Extinction recall of fear memories formed before stress is not affected despite higher theta activity in the amygdala

Patients with stress-related psychiatric disorders experience debilitating emotional symptoms, including excessive fear that they are unable to control. Decades of research have shown that such disorders have opposite effects on two key structures in the brain. Normally, a region called the amygdala helps to form fear-related memories, while the prefrontal cortex helps control these memories and eliminate them through a process called extinction. But brain imaging on patients with stress-related psychiatric disorders reveals a smaller prefrontal cortex, and an overactive amygdala. Animal studies confirm that chronic stress shrinks brain cells in the prefrontal cortex, but grows them bigger in the amygdala.

These and other studies have led scientists to believe that stress causes people to both form stronger fear memories and then have difficulties getting rid of such memories. These include studies in which stressed animals were trained to fear a sound, and then followed while they learned to overcome that fear. One problem with many of these studies is that the animals were repeatedly stressed before the fear memory was formed. This made it hard to tease apart whether the strength of the fear memory itself or a problem extinguishing the fear memory were to blame for the animals’ difficulties overcoming their fear.

Now, Rahman et al. address this problem by exploring how the timing of chronic stress affects how well an animal can overcome fear memories. In the experiments, some rats learned to fear a sound before exposure to chronic stress, while a second group was exposed to chronic stress first then learned to fear the sound. When the animals were stressed after they learned to fear the sound, they could still eliminate their fear. But the animals stressed before exposure to the fear-inducing sound struggled to extinguish the fear. Recordings of the brain activity in the rats that were exposed to stress after learning to fear the sound showed the amygdala remained overly active even after these animals overcame their fear. However, the stress did not seem to disrupt the normal activity of the prefrontal cortex in these rats. This shows that memories formed before stress reflect normal activity in the prefrontal cortex and not the abnormally high activity in the amygdala.

Exposure therapy helps people overcome stress-disorder related fears. For the therapy to work, the prefrontal cortex must be able to extinguish fear. Rahman et al. show that this is possible when the fear-enhancing effects of prior stress are not in play. More studies exploring why prior stress makes fears stronger and harder to overcome may help scientists develop ways to make therapies for stress disorders more effective.

Accumulating evidence from animal models shows that stress elicits divergent patterns of plasticity across brain regions (Chattarji et al., 2015). For instance, repeated stress causes loss of dendrites and spines in the medial prefrontal cortex (mPFC) (Shansky and Morrison, 2009). In the basolateral amygdala (BLA), by contrast, chronic stress strengthens the structural basis of synaptic connectivity through dendritic growth and spinogenesis (Chattarji et al., 2015). Physiological and molecular measures of synaptic plasticity also exhibit these contrasting features. As useful as these studies have been in examining the effects of stress across biological scales, much of this evidence was gathered from postmortem analyses (Chattarji et al., 2015). Less is known about how stress affects neural activity in the intact brain of behaving animals. Further, in many of these studies, stress-induced plasticity was viewed as stand-alone effects intrinsic to individual brain areas, despite extensive interconnections between them. Indeed, interactions between these brain areas together give rise to behaviors that are affected by stress (Quirk and Mueller, 2008).

