Fear limits the behaviors available to an animal to its species-specific defense reactions (SSDRs), thereby precluding more flexible voluntary behavior (Bolles, 1970). This characteristic is one reason that conditions characterized by high fear levels such as anxiety disorders are so maladaptive (Fanselow, 2018). It is also one reason that Pavlovian fear conditioning is so easy to measure in the laboratory, one can simply measure innate defensive responses (i.e. SSDRs) to diagnose fear and fear-related memory. This has made fear conditioning one of the major rodent assays of learning, memory, and anxiety disorders. Over the last four decades, fear conditioning studies have extensively used one of these defensive behaviors, freezing, more than any other response (Anagnostaras et al., 2010; Bouton and Bolles, 1980; Do-Monte et al., 2015; Fanselow and Bolles, 1979; Grewe et al., 2017; Kim and Fanselow, 1992; Kwon et al., 2015; Nader et al., 2000; Roy et al., 2017). Freezing is a common and adaptive defensive behavior as it reduces the likelihood of detection and attack by a predator (Fanselow and Lester, 1988).

However, if rodents have multiple defensive responses, an important theoretical question is what are the conditions that select between different SSDRs (Fanselow, 1997). An influential model of SSDR selection applied to both humans and rodents is Predatory (or Threat) Imminence Continuum theory, which states that qualitatively distinct defensive behaviors are matched to the psychological distance from physical contact with a life-threatening situation (Bouton et al., 2001; Fanselow and Lester, 1988; Mobbs, 2018; Mobbs et al., 2007). Stimuli that model particular points along this continuum elicit behaviors appropriate to that level of predatory imminence. For example, rodents freeze when they detect a predator but show vigorous bursts of activity to contact by the predator (Fanselow and Lester, 1988). The former, labeled post-encounter defense, relates to fear-like states. The latter, referred to as circa-strike defense, relates to panic-like states (Bouton et al., 2001; Perusini and Fanselow, 2015). According to this account, in fear conditioning experiments the shock unconditional stimulus (US) models painful contact with the predator and therefore invariably produces circa-strike activity bursts but not freezing (Fanselow, 1982). On the other hand, stimuli associated with shock such as an auditory conditional stimulus (CS), model detection of a predator and therefore invariably produce post-encounter freezing as a conditional response (CR) but not activity bursts (Fanselow, 1989).

Recently, there have been reports that challenge this view. Fadok et al., 2017 used a unique two-component serial CS consisting of a 10 s tone followed immediately by a 10 s white noise ending with a 1 s shock and found that the initial component (tone) produced freezing, while the second component (noise) produced bursts of locomotion and jumping in mice. Gruene et al., 2015 reported that in rats a tone CS resulted in a similar burst of locomotion, labeled darting, and this was replicated in subsequent studies (Colom-Lapetina et al., 2019; Mitchell et al., 2021). The results were interpreted as a competition between ‘active’ and ‘passive’ defenses. These findings not only challenge the above response selection rule but also call for a ‘reinterpretation of rodent fear conditioning studies’ because if only one SSDR is measured (e.g. freezing) but the situation is characterized by a different SSDR, fear and fear-related learning may be misdiagnosed (Gruene et al., 2015). Also note that contrary to Predatory Imminence Theory, Gruene et al., 2015 suggested that freezing and darting were competing CRs to the same level of threat (Fanselow, 1989).

Both previous reports concluded that these activity bursts were CRs because they increased over trials during acquisition when CS and US were paired and decreased during extinction when the CS was presented alone (Fadok et al., 2017; Gruene et al., 2015). While these behavioral patterns are certainly properties of a CR, they are not diagnostic of associative learning as these changes could also result from nonassociative processes such as sensitization and habituation (Rescorla, 1967). Additionally, no formal assessment was made of what properties of the CS led to the alternate CRs (e.g. its serial nature, the ordering of the two sounds, or stimulus modality). One subsequent study using this serial conditioning procedure in mice has suggested that this white-noise-elicited activity burst is mainly a result of the stimulus salience or intensity of the white noise and does not depend on any particular temporal relation to the US (Hersman et al., 2020). Another recent study using this procedure in rats has suggested that this flight behavior only occurs in contexts in which fear has been established and is a result of associative processes (Totty et al., 2021). Therefore, to better understand the associative nature of these flight responses, we embarked on a series of experiments to test these theoretical views and assess the validity of these concerns (Tables 1–4).

