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. 2022 Oct;29(10):349–354. doi: 10.1101/lm.053607.122

Higher-order trace conditioning in newborn rabbits

Gérard Coureaud 1, Nina Colombel 1,2, Patricia Duchamp-Viret 1, Guillaume Ferreira 2
PMCID: PMC9536754  PMID: 36180128

Abstract

Temporal contingency is a key factor in associative learning but remains weakly investigated early in life. Few data suggest simultaneous presentation is required for young to associate different stimuli, whereas adults can learn them sequentially. Here, we investigated the ability of newborn rabbits to perform sensory preconditioning and second-order conditioning using trace intervals between odor presentations. Strikingly, pups are able to associate odor stimuli with 10- and 30-sec intervals in sensory preconditioning and second-order conditioning, respectively. The effectiveness of higher-order trace conditioning in newborn rabbits reveals that very young animals can display complex learning despite their relative immaturity.

Temporal contiguity between stimuli is usually considered essential for associative learning in adult individuals (Pavlov 1927). However, first-order conditioning remains effective when a trace interval (TI), usually 10–30 sec, is inserted between the conditioned stimulus (CS) and unconditioned stimulus (US) (e.g., Kamin 1954; Ost et al. 1968; Kirkpatrick and Balsam 2016). In higher-order conditioning such as sensory preconditioning and second-order conditioning, two CSs, CS1 and CS2, are paired before or after the CS1 is paired with a US, respectively (Brogden 1939; Rescorla 1980a). Here again, conditioning is possible in adult rats when the CS1 and CS2 are separated by a short TI, and this is true for both sensory preconditioning (Silver and Meyer 1954; Lavin 1976; Lyn and Capaldi 1994; Holmes and Westbrook 2017) and second-order conditioning (Rescorla 1982; Stout et al. 2004).

Very young individuals exhibit robust first- and higher-order conditioning when pairings involved simultaneous presentations of the to-be-conditioned stimuli (Cheslock et al. 2003; for review, see Cuevas and Giles 2016). However, a few studies suggest that they might be particularly sensitive to the insertion of a TI between stimulus presentation in training (e.g., for first-order conditioning, see Moye and Rudy 1987; Ivkovich et al. 2000; Barnet and Hunt 2005; for higher-order conditioning, see Cheatle and Rudy 1979; Cheslock et al. 2003). Indeed, sequential conditioning becomes more efficient with age in human infants (Cuevas and Giles 2016) and young animals (Chen et al. 1991).

In the European rabbit, newborns can learn new odorants through first- and higher-order conditioning. The mammary pheromone (MP) emitted by lactating rabbit females in their milk not only triggers stereotyped orocephalic movements, allowing for pups to search and grasp the maternal nipples (Coureaud 2001; Schaal et al. 2003), but also remarkably promotes associative odor learning. Indeed, the MP acts as a US, inducing appetitive conditioning to an odorant (CS1) by simultaneous and brief pairing; 24 h later, the CS1 triggers a conditioned orocephalic searching–grasping response similar to the response triggered by the US (Coureaud et al. 2006, 2009). Rabbit pups are also able to respond to a second odorant (CS2) when CS1 + MP pairing is followed by simultaneous CS1 + CS2 pairing, demonstrating second-order conditioning (Coureaud et al. 2011), and also when simultaneous exposure to CS1 + CS2 preceded CS1 + MP pairing, demonstrating sensory preconditioning (Coureaud et al. 2013). These higher-order conditionings seem to be associative in nature, as unpaired presentations of either CS1 and US or CS1 and CS2 impede CS2 responding (Coureaud et al. 2011, 2013). In particular, sensory preconditioning and second-order conditioning do not occur if CS1 and CS2 are separated by a 1-min TI (Coureaud et al. 2011, 2013). However, the effectiveness of shorter TIs in supporting higher-order conditioning remains to be evaluated in newborn rabbits. The present study provides this evaluation.