One such behavior involves the expression of fear memories, various facets of which depend on both the BLA and mPFC (Sierra-Mercado et al., 2011). Repeated stress has been shown to enhance fear memories, as well as impair their extinction (Miracle et al., 2006; Suvrathan et al., 2014). These studies, however, first exposed animals to stress, and then subjected them to fear conditioning followed by extinction (Izquierdo et al., 2006; Miracle et al., 2006). In other words, these studies analyzed the impact of stress on both the formation and extinction of fear memories, not the latter alone. This experimental design has led to two broad classes of findings. In a majority of these studies, stress did not necessarily lead to higher freezing levels during fear recall. Even though expression of fear was not elevated by prior exposure to stress, it was resistant to subsequent extinction in stressed animals (Noble et al., 2017; Zhang and Rosenkranz, 2013). In a few studies, however, the behavioral data suggest that prior exposure to stress may have also led to stronger fear memories manifested as higher levels of freezing in stressed animals at the beginning of extinction training (Chauveau et al., 2012; Hoffman et al., 2014; Miracle et al., 2006). This too could have contributed to the subsequent deficit in fear extinction recall. An alternative strategy to test if stress impairs the extinction of fear memories would be for animals to form fear memories before stress exposure, thereby dissociating the effects of stress on acquisition versus extinction of conditioned fear. This would offer an opportunity to examine how stress specifically affects expression of fear during and after extinction, without the confounds of stronger fear memories caused by prior exposure to stress. Hence, the present study combines simultaneous behavioral and in vivo electrophysiological analyses to address this question.

Rats were first subjected to auditory fear conditioning (Day 0, Figure 1) at the end of which they exhibited significantly higher freezing behavior in response to the tone conditioned stimulus (CS) (Figure 1b). These animals were then divided into two groups – one was subjected to 10 days of chronic immobilization stress (Days 1–10, Figure 1a) while the other served as unstressed control. 24 hr after the end of chronic stress there was no difference in CS-induced freezing behavior between the two groups (Day 11, Block1, Figure 1b). Thus, the recall of fear memory formed earlier was not affected by subsequent stress. This ensured that both stressed and unstressed animals were at the same levels of freezing when the extinction protocol was initiated after stress. Next, repeated tone presentations reduced freezing levels significantly such that both groups eventually underwent comparable extinction of fear, though the stressed rats were slower in achieving the same reduction in freezing (Day 11, Figure 1b). Notably, a day later stressed animals showed no difference in recall of extinction memory compared to unstressed animals (Day 12, Figure 1b). Thus, freezing levels during both fear and extinction recall were unaffected in stressed animals. This result differs from past reports of stress-induced deficits in fear extinction. However, as mentioned earlier, those earlier studies subjected animals to fear conditioning and extinction after exposure to stress (Izquierdo et al., 2006; Maren and Holmes, 2016; Miracle et al., 2006). Taken together, this suggests that the timing of stress may be a critical determinant of whether extinction recall is impaired. Thus, to examine this possibility we repeated the experimental design adopted in earlier studies by administering the same 10 day chronic immobilization stress protocol before (Figure 1c,e) the same fear conditioning paradigm depicted in Figure 1a. Consistent with earlier findings, prior exposure to chronic stress caused a significant impairment in the recall of fear extinction (Figure 1e). However, these animals, unlike those used in Figure 1b (i.e. conditioning before stress) were not implanted with electrodes for simultaneous in vivo recordings. Hence, we repeated the behavioral experiments described in Figure 1b without surgical interventions related to in vivo recordings. This too yielded the same results as seen in the implanted animals – extinction recall was intact in stressed animals (Figure 1d,f) when they were subjected to conditioning before chronic stress.

Figure 1

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Data for animals across groups representing freezing response to CS and pretone during the different phases of behaviour (Figure 1b,e and f).

