For almost a century, researchers have described oscillations in the olfactory system following sensory stimulation. While the spatial pattern of gamma-band oscillations does not appear to reflect odorant identity, work on insect olfaction suggests that these oscillations may represent a critical timing signal that temporally separates different cell assemblies that encode sensory information. The cellular basis of gamma-band oscillations remains unknown. There are three predominant theories of how gamma-band oscillations arise in the olfactory system. Freeman and colleagues originally proposed gamma-band oscillations reflect the timing of reciprocal synaptic interactions between mitral cells and the granule cells. More recently, Kopell and colleagues proposed that these oscillations are driven primarily by subthreshold oscillations in mitral cells. Finally, work on potentially analogous oscillations in the hippocampus raises the possibility that olfactory gamma may arise from activity in an autonomous network of interconnected interneurons. While several groups have described features of olfactory gamma oscillations that are consistent with each of these three models, no group has systematically attacked the question of the cellular mechanism of these network oscillations. Defining this mechanism will potentially have high significance for understanding how sensory information is processed in the olfactory system, other systems are likely to be mediated by the same neurons that generate gamma-band network oscillations, and may be mechanistically related. I propose to use intracellular recordings in acute rodent brain slices to define the cellular mechanisms underlying gamma-band oscillations in the olfactory bulb. My preliminary studies have generated a novel "minislice" preparation in which pharmacological tools can be tested on specific layers of the olfactory bulb. I will test the ability of mitral cell spiking to drive gamma oscillations when selectively activated in minislices. I will perform three complementary measurements of gamma oscillations in olfactory bulb minislices: measuring the local field potential, performing cell-attached recordings from two mitral cells, and amplification of inhibitory inputs in voltage-clamp whole-cell recordings of a mitral cell. I will assay the effects of inhibition by removing the tonic Mg block of NMDA receptors that regulate these microcircuits, and by application of a pharmacological blocker of GABAa receptors. By selectively activating granule cells with bath application of the muscarinic receptor agonist MCN-A 343, and focal stimulation in the granule cell layer I will test the effect of granule cell spiking on gamma oscillations.
By elucidating how clearly defined circuits of a limited number of cell types generate large amplitude gamma- band oscillations occur within the olfactory bulb, a better understanding of how complex systems in other deeper brain structures, in both normal functioning and disease states, operate may be elucidated. This better understanding could lead to novel therapeutic approaches using deep brain stimulation paradigms that more accurately reflect the modalities of biological information processing.
|Schmidt, Loren J; Strowbridge, Ben W (2014) Modulation of olfactory bulb network activity by serotonin: synchronous inhibition of mitral cells mediated by spatially localized GABAergic microcircuits. Learn Mem 21:406-16|