To that goal, we used 305 newborn rabbits (from 64 litters) and odorants A, B, and MP (see below) purchased from Sigma-Aldrich. Only four or five pups per litter were used per experiment (they were included in a single group; i.e., not used in more than one condition). To avoid interference with the pups’ prandial state (Montigny et al. 2006), experiments always occurred at 10:30 a.m., 1 h before the daily nursing. Proportion of responding pups to the stimuli was compared using the Cochran Q-test and χ2 test of McNemar when pups from the same group are tested to distinct stimuli, and χ2 test of Pearson when pups from distinct groups are tested to the same stimulus.

First, in order to confirm that simultaneous pairing of CS1 + CS2 promotes sensory preconditioning, 1-d-old pups (n = 15) were exposed in a behavioral room (adjacent to the animal housing room) using a subgroup of five neonates as a maximum (in order to optimize their exposure) to a mixture of odorants A (10−5 g/mL ethyl-isobutyrate) and B (10−5 g/mL ethyl maltol). The exposure happened in a plastic basin through a scented cotton glove positioned 1 cm above the litter for 5 min (timer-controlled by a second experimenter) and then was immediately retired. On day 2, the pups were conditioned to odorant A by simultaneous pairing with MP (10−5 g/mL 2-methylbut-2-enal) for 5 min in a new basin and through a new glove (the basins were rinsed with alcohol and water and then dried after each use; the gloves were used only once per experiment). On day 3, the pups were individually tested in an oral activation test (e.g., Schaal et al. 2003; Coureaud et al. 2009, 2011, 2013), during which each pup was immobilized in one hand of the experimenter, its head being left free, and the test odor was presented for 10 sec with a glass rod 0.5 cm in front of the nares. The response was positive when the stimulus elicited vigorous scanning movements of the head while stretching toward the rod followed by oral grasping of the rod; nonresponding pups displayed no response but sniffing. Under the present conditions, the pups responded to both odorants A and B as well as to MP (A vs. B vs. MP: Cochran's Q-test = 2, P = 0.37). For second-order conditioning, 1-d-old pups (n = 9) were conditioned to odorant A (by simultaneous pairing with MP for 5 min) and exposed on day 2 to A + B for 5 min (here and hereafter, the same procedure of exposure as above). On day 3, pups responded in a strong and similar manner to A, B, and MP (A vs. B vs. MP: Q = 2, P = 0.37).

To determine whether a TI between presentations of neutral odorants would affect sensory preconditioning, 1-d-old pups were exposed to odorants A then B for 2.5 min each with a 10-sec (n = 15) or 30-sec (n = 15) TI; the exposure to each odorant was made in distinct basins separated by >1 m in a permanently ventilated room to avoid any contamination between the different odorants. On day 2, they were conditioned to odorant A (by simultaneous pairing with MP for 5 min). Strikingly, pups responded strongly and similarly on day 3 to A, B, and MP after a 10-sec TI (A vs. B vs. MP: Q = 3, P = 0.22). However, pups responded to A and MP but not to B after a 30-sec TI (A vs. B vs. MP: Q = 18, P < 0.001; 2 × 2 comparisons by χ2 test of McNemar: B vs. MP or A: χ2 ≥ 7.1, P < 0.01) (Fig. 1A,B). These results support the presence of sensory preconditioning in the 10-sec but not the 30-sec condition. Indeed, the proportions of responders to A after 10- and 30-sec TIs were strong and similar (χ2 < 0.5, P > 0.05), although the proportions of responders to B dropped dramatically after a 30-sec compared with a 10-sec TI (χ2 = 13.5, P < 0.001).

Figure 1.

Figure 1.

