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. Author manuscript; available in PMC: 2026 Aug 7.
Published in final edited form as: Brain Res. 2025 Aug 7;1865:149877. doi: 10.1016/j.brainres.2025.149877

Context controls the ability of unconditional stimulus deflation to mitigate fear relapse

Payton K Robinson 1, Sydney Trask 1
PMCID: PMC13358201  NIHMSID: NIHMS2104966  PMID: 40782953

Abstract

Our lab, and others, have recently demonstrated that fear behavior can be weakened following fear acquisition with a footshock unconditional stimulus by presenting a weaker version of that footshock, a phenomenon termed ‘unconditional stimulus deflation’ or US deflation. Unlike extinction, US deflation putatively functions by modifying the original fear memory, potentially making it a more effective candidate for reducing fear and preventing relapse effects often observed following extinction. Here, we adapted our contextual fear US deflation procedure to a delay conditioning paradigm in order to examine common relapse phenomena: renewal and reinstatement. We found that while ABA renewal and reinstatement were unaffected by US deflation, AAB renewal was reduced by US deflation. Our results support similar work in suggesting that prevention of relapse is at least partially dependent on deflation occurring in the same context as training when using a delay fear conditioning procedure.

In recent years, the rate of anxiety disorder diagnoses has rapidly increased both nationally and worldwide (Goodwin et al., 2020; Javaid et al., 2023). Between 1990 and 2019 there was a 55% increase in anxiety disorders globally (Javaid et al., 2023), with an additional 25% increase observed in the prevalence of anxiety and related disorders as a direct result of the COVID-19 pandemic (WHO, 2022). Increases in diagnoses are comparable among all age groups and across biological sex, with anxiety being the second-most common psychiatric disease following depression (for a review, see Szuhany & Simon, 2022). These statistics do not account for those living undiagnosed or misdiagnosed, capturing only a fraction of these disorders’ impact.

Due to the significant disruption in daily functioning caused by anxiety-based disorders, developing effective treatments is paramount. Like many other psychiatric conditions, pharmacotherapy is a common route of treatment with antidepressant selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) being widely prescribed to treat anxiety (Bandelow, 2022). However, these medications often have a delayed latency accompanied by adverse side-effects at the time of introduction, leading to difficulties sustaining treatment compliance. Psychotherapies or combination therapies are therefore found to be more effective in mitigating symptoms, with cognitive behavioral therapy (CBT) being the most well-studied and widely-implemented (Curtiss et al., 2021; Pegg, 2022). Exposure therapy is a well-known form of CBT used to reduce fear- and anxiety-related symptoms in anxiety disorders. In a typical version of this procedure, an individual is increasingly exposed to their specific anxiety-inducing stimulus in a controlled, safe setting to aid in the reduction of fear to that stimulus (Craske et al., 2018).

Preclinical rodent studies use a similar procedure called extinction to reduce fear behaviors observed following fear conditioning. In extinction, repeated, unreinforced exposure to a conditional stimulus (CS; e.g., a tone) that was previously paired with an unconditional stimulus (US; e.g., a footshock) results in the formation of a new CS-No US association (Bouton, 2022). Not presenting a US following a CS when one is expected introduces a high amount of prediction error and creates a new, inhibitory memory (Kennedy et al., 2024). Successful retrieval of the extinction memory is crucial for successfully mitigating fear symptoms (Bouton, 1993; Trask et al., 2018). The presence of competing excitatory (learned in acquisition) and inhibitory (learned in extinction) memories could provide a possible explanation for the failure of extinction retrieval in vulnerable populations, including adolescent (Baker et al., 2014) and aged individuals (Robinson et al., 2024), as well as the high incidence of fear relapse of a previously extinguished behavior (Bouton, 2002). Relapse can be described as a reemergence of symptoms following extinction, and can occur due to removal from the extinction context (i.e., renewal) or re-exposure to the original stimulus (i.e., reinstatement) (Bouton, 2002).

In some circumstances, the original excitatory memory can become labile, allowing for memory modification through reconsolidation-like processes (Sevenster et al., 2013; 2014; for review see Ferrara et al., 2023). A procedure that reliably retrieves and weakens the original fear memory, rather than relying on formation of a new CS-No US association, would be an effective treatment that could possibly overcome relapse. Stimulus deflation is the reduction of the fear-eliciting value of the US following exposure to a less intense version of the US (Bonanno et al., 2023). Early work demonstrated that habituation to a fear-evoking US reduced later responding to the previously-paired CS (Rescorla, 1973; see Holland, 1990 for related arguments). More recent work built upon this foundation with findings supporting the effectiveness of a weaker US to manipulate the original memory and produce changes in fear responding following context fear conditioning (CFC; Bonanno et al., 2023; Ferrara et al., 2019; see also Brooks et al., 2025). In those experiments, following CFC with a strong shock (1.0 mA), exposure to 10 presentations of a weaker shock (0.3 mA) over the course of 1 session reduced behavioral responding. Related studies (Kennedy et al., 2024; Popik et al., 2020; 2023) have demonstrated that several sessions that include weaker presentations of the shock over the course of days lead to persistent, relapse-resistant changes in delay fear memory.

