In this proposal we describe a set of experiment designed to test how sensory signals are represented at the first synapse of the accessory olfactory system. The accessory olfactory system detects chemical signals pertinent to behavioral responses ranging from aggression to neuroendocrine control of reproduction in animals. Sensory neurons in the nose project to the accessory olfactory bulb, where axons from neurons expressing the same receptor type co-converge on small regions of neuropil called glomeruli. Individual receptor types converge within subsets of glomeruli in a single lamina of the laminar accessory olfactory bulb. Within these glomeruli, sensory neurons synapse on mitral cells, which encode sensory signals and project out of the olfactory bulb. It is unknown whether the response patterns of the sensory neurons and mitral cells have a spatial correlate in the glomeruli. In addition to connections with mitral cells, sensory neurons drive activity in glomerular inhibitory interneurons. GABA(A) and (B) receptors are expressed both pre- and post-synaptically;these inhibitory receptors are candidate effectors for a variety of circuit and sensory processing tasks from scaling and normalization of inputs to the encoding of specific memories for the scent of other animals. However, virtually nothing is known about the degree to which inhibition shapes responses within the glomeruli. For example, it is unknown whether the inhibition is "lateral" (meaning, it acts between glomeruli corresponding to different receptors), and what the consequences of inhibition are for the output neurons of the bulb, the mitral cells. To examine the specificity of glomerular activation and mechanisms of inhibition, we will exploit the fact that the levels of signaling in sensory neuron terminals within the glomeruli are optically measurable as changes in calcium concentration, thus rendering the entire population response to a stimulus amenable to optical recording.
In Aim 1, we will identify the spatial patterns of glomerular activation within the accessory olfactory bulb using sulfated steroids known to drive activity in both sensory neurons and mitral cells. We predict that glomerular activations by different ligands will be functionally separate and have stereotyped spatial distributions.
In Aim 2, we will determine the role of inhibitory neurotransmission in shaping the responses of co-activated glomeruli. Populations of glomeruli will be identified by responses to individual sulfated steroids, and then the inhibitory interactions will be measured when the populations are simultaneously activated. The role of both GABA(A) and GABA(B) receptors will be measured, via GABA(A) and (B) antagonism. We predict that GABAergic inhibition of sensory neuron pre-synaptic terminals will occur both within glomeruli and between adjacent co-active glomeruli. If successful, these experiments will provide a mechanistic basis for recent observations such as diminished estrogen sulfate responsiveness of mitral cells relative to sensory neurons and sex-specific odor opponency.

Public Health Relevance

The goal of the research plan presented in this proposal is to understand the how the accessory olfactory system detects and represents chemical signals in the environment. Specifically, this study will characterize both the spatial organization of chemosensory neuron response patterns and the role of inhibition in shaping complex stimulus response patterns in the accessory olfactory bulb glomeruli. These studies in the accessory olfactory system will record functional information from all sensory neurons in the accessory olfactory system, providing a broad perspective from which to form hypotheses about sensory processing.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DC011673-04
Application #
8609564
Study Section
Communication Disorders Review Committee (CDRC)
Program Officer
Sklare, Dan
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$47,676
Indirect Cost
Name
Washington University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Hammen, Gary F; Turaga, Diwakar; Holy, Timothy E et al. (2014) Functional organization of glomerular maps in the mouse accessory olfactory bulb. Nat Neurosci 17:953-61
Doyle, Wayne I; Hammen, Gary F; Meeks, Julian P (2014) Ex vivo preparations of the intact vomeronasal organ and accessory olfactory bulb. J Vis Exp :e51813