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Sensory preconditioning with two odorants. (A,B,E,F) Case of conditioning to the odorant A. Newborn rabbits were sequentially exposed to odorants A then B (A,B) or odorants B then A (E,F) with a 10-sec (A,E) or 30-sec (B,F) trace interval (TI) on day 1 (d1) and then conditioned to odorant A by association with the mammary pheromone (MP) on day 2 (d2). Their behavioral response to A and B, and to the MP as a control, was tested 24 h later (d3). Sensory preconditioning tolerated a 10-sec TI during the pre-exposure phase, since pups responded later to A and B, but not a 30-sec TI. (C,D,G,H) Case of conditioning to the odorant B. Rabbit pups were sequentially exposed to odorants A then B (C,D) or odorants B then A (G,H) with a 10-sec (C,G) or 30-sec (D,H) TI on d1 and then conditioned to odorant B by association with the MP on d2, and their behavioral response to B, A, and MP was tested on d3. Again, sensory preconditioning tolerated a 10-sec but not a 30-sec TI during the pre-exposure phase. (*) P < 0.05, (**) P < 0.01, (***) P < 0.001.

Similar results were obtained when preconditioning to A then B was followed by conditioning to B (Fig. 1C,D) and after reverse exposure to the odorants (B then A) during preconditioning and then conditioning to odorant A or B (Fig. 1E–H): Pups responded to A, B, and MP after a 10-sec TI, but only to the conditioned odorant after a 30-sec TI (n = 10 per group; Q = 2, P > 0.05 with a 10-sec TI; Q > 12, χ2 ≥ 7.1, and P < 0.05 in comparisons between A and B or MP with a 30-sec TI) (Fig. 1, drop in responsiveness to A in C vs. D and G vs. H [χ2 ≥ 7.2, P < 0.05], and in responsiveness to B between the 10- and 30-sec conditions in E,F [χ2 = 9.8, P < 0.01]). Therefore, two main results emerged from these data: (1) Sensory preconditioning was still effective when a short TI (10 sec) takes place between the odorants during initial exposure, and (2) it was present and equivalent in the forward (CS2//CS1, CS1 + US) and backward (CS1//CS2, CS1 + US) protocols.

To assess whether second-order conditioning would also tolerate TIs, 1-d-old pups were conditioned to odorant A (by simultaneous pairing with MP for 5 min) and exposed the day after to odorants A then B for 2.5 min each with a 10-sec (n = 10) or 30-sec (n = 10) TI. On day 3, pups responded highly and similarly to A, B, and MP after the 10-sec TI (A vs. B vs. MP: Q = 2, P = 0.37) but also after the 30-sec TI (A vs. B vs. MP: Q = 4, P = 0.14) (Fig. 2A,B). When the same experiment was conducted with a 60-sec TI between A and B, pups significantly responded to A and MP but not to B (n = 10; A vs. B vs. MP: Q = 11, P < 0.01; B vs. MP: χ2 = 5.1, P < 0.05; A vs. MP: χ2 = 1.3, P = 0.25; drop in responsiveness to B between 30 and 60 sec: χ2 = 7.9, P < 0.01) (Fig. 2C). Similar results were obtained after conditioning to odorant A and reverse exposure to the odorants (B then A) (Fig. 2D–F) and conditioning to B followed by exposure to B then A (Fig. 2G,H): Pups responded to A, B, and MP after the 10- and 30-sec TI, but only to the conditioned stimulus after a 60-sec TI (n = 10 per group; Q ≤ 4, P > 0.05 with a 10- and 30-sec TI; Q > 15, χ2 ≥ 5.1 and P < 0.05 in comparisons between A and B or MP with a 60-sec TI) (Fig. 2, responsiveness to odorant B in E vs. F [χ2 = 7.9, P < 0.01], and responsiveness to odorant A in G vs. H [χ2 = 5.2, P < 0.05]). Thus, second-order trace conditioning was functional in the forward (CS1 + US, CS2//CS1) and backward (CS1 + US, CS1//CS2) protocols in newborn rabbits with longer TIs (30 sec instead of 10 sec) than sensory preconditioning.

Figure 2.

Figure 2.

