to the state of the circuit and the extent of feedback from extra-bulbar areas. How do the activity patterns in the bulb correlate with the awake versus anesthetized brain, or with varying degree of motivation, arousal or stress? More importantly, what changes occur at the synaptic level within the circuit, as animals learn olfactory tasks?