The amygdala and medial prefrontal cortex (mPFC) are highly interconnected telencephalic areas critical for cognitive processes, including associative learning and decision making. Both structures strongly innervate the lateral hypothalamus (LHA), an important component of the networks underlying the control of feeding and other motivated behaviors. The amygdala–prefrontal–lateral hypothalamic system is therefore well positioned to exert cognitive control over behavior. However, the organization of this system is not well defined, particularly the topography of specific circuitries between distinct cell groups within these complex, heterogeneous regions. This study used two retrograde tracers to map the connections from the amygdala (central and basolateral area nuclei) and mPFC to the LHA in detail, and to determine whether amygdalar pathways to the mPFC and to LHA originate from the same or different neurons. One tracer was placed into a distinct mPFC area (dorsal anterior cingulate, prelimbic, infralimbic, or rostromedial orbital), and the other into dorsal or ventral LHA. We report that the central nucleus and basolateral area of the amygdala send projections to distinct LHA regions, dorsal and ventral, respectively. The basolateral area, but not central nucleus, also sends substantial projections to the mPFC, topographically organized rostrocaudal to dorsoventral. The entire mPFC, in turn, projects to the LHA, providing a separate route for potential amygdalar influence following mPFC processing. Nearly all amygdalar projections to the mPFC and to the LHA originated from different neurons suggesting amygdala and amygdala–mPFC processing influence the LHA independently, and the balance of these parallel pathways ultimately controls motivated behaviors.

Associative learning can enable cues from the environment to stimulate feeding in the absence of physiological hunger. How learned cues are integrated with the homeostatic regulatory system is unknown. Here we examined whether the underlying mechanism involves the hypothalamic orexigenic neuropeptide regulators orexin/hypocretin (ORX) and melanin-concentrating hormone (MCH). We used a Pavlovian conditioning procedure to train food-restricted rats to associate a discrete cue, a tone, with food pellets distinct from their regular lab chow diet. Rats in the conditioned group (Paired) received presentations of a tone immediately prior to food delivery, while the rats in the control group (Unpaired) received random presentations of the same number of tones and food pellets. After conditioning rats were allowed ad libitum access to lab chow for at least 10 days before testing. At test sated rats were presented with the tones in their home cages, and then one group was allowed to consume food pellets, while another group was left undisturbed until sacrifice for Fos induction analysis. The tone cue stimulated food consumption in this setting; rats in the Paired group consumed larger amounts of food pellets than rats in the Unpaired group. To examine Fos induction we processed the brain tissue using fluorescent immunohistochemistry methods for combined detection of Fos and characterization of ORX and MCH neurons. We found a greater percentage of ORX and Fos double-labeled neurons in the Paired compared to the Unpaired condition, specifically in the perifornical area. In contrast, there were very few MCH neurons with Fos induction in both the Paired and Unpaired conditions. Thus, the food-cue selectively induced Fos in ORX but not in MCH neurons. These results suggest a role for ORX in cue-induced feeding that occurs in the absence of physiological hunger.

Cues that predict food can stimulate appetite and feeding independent of physiological hunger. How long such effects might last is currently unknown. Here we began to characterize long-term effects in a rodent model of cue-potentiated feeding. Rats were conditioned to associate a tone with food pellets distinct from their regular laboratory chow, and then were tested along with controls for food consumption following tone presentations. In Experiment 1, rats were tested under sated or food-deprived conditions to determine whether fasting would augment cue-driven feeding. Rats in the control group regulated intake based on physiological state, while conditioned rats consumed similar large amounts of food regardless. Experiment 2 tested the durability of cue-potentiated feeding to repeated testing in sated rats. We observed robust cue-potentiated feeding during the first two tests, while in the third and fourth tests both groups ate similar large amounts of pellets. In both experiments the conditioned tone-cue induced binge-like consumption of the cued food and persistent feeding for the duration of 4-hour tests. Rats then failed to adjust daily chow consumption to account for their increased intake post-cue. In summary, brief cue priming stimulated substantial intake in sated states that was behaviorally uncompensated for by homeostatic mechanisms.

Social play is a highly rewarding and motivated behavior predominately displayed by juveniles and expressed by nearly all mammalian species. Prior work suggested that the vasopressin (AVP) and oxytocin (OT) systems can regulate the expression of social play in sex-specific ways. Here we investigated whether there are sex differences in the recruitment of vasopressinergic and oxytocinergic brain regions following social play exposure in juvenile rats. Single-housed rats were allowed to play, in their home cage, with an age- and sex-matched unfamiliar conspecific for 10 min, or received similar handling but no partner. Double-labeled fluorescent immunohistochemistry for Fos and either AVP or OT was completed in adjacent series of tissue to determine recruitment of AVP- and OT-immunoreactive neurons in response to social play. Exposure to social play did not increase recruitment of AVP or OT neurons in the supraoptic (SO) or paraventricular (PVH) hypothalamic nuclei of either sex compared to the no-play control condition. Interestingly, there was a robust sex difference in SO recruitment, irrespective of social play condition, with males exhibiting twice the recruitment of SO-AVP and SO-OT neurons compared to females. Lastly, exposure to social play increased recruitment of the posterior bed nuclei of the stria terminalis (pBST) and the posterodorsal medial amygdalar nucleus (MEApd) compared to the no-play control condition, and this effect was most pronounced in females. Our findings revealed sex differences in the recruitment of brain regions (i) independent of play condition (i.e., SO) possibly representing a sex difference in the baseline levels of AVP and OT signaling required for typical functioning and (ii) specific to play condition (i.e., pBST, MEApd). In sum, this study provides further evidence that the neural substrates underlying social play behavior are sex-specific. This article is protected by copyright. All rights reserved.

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