https://doi.org/10.7554/eLife.35450.004

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Next, we examined the neural basis of this result by recording local field potentials (LFPs) in these freely behaving rats (Karalis et al., 2016; Likhtik et al., 2014). While a role for potentiation of amygdalar neuronal responses to the tone CS in conditioned fear behavior is well established, in vivo recordings have also shown correlations of tone responses in the dorsal mPFC (dmPFC) with freezing behavior in fear conditioning and extinction. Taken together with earlier pharmacological inactivation studies, these findings identified an important role for the dmPFC in underlying conditioned fear responses and the expression of fear extinction (Burgos-Robles et al., 2009; Sierra-Mercado et al., 2011). Therefore, in addition to the BLA, we also monitored responses in the dmPFC (Figure 2a, Figure 2—figure supplement 1). We first analyzed CS-evoked LFPs in the BLA at three key behavioral time points described in Figure 1 – tone habituation before conditioning, fear recall and extinction recall (Figure 2b–d). We measured auditory evoked potential (AEP) amplitudes as the difference between first peak and first trough in the AEP (Figure 2—figure supplement 1). During fear recall, AEP amplitudes (Rogan et al., 1997) were enhanced in both stressed and unstressed animals (Figure 2c,e). However, while this increase was reversed in unstressed animals, it persisted in stressed rats even during extinction recall (Figure 2c,e). Previous work also identified increase in CS-evoked theta power as a neural correlate of conditioned fear (Likhtik et al., 2014). We found BLA theta power (measured as the power of auditory evoked responses in the 2–12 Hz frequency band) in unstressed animals also paralleled the increase, followed by decrease, in freezing during fear and extinction recall respectively (Figure 2d–e). By contrast, BLA theta power remained high in stressed animals (Figure 2d–e). Thus, despite stress-induced theta hyperactivity in the BLA, fear expression was not enhanced during extinction recall. To probe this further, we also analyzed the same LFP parameters in the dmPFC, which according to recent studies plays an important role in fear expression (Karalis et al., 2016; Likhtik et al., 2014). In the dmPFC of unstressed rats, AEP amplitude increased during fear recall, and this was reversed during extinction recall (Figure 2f). Stressed animals, however, did not exhibit any change in dmPFC AEP amplitudes during either fear or extinction recall. Further, fear conditioning enhanced dmPFC theta power in both stress and unstressed animals (Figure 2f). Interestingly, this was reversed in both groups during extinction recall. In other words, unlike the BLA, changes in theta power in the dmPFC, during fear and extinction recall, were not affected by stress. Moreover, in stressed animals, bidirectional modulation of theta power in the dmPFC, but not the BLA, accurately mirrored the changes in freezing, a behavioral expression of fear. Interestingly, the gradual decrease in dmPFC theta power paralleled the significant within-session reduction in freezing during the acquisition of extinction (Day 11, Figure 1b) in both control and stressed animals (Figure 2—figure supplement 2b,d). However, unlike the slower time course of extinction in the stressed rats, there was no difference in the time course of reduction in dmPFC theta power between stressed versus control animals. Similar analysis of BLA theta power during extinction learning (Day 12, Figure 1b) did not reveal any significant differences that paralleled the gradual within-session decrease in freezing levels (Figure 2—figure supplement 2b,c).

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Data for animals representing freezing response to CS (Figure 2b) and AEP amplitude and theta power in dmPFC and BLA (Figure 2e,f)

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Figure 2—source data 2

Data for animals representing freezing response to CS (Figure 2—figure supplement 2b) and AEP amplitude and theta power in dmPFC and BLA (Figure 2—figure supplement 2c,d)