Prior work reported that contact/pain-related stimuli (e.g. shock) disrupt post-encounter freezing and provoke panic-like circa-strike defensive behaviors (Fanselow, 1982). The current results suggest a modification of the rules governing a transition between these behavioral states. The rule is that when you are in the post-encounter mode (fear) a sudden change in stimulation, particularly the onset of an intense novel stimulus, can cause an immediate transition to the circa-strike mode (panic). Indeed, the vast majority of the activity bursts/darting behavior occurred at the onset of the stimulus (Figures 3, 5, 7 and 8). The effectiveness of this transition depends on the qualities of the stimulus. Stronger shocks cause a greater disruption of freezing and a longer activity burst, yet the same stronger shocks simultaneously condition more freezing to the prevailing cues (Fanselow, 1982). The current data call for an expansion of this rule to non-nociceptive stimuli. Like shock, both tone and noise disrupted ongoing freezing, the noise did so for longer than the tone (Figure 10), and noise on its own was able to support a minimal level of fear conditioning (Figure 6, Figure 4—figure supplement 1, Figure 8—figure supplement 1). The rule is: when in a state of fear (post-encounter defense) sudden stimulus change provokes panic-like circa-strike defenses proportional to stimulus intensity and novelty.

Figure 10

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Figure 10—source data 1

Source data for the ability of cues and shock to disrupt freezing.

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As the majority of the experiments presented here and in most prior studies conduct both training and testing in the same context (Fadok et al., 2017; Gruene et al., 2015; Hersman et al., 2020), these animals would already be in a high state of fear or post-encounter defense (from any learned contextual fear during training), thus endowing the presentation of the white noise to be a particularly startling stimulus change that can provoke these panic-like flight responses. Novelty of the stimuli is an important factor and familiarity with the CS during conditioning and/or habituation reduced CS novelty for the test. In the experiments presented here, the mice that received noise-shock pairings and were tested with noise showed lower flight to the noise than mice trained only with shock and then received noise for the first time. Additionally, prior habituation to the noise or experience with the noise during training (i.e. paired and unpaired groups) further reduced noise-elicited flight at test.

Another important factor to consider is the timing of the activity burst with respect to CS and US onset. With poorly timed and sustained conditional responses such as freezing the CR tends to fill the entire CS-US interval and spill over beyond the time of expected US delivery (e.g. Ayres and Vigorito, 1984; Gale et al., 2004). However, shorter duration ballistic responses such as the darting response allow a clearer assessment of when the CR occurs with respect to CS and US delivery, and such CRs are expected to anticipate US delivery. Hull, 1934 cautioned conditioning researchers that it is important to distinguish true conditional responses from unconditional responses to the CS, which he named alpha responses. These alpha responses occur at the onset of the CS, rather than the time of the expected US. Alpha responses have been most studied with the Pavlovian conditional eyeblink response, where the true CR is well timed to US delivery (McCormick and Thompson, 1984; Perrett et al., 1993). Blinks that occur to CS onset are classified as alpha responses, which are considered to be nonassociative startle responses to the CS and not CRs (e.g. Gerwig et al., 2005; Nation et al., 2017; Schreurs and Alkon, 1990, Woodruff-Pak et al., 1996). Typically, in eyeblink studies alpha responses are excluded from analysis by omitting any responses that occur at the beginning of the CS. Our darting responses almost exclusively occurred at CS onset and there were rarely any US anticipatory-like responses. Thus, traditional Pavlovian analyses for ballistic CRs would have categorized darting as an unconditional alpha response and not a bona fide CR. Consistent with this analysis is that darting occurred to the noise during the first few trials of the habituation session in Experiment 4 (Figure 8—figure supplement 1).

