Joseph D. Zak, Ph.D. - US grants

DESCRIPTION (provided by applicant): Sensory input in the mammalian olfactory bulb arises from olfactory sensory neurons located within the nasal epithelium that project their axons to distinct networks known as glomeruli, each corresponding to a unique feature of an odorant molecule. A biological limitation of the olfactory system is the inability of odorant receptors located on olfactory sensory neurons to be perfectly selective. Odorant receptors have a preferred ligand, although they may also bind additional ligands across a spectrum of affinities. The ability of odorant receptors to bind both preferred and non-preferred ligands could obscure the brain's interpretation of the actual ligand present. I propose that this problem is addressed mainly through the activation of the local network of neurons that surround glomeruli. These cells, which include glutamatergic external tufted (ET) cells and GABAergic periglomerular (PG) cells, act as a signal detection mechanism, selectively filtering out weak signals in favor of strong signals. Aim 1 will examine the possibility that PG cells and ET cells are activated by varying degrees of sensory input, allowing for low-level olfactory input to selectively activate inhibitory PG cells, thus effectively filtering weak sensory input signals. Ai 2 explores whether PG cell activity can be modulated by local glutamate released from ET cells, which may increase the effectiveness of weak signals and produce temporal patterning in glomerular activity. Aim 3 tests the ability of the ET cell-PG cell microcircuit to control the probability of mitral cell activation and also employs a novel population analysis that allows for identification of excitatory and inhibitory neurons in the glomerular layer of the olfactory bulb. This proposal examines a model for intra-glomerular interactions in which PG cells gate glomerular activation.

Project Summary Animals, including humans, interact with their chemical environment through specialized receptor cells found within the nasal epithelium. Upon odorant binding, these neurons transmit information to the olfactory bulb, the initial site of olfactory sensory processing. However, at present, our understanding of how these cells ultimately communicate information about odor identity and concentration to the brain in intact animals is limited. I propose that olfactory receptor neurons are a highly diverse population of cells in terms of their odor responses within a sampling event. Furthermore, heterogeneous activity among receptor neurons may be a mechanism to preserve non-redundant information about the sensory environment. Aim 1 will examine how populations of olfactory receptor neurons encode odor mixtures. Aim 2 will test the hypothesis that individual olfactory receptor neurons heterogeneously respond to odors. Together, these aims will provide novel insights into mechanisms of sensory transduction in the mammalian olfactory system.

PROJECT SUMMARY/ABSTRACT To reliably encode information about the environment, neurons must modify their activity profiles and even connectivity to accurately interpret complex stimuli. Cortical feedback projections to the olfactory bulb are uniquely positioned at the interface between detection-based processing that is driven by sensory input and analytical processing occurring in the piriform cortex. This arrangement makes these projections an ideal target to study how learning reshapes neuronal activity profiles. I have developed an approach that will allow for a comprehensive analysis of the axonal activity of principal neurons in the piriform cortex, while mice learn a task requiring them to identify a specific odor embedded in complex mixtures, thereby providing unique insight into olfactory scene analysis. My approach will also provide a detailed analysis of the connectivity between cortical axons and their postsynaptic targets in the olfactory bulb, which will reveal how the olfactory bulb integrates processed information from the piriform cortex. The hypothesis I will test is that learning reshapes cortico-fugal input to the olfactory bulb, leading to enhanced odor-scene segmentation through the disambiguation of olfactory bulb output neuron activity profiles. The outcomes of these studies will provide novel insight to how the brain to updates its stimulus-encoding scheme from a synthetic to analytical representation of a stimulus environment. The studies proposed here are novel technically as well as conceptually, and the results will be broadly applicable to other sensory systems. In Aim 1, I will characterize how learning shapes the activity of cortical feedback projections to the olfactory bulb. Aim 2 will determine how the synaptic strength and number of cortical inputs to individual olfactory modules are updated during learning. Finally, Aim 3 will determine how cortical input shapes the activity profiles of bulbar output neurons. The training phase of this award will be conducted at Harvard University in the laboratories of Prof. Venkatesh Murthy and Prof. Naoshige Uchida. Together with my mentors and advisory committee, I have developed a comprehensive training plan that will provide me with new technical skills and provide professional development that will enable my successful transition to an independent investigator. The completion of this project will provide the basis for future experiments related to learning-mediated plasticity in the olfactory system and other sensory systems.