Post-traumatic stress disorder (or PTSD for short) is a condition that can cause people to overreact to harmless cues, vividly re-experience a traumatic event, or freeze in place. To understand why this happens, researchers often study fear responses using an approach called fear conditioning, where laboratory animals learn to associate the sound of a tone with a mild electric shock. This conditioning causes animals to freeze with fear when they hear the tone.

However, focusing on freezing overlooks the range of defensive actions animals may carry out, such as escaping or fighting. Capturing this complexity in experiments is important for understanding the dynamic nature of fear responses that occur in PTSD. Previous work showed that conditioning mice with a two-part cue, such as a tone followed by white noise, caused mice to freeze during the first cue and jump during the second cue. However, whether the mice learned this behaviour through conditioning or if it was an instinctive response to the cues remained unclear.

To investigate this phenomenon, Le et al. – including some of the researchers involved in the previous work – conditioned mice with a variety of different cue combinations and monitored how they responded. As before, mice conditioned to associate a tone followed by white noise with an electric shock froze when they heard the tone and transitioned to jumping during the white noise. However, if during conditioning the sounds and shocks occurred at unpredictable times, the mice did not associate the sounds with the shock and therefore they froze less and rarely jumped. Similarly, reversing the order of the sounds so that the white noise happened before the tone also reduced jumping but not freezing.

To investigate whether the mice could unlearn this fear response, Le et al. exposed the fear-conditioned mice to the cues without an accompanying electric shock. The mice that had been conditioned with a tone followed by white noise showed a weaker response to the cues, only freezing and not jumping. However, the mice with the reversed cues still froze even after this exposure, and the mice with the non-associated cues maintained very little freezing and jumping.

Taken together, the findings suggest that while fear responses can be influenced by the association between certain noises and an electric shock, other factors such as the timing and the order of the sound cues can also impact the intensity of the fear response. The experiments also showed that this method of fear conditioning can be used for both learning and unlearning fear responses, revealing an approach for future studies into how fear responses change over time. Combining this more complex approach with other experimental techniques could help researchers identify the brain regions that drive fear responses, which may eventually benefit people with PTSD and other fear disorders.

Defensive responses have evolved to maximize survival (Anderson and Adolphs, 2014), and animals rapidly switch behaviors depending on threat imminence, the context of exposure, and previous experience with stimuli (Perusini and Fanselow, 2015). Understanding the mechanisms underlying adaptive defensive behavior may grant insight into the pathophysiology of post-traumatic stress and panic disorders, wherein heightened responses to external stimuli are observed, yet neuroscientists need more tractable methods with which to investigate how the nervous system controls complex experience-dependent behavior.

Pavlovian fear conditioning has been widely used as a model system to understand the neural mechanisms underlying fear-related learning and memory (Bolles, 1970; Bolles and Collier, 1976; Grewe et al., 2017; Roy et al., 2017; Bouton et al., 2021). In standard Pavlovian conditioning paradigms, freezing is the dominant defensive behavior evoked by contexts and learned cues that are paired with an aversive unconditioned stimulus (US), like footshock (Blanchard and Blanchard, 1969; Bolles and Collier, 1976). Other defensive responses like escape jumping (Chu et al., 2024) and darting (Gruene et al., 2015) are measured less often within conditioning, limiting insight into defensive response dynamics. To address this critical need, we developed a modified Pavlovian conditioning paradigm that elicits both freezing and flight behaviors in response to conditioned stimuli (Fadok et al., 2017; Borkar et al., 2020; Borkar and Fadok, 2021; Borkar et al., 2024), findings that have been replicated by others in both mice and rats (Dong et al., 2019; Totty et al., 2021). In this paradigm, mice are conditioned with a SCS consisting of a pure tone followed by WN, which terminates with a strong electrical footshock. After conditioning, mice exhibit contextual freezing which significantly increases in response to tone, and mice switch to robust flight responses upon WN presentation. These findings demonstrate that the magnitude and mode of defensive behavior change with the psychological distance of threat, consistent with the predatory imminence continuum theory (Perusini and Fanselow, 2015).