Our interpretation that noise unconditionally elicits a ballistic activity burst bears some relationship to the unconditional acoustic startle response. Loud noises will elicit an unconditional startle response that wanes with repeated presentations of that noise (i.e. habituation; e.g. Davis, 1980; Hoffman and Fleshler, 1963; Leaton, 1976). The unconditional startle response to the loud noise can be potentiated if the loud noise is delivered in the presence of a cue or a context that has been associated with shock/fear (Brown et al., 1951; Davis, 1989). While our 75 dB noise stimulus is less intense than the 98–120 dB noise used in typical acoustic startle studies, we observed an unconditional noise-elicited response that also decreased with habituation (Experiment 4). Furthermore, our data and those of Totty et al., 2021 indicate that these responses require a fearful context in order to occur. Fear is well known to potentiate startle responses (Brown et al., 1951; Davis, 1989). Perhaps the low intensity noise is below threshold to elicit a startle response on its own, but a fearful context potentiates this unconditional startle response and brings it above threshold. Additionally, there appears to be considerable overlap in the neuroanatomy that supports this circa-strike behavior and fear potentiated startle. Totty et al., 2021 found that inactivation of the central nucleus or the bed nuclei of the stria terminalis disrupts the flight response. These two regions have been shown to be important mediators of fear’s ability to potentiate startle (e.g. Campeau and Davis, 1995; Davis and Walker, 2014). Furthermore, Fadok et al., 2017 reported that it is corticotropin-releasing hormone (CRH) expressing cells, but not somatostatin expressing cells, within the central nucleus that support flight behavior. Again, there is extensive data implicating CRH and fear potentiated startle (Lee and Davis, 1997).

It is of note that the relationship between startle (circa-strike defense) and freezing (post-encounter defense) was described by Fanselow and Lester, 1988 when accounting for how rats rapidly transitioned between these behaviors when a detected predator launches into attack. “It is as if the freezing animal is tensed up and ready to explode into action if the freezing response fails it. This explosive response probably has been studied in the laboratory for over 30 years under the rubric of potentiated startle… It seems that the releasing stimulus for this explosive motor burst is a sudden change in the stimulus context of an already freezing rat (Fanselow and Lester, 1988, p 202).”

Neither Fadok et al., 2017 nor Gruene et al., 2015 included any controls for nonassociative behavior, which is something required in order to conclude that a response is conditional (Rescorla, 1967). Both of these research groups concluded from their single-group experiments that flight/darting was a CR because the behavior increased with successive shocks during the shock phase and decreased with shock omission during the test phase, likening these behavioral changes to acquisition and extinction. While acquisition and extinction are characteristics of a CR, learning theorists have never taken these as diagnostic of a CR. For example, increases in responding with successive shocks could arise via sensitization and decreases in responding when shocks are omitted could arise from habituation. Indeed, that is exactly what we believe caused these behavioral changes that we also observed in our study. Shocks, by conditioning fear to the context, sensitize or potentiate the darting response and repeated presentations of the noise alone cause the response to habituate. The behavior of our pseudoconditioning control provides clear evidence of this. Just giving shocks conditioned fear to the context such that when the noise was presented for the first time during test it caused a strong activity burst. The behavior gradually decreased during testing because repeated presentations of the noise led to habituation of this unconditional response.

Given our argument that the flight/darting behavior is nonassociative, Totty et al.’s finding that noise-shock paired rats showed more noise elicited activity burst behavior than rats that had unpaired noise and shock requires additional comment. Since both unpaired and paired rats were exposed to noise during acquisition those exposures could lead to habituation of the unconditional response to the noise. However, it would be expected that habituation would be greater in the unpaired group because pairing a stimulus (noise in this case) with another stimulus (shock in this case) is known to reduce the magnitude of habituation (Pfautz et al., 1978). This reduction in habituation is observed even if the second stimulus is not an unconditional stimulus (Pfautz et al., 1978). Additionally, pairing a habituated stimulus with a US can also cause a return of the habituated alpha response, and this loss of habituation is not observed when the two stimuli are not paired (Holland, 1977). Thus, the difference between the paired and unpaired groups reported by Totty et al., 2021 is likely due to differential habituation of the noise during training. This effect of habituation was probably enhanced by Totty et al. including a noise habituation phase prior to training.

While many of the findings presented in Totty et al., 2021 are in line with our own or can be readily explained through a nonassociative lens, Figure 5 of Totty et al., 2021 presents data in which noise-elicited flight is greater for animals that have SCS-US pairings compared to those that have received only the US during training (comparable to paired vs shock only groups in Experiments 2–4 here). It is possible that Totty et al.’s additional habituation to the SCS in an alternate context prior to SCS or US-only training is a potential explanation for this difference. Indeed, the results here from Experiment 4 in which habituation was conducted in the training/testing context suggest that such habituation would primarily function to reduce darting, particularly in groups that only had US presentations. The use of a serial tone-noise compound may have also served to further reduce a startle response to the noise in Totty et al. It is well known that if a startle stimulus is preceded by another stimulus, the startle response is reduced in a phenomenon called pre-pulse startle inhibition (Louthan et al., 2020; Groves et al., 1974). Thus, two factors may contribute to Totty et al.’s failure to see darting behavior in the animals that did not receive SCS-shock pairings: the use of habituation prior to conditioning and the use of a two-stimulus compound. Another factor that may be important is species. Overall, the amount of darting seen in the studies using mice (Fadok et al., 2017; Hersman et al., 2020; the present study) was greater than in the studies using rats (Gruene et al., 2015; Totty et al., 2021).