The goal of the present experiments was therefore to extend our results using 10-weak shock exposures within the same session to a delay fear conditioning (DFC) procedure in which the US is signaled by a discrete CS (rather than contextual cues) and test the ability of this procedure to reduce common forms of relapse, including renewal and reinstatement.

Experiment 1: Introduction

We have previously shown that unconditional stimulus deflation is effective at reducing context fear (Bonanno et al., 2023). It is still unclear, however, if US deflation can reduce cued fear in an analogous delay fear task in which the 10 deflating shocks are presented within the same session. Here, we directly compare the weak shock procedure to extinction following delay fear conditioning.

Experiment 1: Methods

Subjects.

Subjects were age-matched (~70 days) male (250–274g) and female (175–199g) Long Evans rats purchased from Envigo (Indianapolis, IN). The colony was maintained on a 12:12 light:dark cycle beginning at 7:00. Behavior occurred during the light portion of the cycle. Animals were acclimated to the colony for 7 days prior to experimentation. All procedures were approved by the Purdue University Animal Care and Use Committee.

Apparatus.

Behavioral procedures occurred in Colbourn conditioning chambers, each housed in its own sound-attenuating cubicle. Each chamber consisted of plexiglass front, rear, and top walls with brushed stainless steel side walls. For training, the chamber floor consisted of a shock grid with 18 rods (0.4cm diameter) spaced 1cm apart. A fan produced continuous 65dB noise. Chambers were lit with a white LED houselight. Between each animal, chambers were thoroughly cleaned with lemon-scented cleaner. Day 2 and testing occurred in a second set of chambers. These chambers were identical except for the following characteristics: no noise was played, the LED light was red, and they were cleaned with Windex between animals.

Behavioral procedures.

Animals were handled for 2 days prior to behavioral training to acclimate to the experimenter. Male and female rats were run in separate experimental sessions. Behavioral methods are depicted in Figure 1A.

Figure 1.

Figure 1.

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Results from Experiment 1. Both extinction and weak shock procedures reduce fear following delay fear conditioning. A) Schematic of behavioral procedures. B) All groups showed an increase in freezing throughout training. C) During the Day 2 session, both groups reduced their freezing and this did not differ between extinction and weak shock groups. D) During testing, while there was no difference in freezing during pre-CS period, both the extinction and weak shock groups reduced CS-elicited freezing relative to the no exposure group. All data are represented as a group mean and SEM; * p < 0.05, ** p < 0.01.

Training.

On the first day, each animal was assigned to and placed inside of a chamber. After a 6-min baseline acclimation period, 4 CS-US pairings were presented; here, a 70 dB 10-s white noise coterminated with a 1-s foot shock. There was an average of 110-s intertrial interval (ITI; ranging from 90 and 130-s), and animals were kept in the chambers for an additional 4 min following the final shock before removal from the chamber.

Day 2: Weak Shock or Extinction.

24 hours later, the animals were split into three experimental conditions (weak shock, extinction, or no exposure). Animals in the weak shock condition were placed in a conditioning chamber in Context B and, following 1-min, 10 30-s CSs that ended with a 1-s 0.3mA footshock were delivered with an ITI of 1 min. Animals were removed from the chamber 15 seconds following the final footshock. Animals in the extinction condition were given identical CS exposure, but no footshocks were delivered. Animals in the no exposure condition remained in their homecages during this time.

Testing.

On the final day of the experiment, animals were tested for fear responding elicited by 10 30-s CS presentations (60-s ITI) in Context B (the same context as Day 2). There was a 1-min baseline period before the first CS presentation and animals were removed from chambers 60 seconds following the final CS presentation.

Data Analysis.

Freezing behavior was used as the main dependent variable of interest and was defined as a lack of mobility except that required for respiration (Fanselow, 1980). Freezing was scored in real time using the Freeze Frame software with thresholds set to match a trained observer. For all experiments, data were analyzed using SPSS v 29 (IBM) with repeated measures ANOVAs and posthoc comparisons using Fisher’s LSD on interactions with planned comparisons being used to follow-up on the main effect time during testing. We chose to examine the main effect of time during testing because a CS that still evokes fear following intervention should be able to elevate responding above the pre-CS period (see Cain et al., 2003), and planned comparisons detailing this within-subject change would confirm that this is the case for each group irrespective of existing differences between either pre-CS or CS freezing in those groups. Final group sizes were: No Exposure n = 6; Extinction n = 6; Weak Shock n = 6. An additional group of 6 naïve rats was sacrificed at the same time as experimental rats (60 min following testing) for follow-up molecular analyses (see Supplemental Information; Supplemental Figures 1–3).

Experiment 1: Results

Training (Figure 1B).

All animals increased their freezing throughout the acquisition session. This was confirmed by a 3 (Group: No Exposure, Extinction, Weak Shock) × 3 (Time Period: Pre-CS, CS-US, Post-CS) ANOVA which found a main effect of time period, F(2, 30) = 480.59, MSE = 73.87, p < 0.001, hp2 = 0.97, but no main effect of group nor an interaction, Fs < 1.

Day 2: Weak Shock or Extinction (Figure 1C).