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Second-order conditioning with two odorants. (A–C) Case of conditioning to the odorant A and recall of A then B. Newborn rabbits were conditioned to odorant A by pairing with the MP on d1 and then sequentially exposed to A then B with a 10-sec (A), 30-sec (B), or 60-sec (C) TI on d2, before testing of their behavior to A, B, and MP on day 3 (d3). Second-order conditioning tolerated a 10- and 30-sec TI during the second conditioning phase, since pups responded to B in addition to A, but not a 60-sec TI. (D–F) Case of conditioning to the odorant A and recall of B then A. Rabbit pups were conditioned to A by pairing with the MP on d1 and then sequentially exposed to B then A with a 10-sec (D), 30-sec (E), or 60-sec (F) TI on d2, and tested behaviorally to A, B, and MP on d3. Second-order conditioning tolerated the 10- and 30-sec TIs but not the 60-sec TI during the second conditioning phase. (G,H) Case of conditioning to the odorant B and recall of B then A. Rabbit pups were conditioned to B by pairing with the MP on d1 and then sequentially exposed to B then A with a 30-sec (G) or 60-sec (H) TI on d2, and tested behaviorally to B, A, and MP on d3. Second-order conditioning tolerated the 30-sec TI during the second conditioning phase, since pups responded to A in addition to B, but not the 60-sec TI. (*) P < 0.05, (***) P < 0.001.

To determine whether this difference was related to the age of the pups at A and B exposure (that is, day 1 for sensory preconditioning but day 2 for second-order conditioning), 12 pups were exposed on day 2 to odorants A then B with a 30-sec TI, and conditioned to A on day 3. On day 4, pups responded to A and MP but not to B (A vs. B vs. MP: Q = 17, P < 0.001; B vs. MP or A: χ2 ≥ 6.1, P < 0.05) (data not shown), indicating that sensory preconditioning was ineffective with a 30-sec TI. Thus, the difference of TI tolerated by the two procedures does not depend on the age of the newborns.

The natural environment of animals is extremely complex chemically: Animals are exposed to numerous odor molecules and mixtures of molecules. We thus investigated higher-order trace conditioning in newborn rabbits using more than two odorants; that is, three odorants. We first demonstrated that pups responded strongly and similarly to A, B, and C (ethyl acetoacetate; Sigma-Aldrich) after simultaneous exposure to the three odorants in both preconditioning and second-order conditioning procedures (n = 10 per group; A vs. B vs. C vs. MP: Q < 2, P > 0.05) (Fig. 3A,D). Thus, rabbit pups exhibit robust higher-order conditioning to three odorants after simultaneous presentation.

Figure 3.

Figure 3.

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Sensory preconditioning and second-order conditioning with three odorants. (A–C) Case of sensory preconditioning. Newborn rabbits were exposed on d1 to the odorants A, B, and C simultaneously (A) or sequentially with a 10-sec (B) or 30-sec (C) TI between the odorants and then conditioned to odorant A by pairing with the MP on d2, and tested behaviorally to A, B, C, and MP on d3. Sensory preconditioning occurred simultaneously and with the 10-sec TI during the pre-exposure phase, since the pups responded to B and C in addition to A, but not with the 30-sec TI. (D–G) Case of second-order conditioning. Pups were conditioned to A by pairing with the MP on d1 and then exposed to A, B, and C simultaneously (D) or with a 10-sec (E), 30-sec (F), or 60-sec (G) TI on d2, before behavioral testing to A, B, C, and MP on d3. Second-order conditioning occurred simultaneously and with the 10-sec TI, but not with the 30-sec TI, during the second conditioning phase. (*) P < 0.05, (**) P < 0.01, (***) P < 0.001.

To assess whether sensory preconditioning was effective with sequential exposure to three odorants, 1-d-old pups were exposed to odorants A then B then C for 2.5 min each with a 10- or 30-sec TI (n = 10 per group). Pups were then conditioned to A on day 2 and tested for their responsiveness to the distinct odorants on day 3. After the 10-sec TI, pups responded highly and similarly to A, B, and MP, but not to C (A vs. B vs. C vs. MP: Q = 23, P < 0.001; C vs. MP, A, or B: χ2 ≥ 6.1, P < 0.05) (Fig. 3B), whereas pups responded only to A and MP after the 30-sec TI (A vs. B vs. C vs. MP: Q = 26, P < 0.001; B or C vs. A or MP: χ2 ≥ 7.1, P < 0.01; drop in responsiveness to B between 30 and 60 sec: χ2 = 12.9, P < 0.001) (Fig. 3C). Thus, backward sensory preconditioning tolerated the same TI with two or three odorants in newborn rabbits; that is, 10 sec but not 30 sec. However, the effect was only partial after the 10-sec TI, as behavioral response extended only to the odorant (B here) that directly followed the odorant that was conditioned (odorant A).

