State-dependent modulation of olfactory behavior - Project Summary Hunger and thirst are powerful motivational states that drive intense attraction to need-related stimuli. Here, we investigate how hunger and thirst differentially focus behavioral attention towards food and drink odors but not other olfactory cues. These studies should help provide insight into long-standing questions in neuroscience, including how various sensory inputs are distinctly represented in the brain, and how physiological state influences behavior. The olfactory system detects a myriad of odors that elicit diverse perceptions, and in mice, food odors, pheromones, and predator odors differentially influence feeding, mating, and fear. One model is that the olfactory system uses parallel processing streams to channel particular sensory inputs into appropriate behavioral outputs. Interestingly, hunger and thirst influence only select olfactory pathways, enhancing attraction to food and drink odors respectively but not pheromones. Yet, molecular and cellular features that distinguish olfactory circuits responsive to food or drink odors are unknown. Here, we will leverage powerful genetic approaches in mice to study how hunger and thirst selectively and differentially gate odor responses. We recently observed that hunger shifts odor preference through a Neuropeptide Y (NPY) spotlight (Nature 2021). Optogenetic stimulation of hypothalamic AGRP (Agouti-related peptide) neurons, like fasting, promotes attraction to food odors but not pheromones through specific projections to the paraventricular nucleus of the thalamus (PVT). Knockout mice lacking NPY or one of its receptors (NPY5R) fail to prefer food odors over pheromones after fasting, with normal behavior restored by cell-specific NPY rescue or acute NPY injection in the absence of further training. Thus, food odor-responsive neurons comprise an olfactory subcircuit that listens to hunger state through thalamic NPY release. Here, we will build off of these findings by using NPY5R as a genetic handle to characterize key neurons involved in food odor responses. Npy5r mRNA is highly expressed in olfactory (piriform) cortex but not PVT, and NPY5R neurons from the piriform cortex are back labeled by tracer injection in the PVT. We hypothesize that NPY5R acts in PVT-projecting axons of food odor- responsive cortical neurons. We made new mouse models for Cre-based knockout and rescue of the Npy5r gene to pinpoint the site of NPY5R action, as well as Npy5r-p2a-Cre mice to enable optogenetics and fiber photometry experiments. Moreover, in preliminary data, we developed a paradigm to measure thirst-driven odor attraction, and are poised to chart how thirst and hunger exert differential control over olfactory responses. Together, these Aims should help reveal how neural circuits represent different classes of olfactory cues and mediate state-dependent behaviors.
