The orexinergic system influences conditioned odor aversion learning in the rat: a theory on the processes and hypothesis on the circuit involved

Abstract

A large variety of behaviors that are essential for animal survival depend on the perception and processing of surrounding smells present in the natural environment. In particular, food-search behavior, which is conditioned by hunger, is directly driven by the perception of odors associated with food, and feeding status modulates olfactory sensitivity. The orexinergic hypothalamic peptide orexin A (OXA), one of the central and peripheral hormones that triggers food intake, has been shown to increase olfactory sensitivity in various experimental conditions including the conditioned odor aversion learning paradigm (COA). COA is an associative task that corresponds to the association between an olfactory conditioned stimulus (CS) and a delayed gastric malaise. Previous studies have shown that this association is formed only if the delay separating the CS presentation from the malaise is short, suggesting that the memory trace of the odor is relatively unstable. To test the selectivity of the OXA system in olfactory sensitivity, a recent study compared the effects of fasting and of central infusion of OXA during the acquisition of COA. Results showed that the increased olfactory sensitivity induced by fasting and by OXA infusion was accompanied by enhanced COA learning performances. In reference to the duration of action of OXA, the present work details the results obtained during the successive COA extinction tests and suggests a hypothesis concerning the role of the OXA component of fasting on the memory processes underlying CS-malaise association during COA. Moreover, referring to previous data in the literature we suggest a functional circuit model where fasting modulates olfactory memory processes through direct and/or indirect activation of particular OXA brain targets including the olfactory bulb, the locus coeruleus (LC) and the amygdala.

Keywords: associative learning; fasting; olfactory memory; orexin; rat.

Figure 1

Effects of icv infusion of orexin (10 µg/3 µl, OXA group), icv infusion of artificial CSF (3 µl, aCSF group) and food-deprivation (Fasted group) on COA acquisition and extinction. The curves represent mean odorized-solution intakes (± SEM) for each group from Day 8 (acquisition) to Day 15. The mean water intake measured on the last day of habituation (Day 7) is also represented for each group for purposes of comparison. The Fasted group was food-deprived only during acquisition. All animals were habituated and tested while food satiated. *, ** and ***: P < 0.05, P < 0.01 and p < 0.001 between OXA and aCSF group. ◯◯ and ◯◯◯ P < 0.01 and 0.001 between Fasted and aCSF group. • P < 0.05 between OXA and Fasted group.

Figure 2

Representation of a hypothetic model according to which OXA terminating in regions such as the OB, LC and amygdala may constitute a pathway for orexinergic modulation of the olfactory memory trace formation underlying COA. The left panel represents the sequence of events that may take place during presentation of a new olfactory CS in the satiated condition. 1a) Olfactory CS induces activation of the OB. 1b) The novelty of the olfactory CS induces LC activation, which results in NA release in the OB and BLA. 2) The olfactory information is transmitted to the BLA where the odor trace is formed pending its association with the US. In the case of a short ISI, this sequence of events results in normal COA. The right panel represents the sequence of events that may take place during presentation of a new olfactory CS in the fasting condition. Fasting induces release of OXA in the OB, BLA and LC, preparing the system to respond to any food-odor event. 2a) Olfactory CS induces activation of the OB, potentiated by activation of the OXA system and LC-mediated NA system in the OB. In the fasting condition, CS leads to improved olfactory detection and processing. 2b) The novelty of the olfactory CS induces LC activation, resulting in enhanced NA release in the OB and BLA. 3) The enhanced olfactory information is transmitted to the BLA. Combined with OXA system activation, LC-mediated NA release in the BLA and potentiated OB activation, the olfactory memory trace strengthened or lengthened, and can thus be associated to a delayed US. This sequence of events results in COA when a long ISI is used.