Regarding second-order conditioning with sequential exposure to three odorants, pups were conditioned to odorant A on day 1 before being exposed on day 2 to odorants A then B then C for 2.5 min each with a 10-sec, 30-sec, or 60-sec TI (n = 10 per group). On day 3, pups responded strongly and similarly to A, B, and MP but not to C with a 10-sec TI (A vs. B vs. C vs. MP: Q = 18, P < 0.001; C vs. MP or B: χ2 = 6.1, P < 0.05; C vs. A: χ2 = 3.1, P = 0.08) and a 30-sec TI (A vs. B vs. C vs. MP: Q = 25, P < 0.001; C vs. MP, A, or B: χ2 ≥ 7.1, P < 0.01) (Fig. 3E,F), whereas pups only responded to A and MP with the 60-sec TI (A vs. B vs. C vs. MP: Q = 30, P < 0.001; B or C vs. A or MP: χ2 ≥ 10, P < 0.005; drop in responsiveness to B between 30 and 60 sec: χ2 = 12.9, P < 0.001) (Fig. 3G). Thus, backward second-order conditioning tolerated the same 30-sec TI with two or three odorants in rabbit pups but, as for sensory preconditioning, with a partial effect as soon as a 10-sec TI with three odorants; pups indeed responded only to the odorant that directly followed the presentation of the conditioned one but not to the third odorant (odorant C here).

According to previous literature in rat pups and human babies, trace conditioning would be nonfunctional in early life, as newborns do not tolerate any delay between stimuli to be associated, whereas older animals do (Cheatle and Rudy 1979; Moye and Rudy 1987; Chen et al. 1991; Ivkovich et al. 2000; Barnet and Hunt 2005; Cuevas and Giles 2016). Similarly, previous studies indicate rabbit pups cannot display first-order trace conditioning with a 0-sec TI (Coureaud et al. 2006, 2011, 2013). Regarding the importance of the hippocampus in first-order trace conditioning with discrete cues (Goldsberry et al. 2015; Kitamura et al. 2015), the failure of this first-order trace conditioning in rabbit neonates might result from the late maturation of the hippocampus.

However, the present study strikingly shows that rabbit pups are able to form higher-order trace conditioning, and that different TIs between odor presentations are tolerated: a 10-sec TI for sensory preconditioning and a 30-sec TI for second-order conditioning, regardless of the order of CS presentation (forward or backward CS1–CS2 pairing). Similar greater tolerance for longer TIs in second-order conditioning over sensory preconditioning was previously demonstrated in newborn rats, as immediate–sequential (0-sec TI) presentation of odor CSs impedes sensory preconditioning but not second-order conditioning, the latter being not effective with a 30-sec TI (Cheslock et al. 2003).

Sequential higher-order conditioning with three odorants provided similar but also novel information compared with two odorants in newborn rabbits. As with two odorants, backward sensory preconditioning was effective with a 10-sec TI and backward second-order conditioning with a 30-sec TI. However, these procedures were only partially effective, since the pups did only respond to the odorant that directly followed the conditioned one (and not to the third one in the sequence). It would now be interesting to investigate what would be the response of the newborns when the conditioned odorant is the second or the third of the sequence (allowing comparison between forward and backward pairings) to further understand how rabbit pups efficiently learn associative information about their environment.

