Appetitive associative learning recruits a distinct network with cortical, striatal, and hypothalamic regions.

The amygdala, prefrontal cortex, striatum and other connected forebrain areas are important for reward-associated learning and subsequent behaviors. How these structurally and functionally dissociable regions are recruited during initial learning, however, is unclear. Recently, we showed amygdalar nuclei were differentially recruited across different stages of cue-food associations in a Pavlovian conditioning paradigm. Here, we systematically examined Fos induction in the forebrain, including areas associated with the amygdala, during early (day 1) and late (day 10) training sessions of cue-food conditioning. During training, rats in the conditioned group received tone-food pairings, while controls received presentations of the tone alone in the conditioning chamber followed by food delivery in their home cage. We found that a small subset of telencephalic and hypothalamic regions were differentially recruited during the early and late stages of training, suggesting evidence of learning-induced plasticity. Initial tone-food pairings recruited solely the amygdala, while late tone-food pairings came to induce Fos in distinct areas within the medial and lateral prefrontal cortex, the dorsal striatum, and the hypothalamus (lateral hypothalamus and paraventricular nucleus). Furthermore, within the perifornical lateral hypothalamus, tone-food pairings selectively recruited neurons that produce the orexigenic neuropeptide orexin/hypocretin. These data show a functional map of the forebrain areas recruited by appetitive associative learning and dependent on experience. These selectively activated regions include interconnected prefrontal, striatal, and hypothalamic regions that form a discrete but distributed network that is well placed to simultaneously inform cortical (cognitive) processing and behavioral (motivational) control during cue-food learning.