Memory is the means by which the past connects with the present to guide our future interactions with the environment. One of the ways in which memory achieves this remarkable feat is by integrating the sensory and emotional elements of experiences that are separated in time but share common elements. For example, suppose that while hiking through a rainforest in tropical Australia you hear an (unfamiliar) deep booming sound and then see the (unfamiliar) bird-like animal who is making that sound. The next day, you see a poster showing a photograph of the animal (a cassowary) with a heading ‘extremely dangerous.’ Finally, when again hiking through the rainforest you hear the booming sound and feel apprehensive, even frightened.

This hypothetical scenario illustrates how the sound-animal memory formed at one point in time and the animal-danger memory formed at a second point were integrated via their common, animal, element to generate defensive/fear reactions to the sound. This type of integration could occur in two ways (Shohamy and Daw, 2015; Schlichting and Preston, 2015). The first is through formation of indirect associations between past sensory experiences and emotional events as they are encountered (Hall, 1996; Holland, 1981; Konorski, 1967; Ward-Robinson and Hall, 1999): that is during formation of the animal-danger memory, the past sound-animal memory is activated and integrated with the emotional memory content (what might be called ‘online’ integration). The second is through retrieval and chaining of memories at choice points (Rizley and Rescorla, 1972; Sadacca et al., 2018; Sharpe et al., 2017): that is re-exposure to the sound activates the sound-animal memory, which in turn, activates the animal-danger memory, resulting in expression of defensive/fear reactions to the sound (‘memory-chaining’).

At present, very little is known about when/how such memories are integrated in the brain to generate action. The present study addressed these questions using an animal model, sensory preconditioning in rats. We specifically examined whether sensory and emotional memories, which are consolidated in distinct regions of the medial temporal lobe (MTL) (Holmes et al., 2013; Holmes et al., 2018; Parkes and Westbrook, 2010), are integrated online when new memories are formed, or through a memory-chaining mechanism when actions are required. The protocol consisted in three stages that were separated by 24 hr. In stage 1, rats are exposed to pairings of two relatively innocuous stimuli (e.g., a sound followed by a light), and in stage 2 they are exposed to pairings of the light and footshock. Finally, in stage 3, rats are tested with the sound and then with the light. Rats typically exhibit defensive reactions (freezing) when tested with the preconditioned sound, even though it had never been paired with danger, and when tested with the conditioned light, that had been paired with danger.

Control conditions confirm that freezing to the sound in this protocol requires formation of sound-light and light-shock memories in training (it is not due to generalization of fear), and previous work in our laboratory has shown that the substrates of these memories are doubly dissociable in the MTL (Holmes et al., 2013; Holmes et al., 2018). The sound-light memory that forms in stage 1 requires neuronal activity, including activation of NMDA receptors, in the most anterior region of the parahippocampal cortex, the perirhinal cortex (PRh), but not the basolateral amygdala complex (BLA) (Holmes et al., 2013; Parkes and Westbrook, 2010); whereas the light-shock memory that forms in stage 2 requires neuronal activity, including activation of NMDA receptors, in the BLA, but not the PRh (Parkes and Westbrook, 2010; Wilensky et al., 2006). The major question of interest is when the sound-light and light-shock memories are integrated to generate freezing responses to the test presentations of the sound.

The experiments reported here provide further evidence that sound-light and light-shock memories have distinct substrates within the MTL. Previous work had shown that formation of the sound-light memory requires activation of NMDAr in the PRh (Holmes et al., 2013), and that the consolidation of this memory requires ERK/MAPK signaling in the PRh (Holmes et al., 2018). The present work shows that this consolidation also requires de novo protein synthesis in the PRh (Experiment 2). In contrast, the PRh is not required for encoding, consolidating or retrieving information about a light-shock fear memory (Phillips and LeDoux, 1995; Romanski and LeDoux, 1992a; Romanski and LeDoux, 1992b; Wilensky et al., 2006). Instead, the BLA is critical for each of these processes (Johansen et al., 2011): encoding of a light-shock fear memory requires activation of NMDAr in the BLA (Campeau et al., 1992; Fanselow and Kim, 1994; Miserendino et al., 1990); consolidation of this memory requires neuronal activity in this region, including de novo protein synthesis (Maren et al., 2003; Schafe and LeDoux, 2000); and retrieval/expression of a light-shock fear memory requires neuronal activity in the BLA, but occurs independently of de novo protein synthesis (Abel and Lattal, 2001; Bourtchouladze et al., 1998; Helmstetter and Bellgowan, 1994; but see Lopez et al., 2015).