Beyond this potential explanation, as mentioned above and detailed below, there are likely at least two different topographical types of locomotion occurring, and such cue-elicited locomotion behaviors in rats in previous studies may preferentially be ‘movement’ that is part of the freezing suite of behaviors, which include locomotion to an ideal thigmotaxic place to freeze (e.g. Fanselow and Lester, 1988). Associative processes would be expected to alter/increase such increased locomotion as it supports/is a part of freezing behavior.

Experimenters that have examined running-like locomotion in fear conditioning situations tend to collapse the behaviors under a single label such as darting, flight, or escape (Colom-Lapetina et al., 2019; Fadok et al., 2017; Gruene et al., 2015; Mitchell et al., 2021; Totty et al., 2021). These behaviors are then thought of as ‘active’ behaviors that compete with a ‘passive’ freezing response (Fadok et al., 2017; Gozzi et al., 2010; Gruene et al., 2015). It is important to recognize that all such movements are not identical and often serve different functions. Here, we will focus on two distinct movements we observed in the present experiments. In several instances, the mice made two movements in response to stimulus presentation. The first was a very high velocity response that occurred to stimulus onset; the other was a slower velocity movement that tended to occur later on during stimulus presentation (Figure 9C, D and E). We will discuss these two behaviors within the predatory imminence framework and suggest that the slower movement is part of the post-encounter freezing module and the faster one is a circa-strike behavior.

Circa-strike activity bursts

Circa-strike behavior occurs at or immediately before contact with the predator and represents a vigorous evasive movement away from the predator. The most effective circa-strike eliciting stimulus in the laboratory setting is shock, as it is directly analogous to painful contact. As can be seen in Figure 9A–B, the movement to shock onset is on average the highest velocity movement we observed. The activity burst to shock is highly protean and poorly directed, sometimes looking as if the animal is bouncing off the walls (Fanselow, 1982). If directed at all, it is directed away from the predator and not toward anything in particular. We argue here that when the animal is in the post-encounter fear mode (freezing), the threshold for these bursts of activity shifts such that sudden stimuli that would not normally cause an activity burst now do so. These are the high velocity movements we see to the noise and the tone at stimulus onset (Figure 9). These are nonassociative responses as they were greatest in animals that never had the sound paired with shock and decreased with familiarity to the stimulus (Figures 5, 7 and 8). Figure 9A–B shows the high velocity movement to tone, noise, and shock onset. The difference between the stimuli seems quantitative, such that shock > noise > tone, but note that in the violin plot some noise-elicited bursts are as fast as the fastest shock responses and many of the shock-elicited bursts overlapped in velocity with those triggered by tone. In all cases, these movements seemed protean and undirected.

A final clarifying note is in order regarding stimulus type and how this impacts cue-elicited flight. As described throughout the paper and detailed above, this flight or darting behavior can and does occur to both tone and noise stimuli, regardless of whether they have been paired with shock or not. There is a slight difference in the magnitude of the response to the tone vs the noise, with the noise having a higher proportion of particularly high-velocity movements—on par with reaction to shock at times. We have also noted that the white noise CS is not really a neutral cue and can/does support fear conditioning as if it were a US. While it is possible that these aversive properties of the white noise stimulus enhance cue-elicited flight in frightened animals, it is clearly not required as the tone can elicit similar flight. Rather than thinking about whether a cue needs to procedurally be a CS or a US to support darting, the data support the hypothesis that when an animal is afraid, any sudden change in stimulation can cause them to shift from post-encounter responses, like freezing, toward more circa-strike responses, like undirected flight. Thus, it is a sudden change in stimulation, regardless of the conditional/unconditional properties of the cue, that elicits flight behavior.

An alternative explanation of the altered timing of flight behavior in animals who have had noise-shock pairings is that these animals are more accurately timing the CS-US interval and are showing better temporal discrimination and potential avoidance of an upcoming threat. While our data do not necessarily rule out this explanation, the bulk of our results suggests that the majority of the cue-elicited flight behavior observed near cue onset in our experiments was nonassociative in nature. The flight behavior we observed later on in the cue presentation, which may have an associative component, may however be temporally driven. However, it is worth pointing out that this second burst of activity was also not particularly well timed to US delivery, it tended to occur in the middle of the noise presentation (see noise-shock group in Figure 5). Future studies that vary the length of the CS in animals who have US-only vs paired CS-US presentations during training are warranted and would help address this alternative explanation.

