Manipulation of the ghrelin receptor in the olfactory bulb affects smell and metabolism Romana Stark (Monash University), Elizabeth Kleeman (Monash University), Jeffrey Zigman (UT Southwestern), Zane Andrews (Monash University) Olfactory dysfunction contributes to many metabolic and mental illnesses in humans and many animals rely on olfaction for normal exploratory behaviour and food acquisition. Interestingly, changes in metabolic state, such as reduced caloric intake during fasting, enhances olfactory processing in both humans and animals. The mechanism linking metabolic state and olfaction remains unknown. Ghrelin is a hormone that regulates metabolism, mood, and memory at various central nervous system (CNS) locations via its receptor under a state of energy deficit. Although the ghrelin receptors are highly expressed in the olfactory bulb (OB), its function remains unknown. We investigated whether ghrelin receptors in the OB increases olfaction performance in fed and fasted conditions and whether or not this influences mood and metabolic parameters using a number of behavioural and metabolic challenges. We employed a viral genetic knockdown approach to chronically delete ghrelin receptors specifically in the OB in ghrelin receptor floxed mice crossed with cre-depednent tdTomato reporter mice to aid viral spread and knockdown validation. 10 week old adult mice were injected with AAV-cre (AAV5 pmSyn1-EBFP-Cre) in to the OB. Deletion of ghrelin receptors in the OB significantly affected olfactory performance in olfactory discrimination and habituation tasks in both fed and fasted mice, as well as increased the latency to find food under both fasted and ghrelin-induced conditions. A two-bottle choice assay for saccharin vs water indicated that mice lacking ghrelin receptors in the OB were completely anhedonic and did not show a preference for saccharin. In support of this, we observed significantly increased anxiety and reduced exploratory locomotor activity in 3 independent anxiety behavioural tasks. Intriguingly, mice increased body weight, fat mass and high blood glucose, indicating metabolic dysfunction. We conclude that OB GHSR maintains olfactory sensitivity under fasted conditions, leading to a number of behavioural and metabolic adaptations to help a mammal detect and respond appropriately to food and odour cues. These results highlight both a new CNS site of action and novel functions for ghrelin as a CNS signalling molecule. These findings can potentially inform future therapies aimed at treating both olfactory and metabolic diseases.