However, the influence of non-associative elements on this ethological profile has recently been discussed (Fanselow et al., 2019; Hersman et al., 2020; Trott et al., 2022). It has been suggested that the inherent salience of the WN stimulus contributes more to WN-evoked flight response than its predictive association with the US (Hersman et al., 2020). Others claim that the immediate transition from freezing to flight behavior is a result of the rapid change and relative increase in stimulus intensity from tone to WN that is caused by non-associative sensitization, or by inherent stimulus properties, akin to an acoustic startle response (Fanselow et al., 2019; Trott et al., 2022). In addition, sensitization and stimulus salience are known to intensify freezing responses to auditory stimuli (Kamprath and Wotjak, 2004), and mice show increased reactivity to a WN stimulus after experiencing stress (Hoffman et al., 2022). These findings highlight the need to better elucidate the associative and non-associative elements of Pavlovian fear conditioning that influence the expression of defensive behavior.

To address this, we utilized four control groups for the non-associative effects of conditioning. To test the importance of the SCS-shock contingency, we utilized an unpaired control procedure in which the US and the SCS were presented in a separated, pseudorandom, and non-predictive fashion (Rescorla, 1967). To test the effects of sensitization by the shock, we presented footshock alone during conditioning. To test the impact of stimulus intensity and salience, we conducted paired and unpaired conditioning using a reversed SCS where the WN preceded the tone. We compared these four control groups against a paired SCS-shock conditioning group to determine the effects of associative learning on SCS-evoked fear behavior. All groups went through two extinction sessions with SCS presentations alone to elucidate the extent to which prior associative pairing affects de-escalating response strategies, as well as to identify defensive behaviors that are expressed in the absence of a strict threat-signaling association.

This study investigated the contributions of associative and non-associative processes to the expression of cue-induced defensive behaviors. The results signify that associative pairings and a proximal stimulus-threat association during fear conditioning produce maximal expression of cue-induced freezing and flight responses. Non-associative elements such as cue salience, change in stimulus intensity, and shock-induced sensitization elicit stress-associated behaviors like tail rattling and activity bursts, as hypothesized before (Trott et al., 2022), but the addition of the WN-threat associative pairing contributes significantly to eliciting high-intensity defensive responses like escape jumping. Therefore, these associative and non-associative factors combine to produce distinct behavioral transitions between freezing and flight.

During conditioning, we observed distinct ethograms for the PA and UN groups in response to the SCS. Freezing to tone and activity to WN were both significantly higher in the PA group compared to the UN group (Figure 2E and K), highlighting the impact of SCS-shock contingency on the magnitude of defensive responses. Notably, comparable results were previously reported in rats conditioned using similar parameters (Totty et al., 2021). Additionally, we found that the PA and PA-R groups showed significant increases in freezing from pre-SCS to tone, while in the UN and UN-R groups, freezing to tone was no greater than contextual freezing, suggesting that the paired groups placed associative value on the tone (Figure 2J). Lastly, the PA group displayed much more intense flight behavior during WN than the PA-R group (Figure 2L), indicating that the proximity of WN to the footshock threat affects defensive scaling.

Previous studies have factored jumping behaviors into normalized measures to gauge conditioned flight behavior (Fadok et al., 2017; Hersman et al., 2020; Borkar et al., 2020), but given the increased activity indices in the PA, UN, and UN-R groups, we examined if the escape jumping we observed was associative or non-associative (Figure 3). We found that the PA group exhibited consistent jumping responses to the WN stimulus during conditioning that were not reproduced in the UN, PA-R, or UN-R groups. Others have found that a salient stimulus is sufficient to induce conditioned jumping responses after multiple sessions (Furuyama et al., 2023). Given that the PA-R group did not display consistent jumping behavior to WN or tone, this suggests that a robust jumping response to WN in the SCS paradigm is not due to the non-associative salience of the WN as others have suggested (Hersman et al., 2020) but is instead due to its association with imminent threat.