Both groups that received CS-weak shock or CS-alone presentations on the second day decreased their CS freezing throughout the session. A 2 (Group: Weak Shock, Extinction) × 11 (Time Period: Pre-CS, CS 1 through CS 10) ANOVA found a main effect of time period, F(10, 100) = 16.42, MSE = 378.09, p < 0.001, hp2 = 0.62, but no main effect of group, F < 1, or an interaction, F(10, 100) = 1.74, MSE = 378.09, p = 0.073, hp2 = 0.15.

Testing (Figure 1D).

During the test, both groups that received CS-weak shock or CS-alone presentations on the second day decreased their CS freezing relative to animals that received no exposure on the second day. This was confirmed by a 3 (Group: No Exposure, Weak Shock, Extinction) × 2 (Time Period: Pre-CS, CS) ANOVA which found a main effect of time period, F(1, 15) = 52.22, MSE = 113.39, p < 0.001, hp2 = 0.78, a marginal effect of group, F(2, 15) = 3.61, MSE = 243.81, p = 0.053, hp2 = 0.33, and an interaction between the two, F(2, 15) = 5.99, MSE = 113.39, p = 0.012, hp2 = 0.44. Planned comparisons found that while there were no group differences during the pre-CS period (smallest p = 0.517), both the weak shock (p = 0.033) and extinction (p = 0.008) groups showed reduced freezing relative to the no exposure group during the CS. All groups showed an increase between the pre-CS and CS periods (No Exposure: p < 0.001; Extinction: p = 0.029; Weak Shock: p = 0.007).

Experiment 1: Discussion

Both the weak shock and extinction procedures reduced CS-elicited fear, evidenced by less freezing at test than the no exposure group. This suggests that both the weak shock and extinction procedures are effective at reducing fear following delay fear conditioning.

Experiment 2: Introduction

We next examined fear behavior following a long retention interval (4 weeks) between the day 2 intervention (either extinction or weak shock) and testing to determine the persistence of this effect.

Experiment 2: Methods

Subjects.

Long Evans rats acquired, housed, and maintained as before were used.

Apparatus.

The same apparatus was used. The lemon-scented chambers served as the training context and the Windex-scented chambers served as the testing context.

Behavioral procedures.

Figure 2A shows a schematic of the behavioral design.

Figure 2.

Figure 2.

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Results from Experiment 2. Neither extinction nor weak shock exposure following acquisition seemed to attenuate fear long-term. A) Schematic of behavioral procedures. B) All groups showed increases in freezing throughout training. C) Both groups decreased CS-elicited freezing throughout Day 2; no substantial group differences were observed. D) During the test, no exposure and extinction groups increased their freezing during the CS relative to the pre-CS period. Pre-CS and CS freezing was not different for the weak shock group. However, no between-subjects differences were observed. All data are represented as a group mean and SEM.

Training.

Training was identical to the previous experiment and occurred in the lemon-scented chambers.

Day 2: Extinction or Weak Shock.

Day 2 occurred exactly as the previous experiment in the Windex-scented chambers.

Testing.

Testing occurred exactly as in Experiment 1 with the exception that it occurred 4 weeks following Day 2 on Day 30 in the Windex-scented chambers.

Data Analysis.

Data were analyzed as before. Because group sizes were relatively small in Experiment 1, we increased group size to 8 in these experiments, in line with other studies examining extinction-like processes (e.g., Bouton & Bolles, 1979; Todd et al., 2017). Final group sizes were: No Exposure n = 8; Extinction n = 8; Weak Shock n = 8.

Experiment 2: Results

Training (Figure 2B).

All groups increased their freezing throughout training as indicated by a 3 (Group: No Exposure, Weak Shock, Extinction) × 3 (Time Period: Pre-CS, CS-US, Post-CS) ANOVA that found a main effect of time, F(2, 42) = 249.06, MSE = 165.33, p < 0.001, hp2 = .92, but no main effect of group or interaction, Fs < 1.

Day 2: Extinction or Weak Shock (Figure 2C).

A 2 (Group: Extinction, Weak Shock) × 11 (Time Period: Pre-CS, CS 1 – 10) ANOVA assessing responding throughout Day 2 found a main effect of time, F(10, 140) = 12.46, MSE = 411.71, p < 0.001, hp2 = .47, and a time by group interaction, F(10, 140) = 3.80, MSE = 411.71, p < 0.001, hp2 = .21, but no main effect of group, F < 1. This interaction appears primarily driven by great pre-CS freezing in the extinction group, with both groups showing similar performance during the CS presentations. It is unclear why the extinction group would show elevated pre-CS freezing to the novel context B.

Testing (Figure 2D).

A 3 (Group: No Exposure, Extinction, Weak Shock) × 2 (Time: Pre-CS, CS) ANOVA conducted to assess responding during the test found a main effect of time, F(1, 21) = 10.82, MSE = 351.62, p = 0.003, hp2 = .34, but no main effect of group nor an interaction, Fs < 1. Planned comparisons to follow-up on the main effect of time found that in both no exposure, p = 0.042, and extinction, p = 0.045, groups the CS resulted in increased responding relative to the pre-CS period, but this was not the case in the weak shock group, p = 0.176. This suggests that while the CS maintained the ability to evoke fear responding in the no exposure and extinction conditions, this was not the case in the weak shock group. Overall, however, no substantial group differences were observed during the test.

