Linking hypothalamic and amygdalar circuits underlying attention to food cues

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 DESCRIPTION (provided by applicant): Hunger selectively enhances attention to food-associated cues, which can lead to excessive eating and obesity. Our lab seeks to establish a genetic mouse model to examine the neural pathways underlying hunger- dependent attention to food-cues. Our proposed circuit includes neurons expressing agouti-related protein (AgRP) in the arcuate nucleus of the hypothalamus (sensing internal state), the amygdala (updating the value of sensory cues and encoding motivational salience), and the higher visual cortical areas that receive selective amygdalar input (object recognition). Our proposed model for hunger-dependent attention is that hypothalamic AgRP neuron activity mirrors a drive to seek food. The amygdala integrates these interoceptive cues with exteroceptive cues about the sensory environment (via inputs from higher visual cortical areas) to identify motivationally relevant cues in the environment and allocate additional sensory processing to these cues. I hypothesize that as the hunger state of the animal changes, so does the motivational relevance or `value' of food-cues, a process dependent on activity in both the hypothalamus and the amygdala. In support of this, in a large number of human neuroimaging studies, the amygdala and ventral visual cortical areas that receive amygdalar input consistently show increased responses to visual food cues during hungry, but not sated, states, an effect likely due to indirect hypothalamic (and possibly direct hormonal) influences on these areas. These studies, however, lack the cellular resolution to dissect the basic microcircuits involved in hunger- dependent attention. Unlike in human neuroimaging studies, our studies in behaving mice involve the simultaneous recording, at single cell resolution, of genetically-identified neurons, across natural and induced states of hunger. I will examine two nodes in our proposed circuit. In Aim 1, I will use electrophysiological recordings in optogenetically-defined classes of neurons in the arcuate nucleus of the hypothalamus to measure state-dependent neural responses to food-associated and neutral visual cues. In Aim 2, I will use two-photon calcium imaging to measure the state-dependent neural responses of amygdala axons projecting to higher visual cortex in an identical task. Our preliminary data suggests that, both AgRP cells and the amygdalar projections to higher visual cortex show hunger-dependent neural biases to food-cues. Finally, I will determine the contribution of hypothalamic pathways in hunger-dependent attention to food-cues by testing whether optogenetic stimulation of AgRP neurons, a manipulation known to drive food-seeking behavior, is sufficient to recapitulate neuronal biases to food-cues (Aim 3). In this way, I can begin to define the relationship between circuits underlying the drive to seek food, and those translating this drive into selective cognitive processing of specific sensory cues. In summary, my proposal will dissect the neural pathways from hypothalamus to cortex important for hunger-dependent attention to food cues, and provide an important step towards the rational design of novel therapies for reducing over-attention and addiction to highly palatable foods.