Darting has been reported to be increased in rodents that undergo stress and fear conditioning, and it is more prevalent in female rats (Gruene et al., 2015; Brzozowska et al., 2017). Previous studies have measured darting to WN as a darts per minute measure (Morena et al., 2021; Hoffman et al., 2022; Trott et al., 2022) or as part of a composite escape score (Hersman et al., 2020), but our data suggests that examining darting requires a more detailed analysis. We found that the PA group exhibited darting across the entire WN period during conditioning, while the response was virtually nonexistent in the UN, PA-R, and UN-R groups (Figure 4). This is consistent with findings where conditioned darting has been shown to occur more often several seconds after a CS, rather than at its onset (Mitchell et al., 2022). This indicates that darting during conditioning is not caused by the salience of the tone-WN transition, but from an associative learned response. Additionally, the absence of darting in the PA-R group indicates that the temporal proximity of the WN to the shock also influences darting. Our data show that the control groups engage primarily in simple locomotor behaviors induced by stimulus salience (Figure 4J). Overall, darting behaviors during conditioning contribute to the higher activity score observed during WN in the PA group, and our data suggests that these contributions are the result of associative learning and threat imminence, rather than non-associative stimulus salience.

During extinction, the PA and PA-R groups showed the highest level of freezing to tone compared to the non-associative control groups (Figure 5A and B). This indicates that the paired groups had the strongest association between the tone stimulus and threat. This is further reinforced by the larger difference between tone-evoked freezing and pre-SCS freezing in the PA and PA-R groups (Figure 5E and F). Freezing during tone in the non-associative control groups, on the other hand, is no greater than freezing in the interstimulus intervals. Interestingly, tone-evoked freezing in the PA group underwent within-session extinction, while that of the PA-R group was resistant to extinction (Figure 5A–D). The sustained tone-evoked freezing over multiple extinction sessions in the PA-R group is likely a product of the temporal proximity of the cue to the footshock, which is set at a greater intensity (0.9 mA) in the conditioned flight paradigm than is traditionally used in Pavlovian threat conditioning (typically 0.2–0.6 mA). Because freezing during the tone is not elevated over contextual freezing levels in the unpaired and SO groups, the reductions in freezing during the tone during extinction in these groups can be attributed to reduced freezing overall.

In response to WN during extinction, the PA group transitioned from explosive circa-strike flight responses containing escape jumps to a combination of anticipatory post-encounter freezing and darting (Figure 6A, Figure 7). This likely reflects a larger perceived psychological distance from threat that influences defensive strategy (Perusini and Fanselow, 2015). The control groups showed only slight changes in WN-evoked activity over extinction, similar to responses of stressed mice to an unfamiliar WN (Figure 4; Hoffman et al., 2022). The lack of decrease in WN-evoked activity over extinction in the PA-R group compared to the PA group, and the lack of the control groups transitioning to freezing behavior, suggests that WN-evoked flight in the PA group is associative and is dependent on the perceived threat value of the WN stimulus.

An examination of jumping and darting behaviors over the first extinction session reveals a distinct ethogram in the PA group (Figure 7). The presence of jumping during early extinction trials in the PA group indicates that the WN initially signaled imminent threat, resulting in an explosive circa-strike escape response. However, the change from jumping to darting may reflect a change in perceived threat imminence in the same vein as the observed change from flight to freezing. This phenomenon was only observed in the PA group, indicating that this behavioral change is associative and is consistent with the predatory imminence continuum. This jumping behavior to WN is associative and can be extinguished, making it a suitable measure for future studies interested in how the nervous system controls experience-dependent high-intensity fear reactions.

The elevated activity indices from the UN and SO groups are similar to other studies that report heightened activity to WN after multiple footshocks, or a sudden change in stimulation (Hoffman et al., 2022; Trott et al., 2022). However, given the lack of darting and jumping from the UN group during extinction (Figure 7A and B), their increased activity is due to other locomotor behaviors unrelated to flight. The SO group maintained a consistent level of darting throughout the first extinction session, which contributed to their overall increased activity index (Figure 7B and D). Given that darting can be elicited in stressed mice (Brzozowska et al., 2017), it is probable that shock sensitization can prime an animal to dart more readily to an unfamiliar, but highly salient, stimulus upon stimulus transition. Indeed, darting behavior has been shown to change based on multiple parameters, decreasing both with increased shock intensity (Mitchell et al., 2022) and with prolonged extinction training (Demars et al., 2022), suggesting that darting is both an associative conditioned response to stimuli associated with threat and a response resulting from non-associative sensitization.