Experiment 2: Discussion

Neither extinction nor the weak shock procedure provided long-lasting reductions in fear responding. There was modest evidence that the weak shock reduced long-term retention in that the weak shock group was the only group in which the CS lost the ability to evoke an increase in freezing above pre-CS levels when tested four weeks following intervention. However, this interpretation is tempered as there were overall no differences in freezing between groups at test suggesting that the long-term impact of deflation is limited to reducing CS control over behavior with no substantial reduction in behavior overall.

Experiment 3: Introduction

We next aimed to test if US deflation would be resistant to the relapse effects often observed following extinction. Some evidence suggests that the weak shock works by modifying the original fear memory instead of forming a new inhibitory memory (e.g., Bonanno et al., 2023; Popik et al., 2020); we therefore hypothesized that behavior reduced through deflation using weak shocks would not be susceptible to relapse. We first tested this hypothesis using an ABA renewal procedure in which acquisition took place in one context (Context A), Day 2 took place in a second context (Context B), and responding was tested in both Contexts A and B. Here, renewal would be evident if CS-elicited freezing was greater in Context A than Context B.

Experiment 3: Methods

Subjects.

Long Evans rats acquired, housed, and maintained as before were used.

Apparatus.

The same chambers as before were used, counterbalanced as Context A and B.

Behavioral Procedure.

A schematic of the behavioral procedure is depicted in Figure 3A.

Figure 3.

Figure 3.

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Results from Experiment 3. Neither extinction nor weak shock reduced ABA Renewal. A) Schematic of behavioral procedures. B) All groups freezing increased over the course of training. C) During Day 2, freezing did not differ between the extinction and weak shock groups. D) During the test, both groups extinction and weak shock had reduced freezing compared to the no exposure group in Context A and Context B. E) When the data are replotted to highlight within-subject effects, it is evident in both extinction and weak shock groups, freezing in Context A was higher than in Context B, demonstrative of renewal. All data are represented as a group mean and SEM; * p < 0.05, ** p < 0.01.

Training.

The training procedure was identical to that described in Experiment 1 and occurred in Context A.

Day 2: Extinction or Weak Shock.

Day 2 proceeded as in Experiment 1 and occurred in Context B.

Testing.

On the final day of the experiment, animals were tested for fear responding elicited by 4 30-s CS presentations (60-s ITI) in each context (with each test separated by 90 minutes). While previous tests used 10 CSes to test behavior, we chose a shorter test session for each test to limit within-session extinction that might impact the subsequent within-subject test, as we often observe within-session extinction with a 10-CS test (e.g., Trask et al., 2025). There was a 1-minute baseline period before the first CS presentation and animals were removed from chambers 60 seconds following the final CS presentation. Testing order was counterbalanced such that half of the animals in each group received the testing order “Context A, Context B” and half received the testing order “Context B, Context A.”

Data Analysis.

Data were analyzed as before. One animal was excluded in the No Exposure group for failing to acquire CS-elicited freezing (< 25% in either Context A or B following acquisition) and one animal was excluded from the weak shock group as it showed abnormally high context-elicited fear (Z = 2.71). Final group sizes were: No Exposure n = 7, Extinction n = 8, Weak Shock n = 7.

Experiment 3: Results

Training (Figure 3B).

All groups increased their freezing throughout training. This was confirmed by a 3 (Group: No Exposure, Extinction, Weak Shock) × 3 (Time Period: Pre-CS, CS-US, Post-CS) ANOVA that found a main effect of time, F(2, 38) = 191.29, MSE = 159.36, p < 0.001, hp2 = .91, but no main effect of group or an interaction, largest F = 1.13, p = 0.356.

Day 2: Extinction or Weak Shock (Figure 3C).

Both groups generally reduced their freezing throughout the session, although this effect was more pronounced in the extinction group. A 2 (Group: Extinction, Weak Shock) × 11 (Time Period: Pre-CS, CS 1 – 10) ANOVA found a main effect of time, F(10, 130) = 11.76, MSE = 401.50, p < 0.001, hp2 = .48, but no other main effects or interactions, largest F = 1.74, p = 0.210.

Testing (Figure 3D–E).

Means during the pre-CS periods (not pictured) for each group were: Group No Exposure: Context A – M = 8.03, Context B – M = 5.59; Group Extinction: Context A – M = 10.57, Context B – M = 3.38; Group Weak Shock: Context A – M = 16.93, Context B – M = 13.93. While freezing was attenuated in both contexts in groups that received either extinction or weak shocks, a strong renewal effect was observed in both groups. A 2 (Time Period: Pre-CS, CS) × 2 (Context: A, B) × 3 (Group: No Exposure, Extinction, Weak Shock) ANOVA conducted to assess responding during the test found main effects of time, F(1, 19) = 156.54, MSE = 112.61, p < 0.001, hp2 = .89, Context, F(1, 19) = 12.02, MSE = 112.61, p = 0.003, hp2 = .39, and group, F(2, 19) = 7.65, MSE = 347.97, p = 0.004, hp2 = .45, as well as time by group, F(2, 19) = 12.81, MSE = 112.61, p < 0.001, hp2 = .57, and context by time, F(1, 19) = 7.91, MSE = 112.61, p = 0.011, hp2 = .29, interactions. No other interactions were significant, largest F = 1.13, p = 0.344. Planned comparisons to follow-up found that all groups showed increased freezing between the pre-CS and CS periods in both contexts (Group No Exposure: Context A – p < 0.001, Context B – p < 0.001; Group Extinction: Context A – p < 0.001, Context B – p = 0.008; Group Weak Shock: Context A – p < 0.001, Context B – p < 0.001). During the CS, both groups Extinction and Weak Shock froze less than controls in both the extinction context, Context B (Group Extinction: p = 0.002; Group Weak Shock: p = 0.042), and the renewal context, Context A (Group Extinction: p = 0.002; Weak Shock: p = 0.047). However, both groups showed a significant renewal effect, with higher CS freezing in Context A than Context B (Group Extinction: p = 0.012; Weak Shock: p = 0.038). This was not the case in the no exposure group, who showed equally high freezing in Contexts A and B (p = 0.255). While the weak shock and extinction groups did not differ in CS freezing in Context A (p = 0.230), the weak shock group showed elevated freezing to the CS in Context B (p = 0.038).