https://doi.org/10.7554/eLife.35450.009

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Finally, there is growing appreciation of the importance of interactions between the mPFC and BLA, not just activity within these areas, in regulating fear behavior (Karalis et al., 2016; Lesting et al., 2011; Likhtik et al., 2014; Popa et al., 2010). This issue comes into sharp focus here because of the distinct effects of stress on the mPFC versus BLA. Thus, in light of recent reports that theta frequency oscillations synchronize dmPFC–BLA circuits during expression of fear behavior (Karalis et al., 2016; Likhtik et al., 2014), we investigated whether the tone-evoked increases in theta power (Figure 2) were accompanied by enhanced theta-frequency synchrony between the two areas, and if this was in anyway affected by stress. Hence, we quantified CS-evoked coherence to assess moment-by-moment synchrony across LFPs recorded from the dmPFC and BLA for all three time points (Figure 3a) (Likhtik et al., 2014). In unstressed rats, consistent with earlier reports, the CS elicited significantly higher theta coherence during fear recall (Likhtik et al., 2014), and this increase persisted during extinction recall as well (Figure 3b). Notably, in stressed animals, there was no change in BLA-dmPFC theta-frequency coherence (Figure 3b). Thus, stress appears to completely suppress the dynamic, behaviorally relevant enhancement in BLA-dmPFC coherence that is seen during both fear and extinction recall in unstressed animals. In light of strong reciprocal connections between the mPFC and BLA, increases in theta synchrony have led earlier studies to analyze the direction of information flow between the two areas (Karalis et al., 2016; Likhtik et al., 2014). Hence, we estimated the directionality of functional connectivity and leads between the dmPFC and BLA using a previously validated method of calculating cross-correlations of instantaneous amplitude of filtered LFPs (Adhikari et al., 2010). This reveals that theta activity in the dmPFC leads that in the BLA during recall of both fear and extinction memories in unstressed rats (Figure 3c). However, this dmPFC-to-BLA directional influence is absent in stressed animals. Together, these data suggest that chronic stress causes a decoupling of activity between the two brain areas, as evidenced by a complete disruption of the increase in dmPFC-BLA theta synchrony and dmPFC-to-BLA directional influence normally seen during the recall of fear and extinction memories. This decoupling is also evident across all trial blocks during the acquisition of extinction the previous day (Figure 3—figure supplement 1). This breakdown in mPFC-BLA theta-frequency synchrony and directional coupling could be one reason why enhanced BLA theta activity was not manifested as higher freezing in stressed animals.

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Data for animals representing theta coherence between dmPFC and BLA (Figure 3b) and dmPFC-BLA phase difference (Figure 3c)

https://doi.org/10.7554/eLife.35450.012

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Figure 3—source data 2

Data for animals representing theta coherence between dmPFC and BLA (Figure 3—figure supplement 1b) and dmPFC-BLA phase difference (Figure 3—figure supplement 1c)

https://doi.org/10.7554/eLife.35450.013

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The present study, specifically designed to administer chronic stress after the formation of fear memory, reveals that when stressed animals started extinguishing fear memories from the same level of freezing as their unstressed counterparts, their ability to recall extinction memory remained intact. This is in contrast to past findings wherein stressed animals exhibited a deficit in extinction recall when faced with the challenge of extinguishing fear memories strengthened by prior exposure to stress. This is consistent with earlier findings that repeated immobilization stress (4 h/day for 14 days) administered after auditory fear conditioning did not affect the expression of previously acquired fear memories (Meyer et al., 2014). However, the same immobilization stress, when administered before fear conditioning, elicited a robust increase in fear recall. Together, these results suggest that the timing of chronic stress exposure, with respect to fear conditioning, is a key determinant of how subsequent extinction of fear is affected by stress. This dissociation of the effects of stress on acquisition versus extinction of fear conditioning suggests that stress acts primarily on acquisition, and the earlier findings from pre-conditioning stress experiments were not the result of a deficit in fear extinction per se. Age may also influence how stress affects fear extinction in rats. For instance, deficient fear extinction was only observed in previously stressed adolescent, but not adult, rats (Zhang and Rosenkranz, 2013).

Interestingly, despite no visible behavioral effect of stress on fear expression, our in vivo recordings reveal a robust impact of stress on amygdalar activity, as evidenced by enhanced theta activity in the BLA that failed to reverse even after the animals exhibited normal extinction recall (Figure 2e). This is consistent with earlier findings on physiological and structural strengthening of excitatory synaptic connectivity, as well as reduced inhibitory tone, in the BLA after stress (Suvrathan et al., 2014). Together, these changes point to possible synaptic mechanisms in the BLA for the stress-induced strengthening of subsequent encoding of fear memories.