Within the UN, UN-R, and SO control groups, we observed a higher degree of tail rattling responses during extinction compared to the PA and PA-R groups, and tail rattling was more prominent during the tone period (Figure 8). Tail rattling has been observed in mice when determining hierarchical relationships (Haber and Simmel, 1976; Terranova et al., 1998; Dorofeikova et al., 2023), anticipating fighting (Miczek et al., 2001), and encountering looming threat (Salay et al., 2018). Thus, tail rattling may be a behavior elicited in stressed mice in the face of uncertain threat. Previously, we found that tail rattling occurs most often during early trials of fear conditioning, with a prominent decline later in conditioning (Borkar et al., 2020). This is consistent with our results from the UN, UN-R, and SO groups, who displayed greater tail rattling to unpaired (UN, UN-R groups) or novel (SO group) SCS presentations within the conditioning context, with reductions in tail rattling over the course of extinction exposure. Taken together, this suggests that tail rattling is not a behavior exhibited during post-encounter or circa-strike levels of threat, but rather within stressful scenarios where danger is uncertain but anticipated. Future studies that are interested in measuring defensive responses to threat signals such as context, odor, or innately aversive sensory stimuli should consider measuring tail rattling as a marker of non-associative anticipatory fear.

Current studies are investigating behaviors beyond freezing within classical Pavlovian conditioning paradigms (Tryon et al., 2021; Laine et al., 2022), but responses like jumping and darting are not always reliably elicited during CS presentation (Colon et al., 2018; Akmese et al., 2023; Biddle and Knox, 2023). Using the SCS flight conditioning paradigm, we elicit a robust continuum of consistent associative defensive responses during CS presentation that are seldom observed within classical Pavlovian conditioning. While behaviors like darting and tail ratting can occur due to non-associative stimulus-inherent properties, transitions between freezing and jumping are robustly present when associative factors signal threat imminence. Future studies can utilize this paradigm to investigate neuronal mechanisms that contribute to threat association and direct dynamic responses to threat, with important implications for developing new treatments for those who suffer from fear and anxiety disorders.

All source datasets for Figures 2–8 are provided in supporting Excel spreadsheet files.

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Author details

1. Quan-Son Eric Le

   1. Tulane Brain Institute, Tulane University, New Orleans, United States
   2. Program in Neuroscience, Tulane University, New Orleans, United States

   Contribution

   Data curation, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1409-7790

2. Daniel Hereford

   1. Tulane Brain Institute, Tulane University, New Orleans, United States
   2. Program in Neuroscience, Tulane University, New Orleans, United States

   Contribution

   Software, Formal analysis, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Chandrashekhar D Borkar

   1. Tulane Brain Institute, Tulane University, New Orleans, United States
   2. Department of Psychology, Tulane University, New Orleans, United States

   Contribution

   Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

4. Zach Aldaco

   1. Tulane Brain Institute, Tulane University, New Orleans, United States
   2. Department of Psychology, Tulane University, New Orleans, United States

   Contribution

   Formal analysis

   Competing interests

   No competing interests declared

5. Julia Klar

   1. Tulane Brain Institute, Tulane University, New Orleans, United States
   2. Program in Neuroscience, Tulane University, New Orleans, United States

   Contribution

   Formal analysis

   Competing interests

   No competing interests declared

6. Alexis Resendez

   1. Tulane Brain Institute, Tulane University, New Orleans, United States
   2. Department of Psychology, Tulane University, New Orleans, United States

   Contribution

   Writing – review and editing

   Competing interests

   No competing interests declared

7. Jonathan P Fadok

   1. Tulane Brain Institute, Tulane University, New Orleans, United States
   2. Department of Psychology, Tulane University, New Orleans, United States

   Contribution

   Conceptualization, Resources, Software, Supervision, Funding acquisition, Validation, Visualization, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   jfadok@tulane.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0608-5151

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