Experiment 3: Discussion

Although the weak shock and extinction groups showed a reduction in freezing in both Contexts A and B at test, both groups froze more in Context A than Context B demonstrating a strong renewal effect. This result replicates prior work demonstrating that extinguished responding is susceptible to ABA renewal following DFC and demonstrates that deflation through weak shock presentations also fails to prevent ABA renewal.

Experiment 4: Introduction

Reinstatement occurs when there is a return of fear expression to the conditional stimulus following re-exposure to the unconditional stimulus. In a typical version of this task, an unsignaled footshock will reinstate fear to a previously-extinguished CS that signaled that footshock. One possibility is the exposure to weak shocks during US deflation may protect against reinstatement by changing the emotional response to the shock itself, limiting its ability to later promote reinstatement. Experiment 4 aimed to compare the weak shock procedure to extinction in a reinstatement paradigm.

Experiment 4: Methods

Subjects.

Long Evans rats acquired, housed, and maintained as before were used.

Apparatus.

The same apparatus was used.

Behavioral procedures.

Behavioral procedures are depicted in Figure 4A.

Figure 4.

Figure 4.

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Results from Experiment 4. Groups did not differ during reinstatement testing. A) Schematic of behavioral procedures. B) All groups increased their freezing over the course of training. C) While the extinction group decreased freezing throughout Day 2, this was not the case for the weak shock group. D) All groups show similar freezing in the 10-minute period following a reinstating footshock. E) No group differences were observed in freezing to the CS following reinstatement. * p < 0.05 effect of group. All data are represented as a group mean and SEM.

Training.

Training was identical to the previous experiments and occurred in the lemon-scented chambers (Context A).

Day 2 Extinction or Weak Shock.

Day 2 occurred exactly as in prior experiments in the Windex-scented chambers (Context B).

Testing.

Testing in Context B occurred exactly as in previous experiments except that animals were given a 1-s 1mA footshock following a 1-minute baseline period followed by a 10-minute period. Following this 10-minutes, animals were given one additional minute in the chamber that served as the pre-CS period before the 10 CS presentations.

Data Analysis.

Data were analyzed as before. Final group sizes were: No Exposure n = 8; Extinction n = 8; Weak Shock n = 8.

Experiment 4: Results

Training (Figure 4B).

All groups increased their freezing during training, as confirmed by a 3 (Group: No Exposure, Extinction, Weak Shock) × 3 (Time Period: Pre-CS, CS-US, Post-CS) ANOVA that found a main effect of time, F(2, 42) = 758.62, MSE = 64.38, p < 0.001, hp2 = .97, but no main effect of group nor an interaction, largest F = 1.44, p = 0.239.

Day 2: Extinction or Weak Shock (Figure 4C).

To assess responding throughout Day 2, a 2 (Group: Extinction, Weak Shock) × 11 (Pre-CS, CS 1 – 10) ANOVA was conducted and found main effects of time, F(10, 140) = 26.58, MSE = 284.96, p < 0.001, hp2 = .66, and group, F(1, 14) = 7.03, MSE = 3511.32, p = .019, hp2 = .33, as well as a time by group interaction, F(10, 140) = 3.03, MSE = 284.96, p = .002, hp2 = .18. This suggests that while both extinction and weak shock reduced behavior over the session, this was faster in the extinction group.

Reinstatement (Figure 4D) and Testing (Figure 4E).

A 3 (Group: Extinction, Weak Shock, No Exposure) × 10 (Time Period: Reinstatement min 1–10) ANOVA assessing responding during the 10 minute period following the reinstating footshock found a main effect of time, F(9, 189) = 21.10, MSE = 320.32, p < 0.001, hp2 = .50, but no group or time by group interaction, Fs < 1. For the CS test, we conducted a 3 (Group: Extinction, Weak Shock, No Exposure) × 2 (Time Period: Pre-CS, CS) ANOVA which found a main effect of time, F(1, 21) = 12.24, MSE = 313.19, p = 0.002, hp2 = .37. There was no main effect of group nor interaction, largest F = 1.36, p = 0.278, suggesting groups did not differ substantially during this test. When following up on the main effect of time, both the no exposure (p = 0.041) and weak shock (p = 0.005) groups increased their freezing between the pre-CS and CS periods; this was not the case in the extinction group (p = 0.443). It is unclear why this may be, but one potential explanation is that following extinction and reinstatement, the context itself became a better predictor of the shock for this group resulting in a lack of control of CS behavior.

