The overall goal of this project is to directly test how cholinergic input from the nucleus of the horizontal limb of the diagonal band of Broca (HDB) alters olfactory bulb (OB) glomerular circuits and how this modulation ultimately affects odor coding, perception, and learning. We will use of both wide-field and 2-photon in vivo and in vitro calcium imaging in mice expressing genetically encoded indicators of neuronal activity in defined OB cell types, to test the novel overarching hypothesis that synaptically-released acetylcholine bidirectionally modulates mitral/tufted cell odor responses as a function of the prevailing odor intensity. We further test the hypothesis that this modulation is due to opposing muscarinic and nicotinic receptor actions on inhibitory periglomerular cells that differentially regulate the strength of presynaptic inhibition of olfactory sensory neuron input to the glomeruli. Using imaging and well characterized olfactory-mediated behaviors, we will also investigate how this cholinergic modulation of the glomerular odor representation affects odor perception and learning. Specifically, we test the hypotheses that HDB-evoked acetylcholine release in the OB: (1) enhances olfactory sensitivity, (2) dishabituates odor responses adapted at the peripheral olfactory sensory neuron level and (3) is critical for associative olfactory learning. By investigating receptor type-specific cholinergic modulation in morphologically- and physiologically-distinct neuron types at both the population and single cell levels, the experiments of this proposal will for the first time elucidate how cholinergic modulation of neural odor responses in the OB impacts olfactory perception and learning behaviorally. The overall findings will dramatically advance our understanding of how acetylcholine modulates sensory representation, odor coding, perception and behavior.
Olfactory dysfunction is an early indicator of several major neurological diseases in humans including Alzheimer's and Parkinson's diseases. As the loss of cholinergic neurons is a hallmark in both of these diseases, it is particularly important to understand the basic mechanisms by which cholinergic modulation affects the neuronal circuits involved in sensory processing, learning, and memory which could help in the diagnosis and treatment of these diseases. This proposal will elucidate how acetylcholine release in a primary cortical sensory structure, the olfactory bulb, impacts sensory coding, stimulus salience, perception, and olfactory learning will provide insights into sensory and cognitive impairments with disturbances in cholinergic function.
