Odor molecules bind to olfactory sensory neurons (OSNs) in the nasal epithelium, which synaptically excite two classes of excitatory output cells in the olfactory bulb, tufted cells (TCs) and mitral cells (MCs). In vivo, TCs and MCs respond differently to odorant stimulation: TCs have broader tuning profiles, faster response times, and are more sensitive to low odor concentrations than MCs. This effectively creates two output channels from the olfactory bulb, that carry different information about the odor to the cortex. This proposal seeks to identify mechanisms that underlie the difference in TC and MC responses to OSN activation. A central focus will be on a potential shunting function of connexin-36 (Cx36)-mediated gap junctions, which appear to be much more highly expressed in MCs than TCs, but the proposal will also examine a number of other potential contributing factors such as inhibition and active conductances in dendrites.
Aims 1 and 2 of the proposal will test the predictions of different mechanisms with experiments in olfactory bulb slices. These include the relationship between the intensity of an applied OSN stimulus (optogenetic or electrical) and the current and voltage responses of MCs and TCs (Aim 1), and also the sensitivity of the stimulus-response relationships to manipulations that modulate each mechanism (Aim 2). The manipulations employed in Aim 2 will include Cx36 KO mice and pharmacological blockade of GABAA receptors and voltage-gated sodium channels.
Aim 3 will use computational modeling to explore whether the identified mechanisms from Aims 1 and 2 are sufficient to explain the difference between TC and MC responses.
Aim 3 will also test alternative mechanisms that are difficult to manipulate experimentally, for example the contribution of cellular morphology. TRAINING AND ENVIRONMENT: To achieve the project?s goal, the applicant will develop expertise in sensory systems neuroscience, through regular meetings with her sponsor Dr. Nathan Schoppa (an expert in olfaction) and co-sponsor Dr. Joel Zylberberg (a computational neuroscientist with expertise in the visual system). Dr. Zylberberg?s expertise in a sensory system besides olfaction will help the applicant maintain perspective on how the specific circuit mechanisms studied within the proposal can generalize to other sensory systems. The applicant will also develop technical expertise in patch-clamp electrophysiology in brain slices and computational modeling, through experience and guidance of her mentors. The research training will take place at University of Colorado, Anschutz Medical Campus (UCAMC) in a collaborative environment that provides multidisciplinary training, covering the breadth of neurobiology. Relevant to the proposal, UCAMC has an especially strong research program in the chemical senses.
Olfactory dysfunction is often a symptom of neurological diseases and disorders, including Parkinson's disease, Alzheimer's disease, and Autism Spectrum Disorder. This proposal will expand our understanding of the neural circuitry behind olfaction, and how odor signals are normally processed.