Experiment 4: Discussion

There were no group differences during the test, suggesting that exposure to the weak shock does not reduce reinstatement. This suggests that exposure to the weak shock during Day 2 did not protect against subsequent exposures to the strong shock.

Experiment 5: Introduction

At this point, the weak shock procedure has not differed from extinction in altering fear behavior following delay fear conditioning. Kennedy et al. (2024) interpreted similar findings to determine that modifying the US along with a change in context between training and day 2 (the procedure employed here in Experiments 1–4) yields enough change to increase prediction error, ultimately resulting in extinction-like processes and leaving behavior susceptible to relapse effects observed after extinction. We next aimed to test the hypothesis outlined in Kennedy et al. (2024): weak shock presentations will have an advantage over extinction if training and day 2 occur in the same context. To this end, we used an AAB renewal paradigm, in which training and day 2 took place in Context A and renewal was tested in a novel Context B.

Experiment 5: Methods

Subjects.

Long Evans rats acquired, housed, and maintained as before were used.

Apparatus.

The same apparatus was used.

Behavioral procedures.

Behavioral procedures are depicted in Figure 5A.

Figure 5.

Figure 5.

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Results from Experiment 5. Weak shock, but not extinction, reduced AAB Renewal. A) Schematic of behavioral procedures. B) All groups increase their freezing during training. C) While we observed overall higher freezing than previously recorded during Day 2, there were no differences between groups. D) Only the weak shock group shows a reduction in their freezing relative to the no exposure group. The extinction group did not differ from the no exposure group. E) During the test two weeks later, both the extinction and weak shock groups were reduced relative to the no exposure group. All data are represented as a group mean and SEM; * p < 0.05, ** p < 0.01.

Training.

Training was identical to the previous experiments and occurred in the lemon-scented chambers.

Day 2 (Extinction or Weak Shock).

Day 2 occurred exactly as in prior experiments in the lemon-scented chambers.

Testing.

Testing occurred exactly as in Experiment 1 and occurred in the Windex-scented chambers.

Data Analysis.

Data were analyzed as before. Final group sizes were: No Exposure n = 8; Extinction n = 8; Weak Shock n = 8.

Experiment 5: Results

Training (Figure 5B).

All groups increased their freezing during training, as confirmed by a 3 (Group: No Exposure, Extinction, Weak Shock) × 3 (Time Period: Pre-CS, CS-US, Post-CS) ANOVA that found a main effect of time, F(2, 42) = 242.68, MSE = 171.82, p < 0.001, hp2 = .92, but no main effect of group nor an interaction, largest F = 1.60, p = 0.193.

Day 2 (Figure 5C).

A 2 (Group: Extinction, Weak Shock) × 11 (Time: Pre-CS, CS 1 – 10) found a main effect of time, F(10, 140) = 27.95, MSE = 276.46, p < 0.001, hp2 = .67, but no main effect of group or an interaction, Fs < 1, suggesting that both groups showed similar increases from the pre-CS to CS periods and decreases during the CSs as time went on.

Testing (Figure 5D).

A 3 (Group: No Exposure, Extinction, Weak Shock) × 2 (Time Period: Pre-CS, CS) ANOVA found a main effect of time, F(1, 21) = 165.68, MSE = 153.47, p < 0.001, hp2 = .89, as well as a time by group interaction, F(2, 21) = 5.20, MSE = 153.47, p = 0.015, hp2 = .33, but no main effect of group, F(2, 21) = 1.17, p = 0.331. Planned comparisons found that while neither experimental group differed from the no exposure control during the pre-CS period (smallest p = 0.529), the weak shock group showed significant reductions in CS freezing relative to the no exposure group, p = 0.046. This was only a trend in the extinction group, p = 0.080, suggesting that extinction did not reliably reduce responding.

Long-term Retention Test (Figure 5E).

We gave animals a second test in Context A 14 days following the first test. We ran the same 3 (Group: No Exposure, Extinction, Weak Shock) × 2 (Time Period: Pre-CS, CS) ANOVA and found a main effect of time, F(1, 21) = 27.20, MSE = 93.38, p < 0.001, hp2 = .56, a marginal interaction, F(2, 21) = 2.59, MSE = 93.38, p = 0.099, hp2 = .20, and no main effect of group, F = 1.68, p = 0.210. Follow-up comparisons to understand the main effect of time found that while both the no exposure, p < 0.001, and extinction, p = 0.006, groups showed an increase in freezing between the pre-CS and CS periods, the weak shock group did not, p = 0.185, mirroring the pattern from the long-term retention test in Experiment 2.

Experiment 5: Discussion

Deflation using weak shock presentations, and not extinction, resulted in a reduced AAB renewal relative to the no exposure control. This suggests that US deflation in the same context as acquisition allows for an optimal amount of prediction error to produce changes to the value of the US. This result supports the interpretation outlined by Kennedy et al. (2024) and demonstrates the efficacy of the weak shock to reduce AAB renewal following DFC.