Given the distinct substrates of the sound-light and light-shock memories in the PRh and BLA, respectively, the major question of interest asked here was when these memories are integrated so that the sound, which is never paired with shock, comes to elicit the defensive or fear response of freezing. To address this question, we examined whether manipulations of the PRh during formation of the light-shock fear memory influenced the test level of freezing to the preconditioned sound. The results showed that pharmacological inhibition of activity in the PRh before light-shock pairings spared freezing to the directly conditioned light, but reduced freezing to the preconditioned sound. They additionally showed that inhibition of PRh activity after light-shock pairings, including inhibition of de novo protein synthesis, produced the same pattern of test results. These manipulations should have left intact the PRh dependent sound-light memory formed in stage 1 and the BLA dependent light-shock memory formed in stage 2. Hence, if these memories were integrated at the time of testing (via the memory chaining mechanism described above), then independently of our PRh manipulations, the sound should have activated its now dangerous associate, the light, and elicited freezing. The fact that this did not occur indicates that integration had occurred in advance of testing, when the light was rendered dangerous via its pairing with shock (see also Coureaud et al., 2013). Nonetheless, we acknowledge that even these results do not completely rule out the possibility that some portion of the integration occurs at the time of testing in stage 3. For example, given the initial coding of the light in the PRh in stage 1 (as part of the sound-light association), it is possible that the light-shock association that forms in stage two is coded in parallel in the amygdala (principally) and PRh. If so, the PRh may further support responding to the sensory preconditioned sound by integrating the sound-light and light-shock associations at the point of testing (or at least the portions of these associations that are represented in the PRh). According to this account, silencing the PRh during stage 2 would have prevented coding of the light-shock association in this region, thereby undermining the possibility of memory chaining during testing in stage 3; and silencing the PRh during stage 3 would have blocked memory chaining directly, thereby disrupting responding to the preconditioned sound.

The present study used a between-subject design to show that freezing to the sensory preconditioned sound is doubly contingent on sound-light and light-shock pairings across the two stages of training; and that the PRh codes a mediated sound-shock association during stage 2 conditioning of the light. It does, however, leave open the question of whether the PRh codes for other types of mediated associations. This question could be assessed using a within-subject design, in which rats are exposed to two sets of stimulus pairings, for example tone-light and noise-flashing light (flash), in stage 1; shocked presentations of the light and non-shocked presentations of the flash in stage 2; and test presentations of the tone and noise in stage 3. Sensory preconditioning would be evident as greater test responding to the tone than the noise (e.g., Jones et al., 2012); see also Sharpe et al., 2017). Such a difference could originate in two distinct associations formed across stage 2 of training: an excitatory light-shock association and an inhibitory flash-no shock association. That is, just as the shocked presentations of the light allow the tone to enter into an association with the shock, non-reinforced presentations of the flash should allow the noise to enter into an inhibitory, no shock association. In other words, the test differences between the tone and the noise could be due to the former enhancing and the latter reducing freezing. Since both the tone-light and noise-flash associations are likely to be encoded in the PRh in stage 1, we predict that silencing activity in the PRh across the discriminative conditioning of the light and flash in stage 2 would eliminate the test differences between the tone and the noise. It would do so by preventing not only the mediated excitatory conditioning of the tone but also the mediated inhibitory conditioning of the noise.

It is worth noting that the within-subject design just described requires many trials to achieve differential responding in stage 2; that is, for the rats to freeze when presented with the shocked light and not to freeze when presented with the non-shocked flash. In contrast, relatively few shocked presentations were used here. This difference may be important with respect to when the information acquired in sensory preconditioning and conditioning is integrated. There is evidence that the likelihood of mediated conditioning decreases with the number of conditioning trials (Holland, 1998). Moreover, Jones et al. (2012) used just such a within-subject, sensory preconditioning design in an appetitive conditioning protocol (one that involved multiple trials to produce the discrimination in stage 2) to show that integration occurred at the time of testing: specifically, they reported that silencing the orbitofrontal cortex prior to testing reduced the expression of sensory preconditioned appetitive responding (see also Sharpe et al., 2017). Nonetheless, it remains to be shown within a single study that variations in the number of stage 2 conditioning trials regulates whether integration occurs in stage 2 (online) or stage 3 (memory chaining).