Initial reports suggest a sex difference in this noise-elicited flight behavior such that female rats show more of this behavior than males (Gruene et al., 2015; Mitchell et al., 2021). Within each experiment, we found no such sex differences between male and female mice for the PAR and darting measures of flight behavior, and Totty et al., 2021 similarly found no sex differences in such behavior in male and female rats. To further increase the power of such an analysis for sex differences, we pooled all of the groups across the four experiments that received noise-shock pairings (Figure 11). In this analysis, again, we saw no sex differences in flight to the white noise across the 2 days of acquisition for PAR (day 1: F[1, 29]=0.323, p=0.58; day 2: F[1, 29]=0.507, p=0.48). For darting, there were no impacts of sex on day 1 (F[1, 29]=0.009, p=0.92). On day 2, there was a trend for a main effect of sex (F[1, 29]=3.752, p=0.06) and CS presentation X sex interaction (F[4, 116]=2.558, p=0.042), such that males darted more than females on the second CS presentation. We further observed no sex differences across testing to the white noise in extinction for both PAR (F[1, 20]=0.099, p=0.76) and darting (F[1, 13]=1.397, p=0.258). Thus, we show no major sex differences other than a potential increase in male darting on day 2 of acquisition. Perhaps initial reports of sex differences with more frequent darting in females could be explained by differences in handling and stress provided to females as a result of monitoring estrous phase, a potentially stressful procedure for the animals for which there is not an ideal control in males. However, results were recently replicated in which females show more darting than males in a sample of animals for which estrous cycle was not monitored (Mitchell et al., 2021). It is worth noting that Gruene et al., 2015, Colom-Lapetina et al., 2019, and Mitchell et al., 2021, generally find very low levels of darting, with a majority of animals classified as nondarters. With the procedure used here, and in mice, we generally do not observe different subpopulations of darters vs nondarters (Figure 11). While there is certainly variation in the level of darting between animals, all animals across all experiments were shown to dart at least once and would be classified as darters using the criteria set forth in Gruene et al., 2015. Finally, while we show no major differences in tone-elicited flight vs noise-elicited flight, we do show some evidence that darts to the tone may be less strong than darts to the noise (Figure 9A). Perhaps there are species differences in such stimulus-evoked flight behavior, such that tone-elicited flight in rats is more sensitive to impacts of sex.

Figure 11

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Figure 11—source data 1

Source data for the potential sex differences in PAR and darting.

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Some have characterized freezing as a passive response (Blanchard and Blanchard, 1969; Fadok et al., 2017; Gozzi et al., 2010; Gruene et al., 2015; Yu et al., 2016) that occurs because no other response is available (Blanchard, 1997; Blanchard et al., 1989). However, because motion is often the releasing stimulus for predatory attacks it is the best thing for a small mammal like a rat or a mouse to do when a predator is detected and will only be replaced if there is a change consistent with contact (Fanselow and Lester, 1988). Rodents choose locations in which to freeze such as corners or objects (thigmotaxis) (Grossen and Kelley, 1972). The current data show that the freezing rodent also prepares to react to sudden stimulus change. There is nothing passive about freezing.

All data generated or analyzed during this study are included in the manuscript and supporting files. R code to extract darts and produce velocity traces is uploaded as Source Code 1. Source Data Files have been provided for Figures 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 as well as Figure 1-figure supplement 1, Figure 2-figure supplement 1, Figure 4-figure supplement 1, Figure 8-figure supplement 1.

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Author details

1. Jeremy M Trott

   Staglin Center for Brain and Behavioral Health, Department of Psychology, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Methodology, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7875-3446

2. Ann N Hoffman

   Staglin Center for Brain and Behavioral Health, Department of Psychology, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

3. Irina Zhuravka

   Staglin Center for Brain and Behavioral Health, Department of Psychology, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Investigation, Methodology, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

4. Michael S Fanselow

   Staglin Center for Brain and Behavioral Health, Department of Psychology, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review and editing

   For correspondence

   fanselow@psych.ucla.edu

   Competing interests

   is a founding board member of Neurovation, Inc

   "This ORCID iD identifies the author of this article:" 0000-0002-3850-5966

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