Cross-Experiment Trends

Given between-experiment variability often observed in experiments on fear conditioning we then aimed to analyze general trends observed in the present data set across all experiments (Figure 6).

Figure 6.

Figure 6.

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Experimental results combined across all experiments, with testing behavior normalized to subtract pre-CS freezing from CS freezing. A) Animals increased their freezing throughout training. B) While both groups decreased freezing throughout the CS presentations on Day 2, this was faster in the extinction group. Groups did not differ by the final CS presentation. C) While both extinction and weak shock groups show less responding than the no exposure group, they did not differ from each other. D) Groups did not differ when tested four weeks later. E) Both the extinction and weak shock groups showed reduced elevation scores relative to the no exposure group in both contexts A and B. Only the extinction group showed an increased elevation score in context A relative to context B. Asterisks indicate between-subject differences comparing experimental groups to no exposure controls. F) Groups did not differ when tested following a reinstating footshock. G) Only the weak shock group showed a lower elevation score than the no exposure group in the AAB renewal test. H) These results held in the long-term retention test 2 weeks later, where only the weak shock group was reduced relative to the no exposure group. * p < 0.05, ** p < 0.01, ***p < 0.001, ‡ p < 0.05 within-subject (Context A vs. Context B). Note: Elevation scores below 0 are not depicted by individual dots due to Y axes ending at 0 but are reflected in the group mean and SEM depicted.

Training (Figure 6A).

Because in all experiments, training consisted of 4 CS-US pairings according to the same protocol, we combined all animals to conduct a 3 (Group: No Experiment, Extinction, Weak Shock) × 3 (Time: Pre-CS, CS, Post-CS) ANOVA which found a main effect of time, F(2, 218) = 1440.14, MSE = 136.33, p < 0.001, hp2 = .93, but no main effect of group nor an interaction, largest F = 1.15, p = 0.335.

Day 2: Extinction or Weak Shock (Figure 6B).

As both extinction and weak shock groups received a similar behavioral experience across experiments (10 CS-alone or 10 CS-weak shock presentations), we ran a similar 2 (Group: Extinction, Weak Shock) × Time (Pre-CS, CS 1 – 10) ANOVA. This found a main effect of time, F(10, 730) = 80.48, MSE = 366.08, p < 0.001, hp2 = .36, but the main effect of group did not reach significance, F(1, 73) = 3.80, MSE = 3997.53, p = 0.055. The interaction, however, was significant, F(10, 730) = 4.27, MSE = 366.08, p < 0.001, hp2 = .06. Both groups showed a reduction in freezing from the third CS when responding was highest to the final CS (Extinction: p < 0.001, Weak Shock: p < 0.001) and the groups did not differ during the final CS presentation (p = 0.108). Together these results suggest that while both groups showed a decrease in responding throughout this session to a similar level, this was faster in the extinction group. This aligns with our prior work (Bonanno et al., 2023) that shows a 0.3 mA footshock can cause modest unconditional freezing relative to a group that receives no footshock.

Test.

Because all tests included different experimental conditions, we chose to analyze them separately. However, to maintain some consistency across experiments, where overall levels of freezing can differ, we calculated elevation scores during testing such that each animal for every experiment had their CS behavior normalized to their own pre-CS freezing. These results are depicted in Figure 6C–H and largely confirm the results from above using non-normalized scores. In Experiment 1 (Figure 6C), a one-way ANOVA was significant F(2, 15) = 5.99, p = 0.01, and both the extinction (p = 0.006) and weak shock groups (p = 0.016) were reduced relative to the no exposure control. In Experiment 2 (Figure 6D) examining long-term retention, the ANOVA was not significant, F < 1. In Experiment 3 (Figure 6E), a 3 (Group: No Exposure, Extinction, Weak Shock) × 2 (Test: Context A, Context B) found main effects of both test, F(1, 19) = 7.91, MSE = 225.22, p = 0.011, hp2 = .29, and group, F(2, 19) = 12.81, MSE = 450.01, p < 0.001, hp2 = .57, but no interaction between the two, F < 1. Only the extinction group showed a higher elevation score in context A than B (p = 0.023), while both the extinction and weak shock groups showed decreased freezing relative to the no exposure group in context A (Extinction: p = 0.009; Weak Shock: p = 0.023) and context B (Extinction: p < 0.001; Weak Shock: p < 0.001). In Experiment 4 (6F), the one-way ANOVA was not significant, F = 1.36, p = 0.278, suggesting no groups differed during the test. During the AAB renewal test of Experiment 5 (Figure 6G), the ANOVA was significant, F(2, 21) = 5.20, p = 0.015, and only the weak shock group differed from the no exposure group, p = 0.004. During the long-term retention test 2 weeks later (Figure 6H), the ANOVA failed to reach statistical significance, F(2, 21) = 2.59, p = 0.099, but the difference between the weak shock and no exposure groups remained, p = 0.033. The previously-observed difference between the extinction and no exposure groups in CS-alone freezing when not accounting for pre-CS freezing was absent, p = 0.295.

