PROJECT SUMMARY
Eating and drinking are rapid processes, but their postingestive effects are slow and delayed. How do animals
correctly associate these delayed effects (detection of nutrients or toxins in the gut) with transient stimuli like
tastes and smells that precede them by minutes or hours? To gain insight into this question, I leveraged the
fact that mice learn to associate novel, but not familiar, foods with gastric malaise signals to investigate what
distinguishes the neural representations of flavors that promote learning versus those that do not. I surveyed
brainwide expression of the immediate early gene Fos during drinking and during postingestive malaise and
discovered that distinct functional networks of flavor-selective brain regions are recruited at different phases of
postingestive learning. This led to two key hypotheses about how the brain is able to link tastes and flavors to
delayed postingestive feedback. During the postdoctoral phase (K99/Aim 1) of this proposal, I will test the
hypothesis that an amygdala network centered on the central amygdala (CEA) represents novel flavors during
drinking and that this representation is then reactivated when postingestive feedback signals from the gut
arrive, providing temporal overlap between the flavor representation and feedback that promotes learning. I will
first use high-density Neuropixels recordings to demonstrate that CEA novel flavor representations are
reactivated during postingestive malaise (Aim 1.1) and then use optogenetic activation of CEA novel flavor
ensembles to show that these postingestive reactivations are sufficient to drive learning (Aim 1.2). In the
independent phase (R00/Aim 2), I will test the hypothesis that a limbic network centered on the lateral septum
(LS) blocks these novel flavor reactivations to gate the formation of postingestive associations when flavors are
recognized as familiar and safe. I will first use axon terminal photostimulation to identify the specific LS
projection that gates learning (Aim 2.1) and then combine this manipulation with high-density neural recordings
in downstream regions (Aim 2.2) and brainwide Fos imaging (Aim 2.3) to investigate how LS activity blocks the
formation and reactivation of novel flavor representations. These experiments will generate key insights into
the cross-region neural mechanisms that support conditioned taste aversion and postingestive learning. During
the K99 phase, I will gain crucial technical expertise — in Neuropixels electrophysiology, advanced
computational tools, and activity-dependent genetic labeling — and professional development that will be
essential for my independent lab’s mission. Our ultimate goal will be to uncover general principles by which
interoceptive signals engage the brain to control behavior and how the mechanisms underlying postingestive
learning go awry in eating disorders and obesity.