Project Summary Understanding how brain states influence sensory coding is fundamental in advancing our knowledge of the mechanisms by which neural circuits encode sensory information. The basal forebrain cholinergic system has long been implicated in such state changes and has been shown to play a crucial role in the detection, selection, and processing of behaviorally relevant stimuli. However, to date, almost all work regarding cholinergic modulation of olfactory circuits has focused on the effects of acetylcholine on olfactory system neurons while largely ignoring the circumstances that drive cholinergic neuron activity. Thus, very little is currently known regarding the conditions that drive basal forebrain cholinergic neuron activity or the characteristics of cholinergic fiber activity within the olfactory bulb. Further, fundamental questions also remain regarding the primary function of ACh release on olfactory coding, as most prior studies have focused on olfactory responses in anesthetized mice. For example, in the olfactory bulb, acetylcholine release is thought to enhance the sensitivity of olfactory bulb output cell odor responses and lead to improved olfactory discrimination. However, no experiments have been performed directly addressing these hypothesized functions in awake animals, leaving acetylcholine’s ultimate function within early olfactory regions unknown. The overall goal of this project is to understand this process by investigating how sensory input, stimulus novelty, and odor discrimination drive olfactory projecting cholinergic neuron activity and how this impacts olfactory odor responses. Our central hypothesis is that olfactory projecting cholinergic neurons preferentially respond to novel stimuli and impart information regarding salience to the olfactory circuits. We will use calcium imaging of defined cholinergic and olfactory system cell types combined with chemogenetic manipulation in awake animals during well-characterized olfactory-mediated behaviors to test this hypothesis. The findings of these experiments will be significant in that they will fundamentally advance our knowledge of the function of cholinergic input during olfactory-related events, how this affects sensory representations at multiple levels within the olfactory system, and how this ultimately impacts olfactory perception and discrimination.