Hunger biases attention to food predicating stimuli (e.g. restaurant logos) over other less relevant stimuli. In obese individuals, this biased attention to food cues persists even when individuals are no longer hungry. How attention is selectively biased to food cues in a state-dependent manner is still poorly understood. Understanding how internal signals shift attention selectively to food images is critical for determining the pathophysiology of obesity and developing new therapeutics to prevent excessive food consumption. This project will investigate the possibility that, during hunger, specific neuromodulatory signals (dopamine and ghrelin) selectively bias populations of basolateral amygdala (BLA) neurons that are important for updating the moment-to-moment value of predictive cues. Levels of dopamine rise in response to unexpected rewards and reward-predicating cues. They also vary with internal state indicating that dopaminergic projections to amygdala may modulate value processing in a state-dependent manner. In addition, during hunger, circulating levels of the stomach-derived hormone ghrelin, the only known peripheral signal that can drive feeding in animals including humans, are elevated. In addition to its behavioral effects, ghrelin injections in humans enhance responses in the cortex, amygdala, and mesolimbic dopamine areas to food images. Recent work in our lab has found that neurons in insular cortex (InsCtx), a visceral/gustatory area that is important for interoception, show biased responses to food predicting cues after learning and these biased responses are modulated by hunger. Connections between BLA and InsCtx may be important for updating the value of food cues as animals go from being hungry to sated. I will address whether dopamine and ghrelin actions in BLA can selectively bias food cue responding neurons by imaging BLA axons in InsCtx and asking the following main questions: 1) Do separate BLA neurons respond to food cues versus aversive cues 2) Does dopaminergic input to BLA gate food cue responses of BLA neurons in hungry animals 3) Are ghrelin receptor expressing (GhSR+) BLA neurons food cue biased and modulated by hunger state? To determine if subsets of BLA neurons respond to food cues versus aversive cues, I will image BLA axons in InsCtx using a microprism implanted alongside InsCtx, which allows for chronic imaging in awake, behaving mice for many weeks (Aim 1). To ask how dopamine activity affects BLA activity, I will monitor the activity of dopamine axons in BLA using fiber photometry and use chemogenetic tools to manipulate the activity of dopamine neurons (Aim 2). To test whether GhSR+ BLA neurons preferentially respond to food cues over aversive cues, I will use a novel GhSR transgenic mouse line to selectively label these neurons allowing me to identify their axons in InsCtx (Aim 3). These studies will begin to define the mechanisms underlying the hunger-dependent sensory processing ? a key step towards development of strategies to reduce overattention to unhealthy food cues.
While humans normally have increased attention to food images when they are hungry, attention that persists even after meal consumption may contribute to the pathophysiology of obesity. This study investigates how internal signals of physiological state (dopamine and ghrelin) modulate amygdala neurons, which are necessary for updating of the motivational value of images. Mechanistic insights from this study may lead to new therapies to quell excessive food seeking and consumption.
