A Genetically Defined Lateral Septum Circuit for Contextual Calibration of Food Reward-Seeking

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For the millions of individuals living with eating disorders (EDs), food-avoidance and -seeking have become debilitating and potentially life-threatening behaviors. If we are to improve treatments and identify novel therapeutics for EDs, it is absolutely critical that we understand brain circuits that calibrate feeding and interpret food-related contextual cues. The hippocampus (HPC) is critically involved in the contextual regulation of motivated behaviors, including feeding, but how contextual signals of the HPC are integrated and relayed to subcortical systems to scale motivated behaviors isn't well known. Leveraging deep molecular and circuit analyses, including single-cell sequencing, optogenetics, and monosynaptic neural tracing, we have uncovered a dorsally restricted subpopulation of LS neurons, characterized by its unique expression pattern of the neuropeptide, prodynorphin (Pdyn). Critically, and in male and female mice, these LS(Pdyn) neurons receive robust monosynaptic input from the dorsal HPC (e.g., CA3/2) and project strongly to feeding-related regions of the lateral hypothalamus (LH). Our preliminary data suggest that LS(Pdyn) neurons exhibit an inhibitory role on feeding. These findings concord with a food-seeking model in which inhibitory LS(Pdyn) neurons reduce food approach and eating by inhibiting food-seeking GABAergic LH(Vgat) neurons. As such, the proposed work will test the central hypothesis that a top-down excitatory dorsal HPC->dorsal LS(Pdyn)->LH(Vgat) circuit mediates context-dependent-regulation of food reward-seeking behavior. Accordingly, and in Aim 1 (spanning the first year of training under the K99 phase), we will deploy longitudinal 1-p calcium imaging in freely behaving mice to test the hypothesis that LS(Pdyn) neural activity negatively correlates with food approach and consumption, and that this activity can be deciphered to discriminate food-associated contexts (that promote feeding) from those that do not. In Aim 2 (in the final phase of the K99 period), we will characterize functional synaptic connectivity between excitatory hippocampal inputs to LS(Pdyn) inhibitory neurons, and we will test for the dependence of context-dependent feeding on hippocampal inputs to the dorsolateral septum [the region in which LS(Pdyn) neurons are expressed] using circuit-specific optogenetics. In the final Aim 3, and in the establishment of my own independent research program (in years 3-5 of the R00 stage), I will implement the techniques established in Aims 1 and 2 to test whether LS(Pdyn) inhibitory neurons synapse onto inhibitory LH(Vgat) neurons and whether this circuit is critical for the context-dependent expression of food reward-seeking (circuit-specific optogenetics). Moreover, Aim 3 will test whether LH(Vgat) neurons are inhibited in vivo following LS(Pdyn) activation (combining cell-type-specific optogenetics of the LS and longitudinal calcium imaging in the LH), directly linking LS(Pdyn) neural activity to the LH for regulation of context-triggered feeding. In total, these studies will identify how dorsal LS(Pdyn) activity patterns encode and deploy environmental signals for the contextual calibration of motivated feeding behaviors.