The present findings have also identified both commonalities and differences between sensory preconditioning and a conceptually-related protocol, second-order conditioning, in which animals are exposed to the same training but in the reverse order, that is light-shock pairings in stage 1 and sound-light pairings in stage 2. Like in sensory preconditioning, rats integrate the memories formed in the two stages of second-order conditioning so that the sound, which is not paired with shock, elicits freezing; and this integration occurs during training rather than at test (Gewirtz and Davis, 2000; Parkes and Westbrook, 2010; Rizley and Rescorla, 1972). However, the integration in second-order conditioning differs from that in sensory preconditioning in two critical respects. First, unlike in sensory preconditioning where the two component memories are encoded and stored in distinct regions of the MTL (Holmes et al., 2013), both of the component memories in second-order conditioning are encoded and stored in the BLA (Holmes et al., 2013; Parkes and Westbrook, 2010). Second, unlike in sensory preconditioning, where consolidation of the integrated (or mediated) sound-shock memory requires de novo protein synthesis in the PRh, consolidation of the integrated second-order memory occurs independently of de novo protein synthesis in the BLA (Lay et al., 2018; Leidl et al., 2018). These differences show that the order in which information is presented (or processed) determines how distinct memories are encoded and stored in the MTL, as well as the mechanisms involved in their integration. The integration of memories stored in distinct MTL regions (the PRh and BLA in sensory preconditioning) requires cellular changes that are supported by de novo protein synthesis; whereas the integration of memories stored within the same MTL region (the BLA in second-order conditioning) does not require this synthesis (Lay et al., 2018; Leidl et al., 2018).

The present findings also extend previous work showing that contextual information encoded and stored in one region of the brain can be retrieved and integrated with motivational information processed elsewhere (Wolosin et al., 2012; Zeithamova et al., 2012): for example memories of specific contexts are encoded and stored in distinct regions of the hippocampus, and when activated (through stimulation of context-specific ensembles, or exposure to reminder cues), can associate with nociceptive information in the amygdala to form a context fear memory (Bae et al., 2015; Matus-Amat et al., 2007; Ramirez et al., 2013; Rudy and O'Reilly, 2001). They extend these findings by showing that animals can integrate a distinct sensory element of one memory (not just context elements) with motivational components of another (even when the two have never been experienced together); and that this integration involves protein synthesis-dependent changes in the PRh. This is generally consistent with current theories of MTL function (for reviews, see Squire et al., 2004; and McGaugh et al., 2002) which hold that: (i) context and stimulus elements are represented in a distributed network of regions, (ii) the values of these representations are updated across the course of experience (i.e., ‘on the fly’ rather than at choice points), and (iii) the amygdala plays a critical role in this updating process. However, the results of the final experiment suggest that these theories require further elaboration: retrieval/expression of the mediated sound-shock memory required activity in the PRh, whereas retrieval/expression of the directly conditioned light-shock memory did not. This difference implies that, as a consequence of its direct pairings with shock, the light was recoded so that responding to this stimulus ceased to depend on the PRh. It is consistent with previous work which showed that danger shifts the encoding and consolidation of innocuous sensory information from the PRh to the BLA (Holmes et al., 2018; Holmes and Westbrook, 2017). Thus, in addition to its role as a modulator of PRh-dependent stimulus representations, the BLA itself encodes and recodes stimulus representations when danger is present; and thereafter, remains involved in the retrieval/expression of information about those stimuli.

In summary, using a sensory preconditioning protocol, the present study provides evidence that the brain integrates sound-light and light-shock memories across the course of training; and that the cortical region that codes for the integration, the PRh, remains critical for the subsequent retrieval and expression of the integrated memory. As noted above, our findings do not preclude the possibility that some portion of the integration in the present study occurred at the point of testing; or indeed, that there are circumstances under which sensory and emotional memories are exclusively integrated at the time of testing (Rizley and Rescorla, 1972; Sadacca et al., 2018; Sharpe et al., 2017). They do, however, suggest that with very simple procedures of the sort used here, the bulk of the integration occurs during training. More generally, our findings reiterate that memory is not a repository of experience, but rather, a process of construction and reconstruction. These constructions are not a limitation of the system, but rather, a feature of its design: they help animals and people to solve novel problems in the absence of further experience, and thereby, adapt to changes in the environment.

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 4 and 5.

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Author details

1. Francesca S Wong

   School of Psychology, University of New South Wales, Sydney, Australia

   Contribution

   Data curation, Formal analysis, Writing—original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8533-9833

2. R Fred Westbrook

   School of Psychology, University of New South Wales, Sydney, Australia

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing—review and editing

   Competing interests

   No competing interests declared

3. Nathan M Holmes

   School of Psychology, University of New South Wales, Sydney, Australia

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Writing—original draft, Writing—review and editing

   For correspondence

   n.holmes@unsw.edu.au

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0592-2026

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