Higher-order trace conditioning is thus functional in newborn rabbits, highlighting their remarkable cognitive capabilities despite their relative immaturity. An important and unexpected result was the equivalent backward and forward higher-order trace conditioning. Indeed, it is classically reported that forward conditioning is more effective than backward conditioning, even for higher-order conditioning (for instance, see Rescorla 1980b; Hussaini et al. 2007), highlighting that the manner in which stimuli are presented influences their integration (for review, see Holmes et al. 2022). This effective backward conditioning in rabbit pups is unlikely to be related to odor contamination according to the well-controlled experimental conditions (distinct recipients separated by 1 m for each odorant in a ventilated room) and the fact that first-order trace conditioning was ineffective (excluding any overlap between odorants). This could rather reflect a rabbit singularity compared with rodent pups (or even babies) due to the ecology of the species (for review, see Cuevas and Giles 2016). Notably, the rabbit is to date the only species in which a pheromone (MP) emitted by lactating females and involved in newborns' adaptation (nipple location/grasping and milk intake) has been described (Schaal et al. 2003; Coureaud et al. 2010). The use of the MP to induce conditioning might promote specific learning abilities, since this molecule is an extremely powerful biological signal and reinforcer. These suggestions would require further comparative studies with other species such as rats, mice, or humans to investigate neonatal learning abilities in different conditioning procedures and their potential species specificity.

The difference of TIs—10 sec versus 30 sec—tolerated between the two procedures used here could be related to distinct levels of arousal (Kikas et al. 2021) and/or types of association involved. Indeed, in sensory preconditioning, the two odorants are completely neutral during their presentation, therefore triggering low levels of arousal, whereas one odorant has already been reinforced in second-order conditioning, which enhances levels of arousal during subsequent CS1 and CS2 presentations. Therefore, stimulus–stimulus association supports sensory preconditioning, whereas stimulus–reward and/or stimulus–response association participates in second-order conditioning (Sharpe et al. 2017). Interestingly, these different types of association may relate to different brain structures. Indeed, several experiments have shown in adult rodents that higher-order conditioning depends on a wide brain network and that neural circuits underlying sensory preconditioning and second-order conditioning differ. For instance, manipulation of the perirhinal or the retrosplenial cortices affects stimulus–stimulus association during sensory preconditioning but not second-order conditioning in rats (Nicholson and Freeman 2000; Holmes et al. 2013; Robinson et al. 2014; Todd et al. 2016). In contrast, the basolateral amygdala is involved in second-order conditioning but not in sensory preconditioning (Hatfield et al. 1996; Blundell et al. 2003; Dwyer and Killcross 2006; Parkes and Westbrook 2010). The selective recruitment of the amygdala during stimulus–reward and/or stimulus–response association may therefore help in tolerating longer TIs compared with sensory preconditioning.

However, much less is known about neural mechanisms that mediate sensory preconditioning and second-order conditioning early in life, and how these mechanisms evolve during development. Different neural circuits have been shown to support first-order aversive learning in young and adult rats, with gradual involvement of the amygdala when the animal is getting older (Shionoya et al. 2006; Raineki et al. 2009). Moreover, noradrenaline depletion in the forebrain alters sensory preconditioning but not first-order aversive conditioning in both preweanling and adult rats (Archer et al. 1986; Chen et al. 1993). Since only very limited data are available in newborns and according to age-related differences in higher-order conditioning, it would be valuable to investigate the neural mechanisms and in particular the neurotransmitters (using pharmacological and molecular approaches) underlying these higher-order conditioning procedures in rabbit pups.

Acknowledgments

We sincerely thank Priscilla Orlando, Océane Meunier, Manon Dirheimer, and the staff of the Center for Research in Neuroscience in Lyon Animal Facility for their cooperation in this study. All experiments were performed in accordance with ethical rules enforced by French law and approved by the ethical committees of Lyon 1 University (CEEA-42 and CEEA-55) and the French Ministry of Higher Education and Research under numbers 9745 and 27 2874. The work was supported by the NEONATOLF (Olfaction, Cognition, and Feeding Behavior in Rabbit Neonates) grant ANR-20-CE20-0019-01 from Agence Nationale de la Recherche.

Footnotes

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