When interpreting the results of the elevation score data, some differences in the interpretation of the results emerge as compared to the raw data reported in the figures above. First, we find that when looking at ABA renewal (Experiment 3; Figure 3 and Figure 6E) the elevation score differs for the extinction group indicative of ABA renewal, but this is no longer the case in the weak shock group. While the weak shock group still shows decreased elevation relative to the no exposure group, the within-subject difference between contexts A and B is no longer present. While it might be tempting to suggest that, using elevation score, US deflation reduces ABA renewal, the lack of difference in either context from the extinction group tempers this interpretation. Further, as noted above, the weak shock group had the highest pre-CS freezing (M = 13.93) which could likely account for differences in elevation score data in this group. Finally, when examining the long-term test following AAB renewal (Experiment 5; Figure 5 and Figure 6H), the extinction group no longer shows a reduction relative to the no exposure group, but the weak shock group still does. This suggests that the effect whereby weak shock reduces AAB renewal when tested the following day (originally observed in Figure 3D and 6G) may therefore be especially long-lasting (unlike when weak shock occurs in novel context as in Experiment 2; Figure 2).

General Discussion

We tested the hypothesis that the weak shock procedure will be more effective at preventing relapse than an extinction procedure, which is highly susceptible to relapse. We first demonstrated that the weak shock procedure was effective at reducing cued fear (Experiment 1). However, no group differences were observed 4 weeks later (Experiment 2), suggesting this was a transitory effect. We then directly compared the weak shock to extinction on measures of relapse following delay fear conditioning: ABA renewal (Experiment 3) and reinstatement (Experiment 4). The weak shock procedure was as ineffective as extinction at preventing renewal and reinstatement. However, when the weak shock occurred in the same context as acquisition (Experiment 5), there was a reduction in AAB renewal both the next day and two weeks later. Based on the current results, deflation via weak shock presentations can reduce relapse, but this seems limited to specific circumstances: AAB renewal. As in Kennedy et al. (2024), weak shock seems most effective at reducing delay fear relapse when applied in the same context as the original acquisition. We found little evidence for changes in neural activity following testing (see Supplementary Figures 1–3), likely due to the relatively long (i.e., 10 CS presentations) testing session leading to washout of these effects.

Although the weak shock procedure falls short in filling the gap for relapse-resistant treatment, it continues to provide insight into the impact of US value on conditional responding. Early work found success reducing conditional responding using US habituation (Rescorla, 1973). However, it is unlikely here that animals would decrease their responding following more presentations of the acquisition shock (1.0 mA) given the strength of conditioning here and in previous work with few CS-US pairings. This suggests nuances surrounding conditioning with different US modalities (e.g., loud noise vs. shock as the US) and that the modification of these memories might require tailored methods.

While this is not the first work to investigate shock modification following DFC, previous work has used several short reactivation periods paired with a weaker shock presentation which resulted in reduced responding as well as mitigated renewal and spontaneous recovery (Popik et al., 2020). Here, the weak shock was presented in a long session that is unlikely to open a reconsolidation window (Ferrara et al., 2023) and while it did reduce conditional responding, relapse remained largely intact. This suggests that in order to reduce relapse following DFC, a procedure more likely to cause reconsolidation-driven memory updating using shorter reactivation sessions might be optimal, especially if acquisition and the weak shock occur in different contexts. Further, we see here that like Kennedy et al., (2024) a simultaneous change of context and US produces a surplus of prediction error than what is necessary for the modification of the original memory suggesting that extinction-like processes observed following a change in context and stimulus value might prevent reactivation of the original memory needed for reconsolidation.

Future work aiming to improve this method should therefore take advantage of procedures that enhance extinction. This could include using more US deflation days to mirror extended extinction protocols as well as the “deconditioning” work (Popik et al., 2020; 2023) while still targeting the original memory for reliable retrieval of this modified version or by conducting deflation in multiple contexts.

Conclusion.

The weak shock procedure implemented here did not result in the predicted prevention of all relapse of an extinguished delay fear memory. However, there is significant insight provided that was not clear before: the weak shock procedure used here can effectively mitigate relapse in a context-dependent manner, with a match between either acquisition and weak shock contexts or a match between weak shock and testing contexts being sufficient for the weak shock to reduce fear. Future work examining the weak shock procedure should therefore carefully consider contextual manipulations and should not rule out extinction-like processes. Instead, it seems that manipulations that capitalize on methods using both memory updating using US deflation and extinction processes may be the most promising avenue towards persistent relapse reduction.

Supplementary Material

1
2

Highlights.

  • CS-weak shock pairings reduce delay fear conditioning.

  • CS-weak shock pairings do not reduce ABA renewal or reinstatement.

  • CS-weak shock pairings reduce ABA renewal.

Acknowledgements

This work was supported by the National Institute of Mental Health (R01MH136311 to ST), the Research Corporation for Science Advancement (#SA-MBC-2022-052 to ST), and the Brain and Behavior Research Foundation (NARSAD to ST). We would like to thank the animal care staff within the Purdue University Department of Psychological Sciences for animal husbandry to support these experiments as well as students enrolled in PSY 39000 for their role in tissue slicing to fulfill course requirements. The experiments and writing herein were completed to fulfill (in part) the requirements for a Masters of Science for PKR. We thank Isra Badar for comments on this manuscript.

Footnotes

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Supplementary Materials

1
NIHMS2104966-supplement-1.pdf (1.1MB, pdf)
2
NIHMS2104966-supplement-2.pdf (74.4KB, pdf)

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