The same chronic stress, on the other hand, did not disrupt normal bidirectional modulation of mPFC theta activity, which in turn was reflected in normal freezing behavior during recall of fear and extinction (Figure 2f). This is consistent with growing evidence for a pivotal role played by the mPFC in fear expression (Dejean et al., 2016; Sierra-Mercado et al., 2011). For instance, recent work has demonstrated strong correlations between mPFC theta-frequency oscillations and conditioning-induced freezing behavior (Likhtik et al., 2014). Furthermore, we find normal mPFC theta activity to be decoupled from theta hyperactivity in the BLA, possibly reducing the latter’s influence on fear expression. This is similar to a report that even a single episode of stress can weaken functional connectivity between the two areas measured by resting state fMRI (Liang et al., 2014). Indeed, such stress-induced disruptions in prefrontal-to-amygdala connectivity is also known to affect social interaction and anxiety-related behaviors in rodents (Adhikari et al., 2015; Hultman et al., 2016).

Our findings, taken together with earlier behavioral studies (Izquierdo et al., 2006; Meyer et al., 2014; Miracle et al., 2006; Rau and Fanselow, 2009; Sierra-Mercado et al., 2011; Suvrathan et al., 2014) suggest a model for why the effects of stress on the recall and extinction of fear memories depend on the timing of stress exposure with respect to when the fear memory is formed and extinguished (Figure 4). Specifically, these findings suggest that the regulation of remote fear memories by stress (i.e. pre-stress conditioning, Figure 4b) is different from that of more recent fear memories (i.e. post-stress conditioning, Figure 4c). As reported here, when fear memories were formed before exposure to the 10 day chronic stress, recall of fear extinction was not affected. Although stress caused a persistent increase in theta activity in the BLA, it did not affect bidirectional regulation of dmPFC theta activity (Figure 4b). While stress-induced disruption in mPFC-BLA directional coupling and theta-frequency synchrony (Figure 3) may explain why enhanced BLA theta activity did not result in stress-induced enhancement in freezing, another intriguing possibility arises from a recent report that neural circuits mediating the recall of fear memories shifts over time (Do-Monte et al., 2015). Specifically, this study showed that optogenetic silencing of BLA reduced freezing when it was performed 6 hr, but not 7 days, after auditory fear conditioning. Since our post-conditioning stress protocol was carried out for 10 days, it may have outlasted BLA involvement in expression of fear and could also explain why enhanced BLA excitability was no longer reflected in freezing at that remote time point (Day 11; Figure 4b). As a first step towards testing this possibility, we carried out in vivo infusions of muscimol directly into the BLA just before fear recall and extinction learning on Day 11 (Figure 4—figure supplement 1). Strikingly, this targeted inactivation of the BLA had no impact on fear expression at this time point in either stressed or control rats (Figure 4—figure supplement 1b). Further, freezing levels in the muscimol-infused control and stressed rats did not differ from the freezing levels seen in stressed/control animals (Figure 4—figure supplement 1c) that did not receive any infusions in earlier experiments (Figure 1f). Thus, we found that in vivo inactivation of the BLA no longer affects the recall of fear memories that were formed before the 10 day stress exposure. While more detailed analyses will be required to test all aspects of this model, these preliminary results suggest that fear memories formed 10 days ago no longer depend on BLA activity in either control or stressed animals. Consequently, the expression of fear after extinction reflects normal regulation of theta activity in the mPFC, not theta hyperactivity in the BLA (Figure 4b).

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Data for animals across groups representing freezing response to CS during the different phases of behaviour (Figure 4—figure supplement 1c,d)

https://doi.org/10.7554/eLife.35450.016

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On the other hand, when fear memories were formed after exposure to the same chronic stress, the behavioural effects on freezing are very different, as has also been reported in earlier studies that employed a post-stress conditioning strategy (Maren and Holmes, 2016; Miracle et al., 2006; Rau and Fanselow, 2009). Animals that were fear conditioned after stress show enhanced freezing during both acquisition and recall of extinction memory. What could be the neural basis for this difference? Electrophysiological data from our post-conditioning stress experiments point to possible mechanisms that can be examined in future studies (Figure 4c). For instance, in contrast to the pre-stress conditioning situation, stressed animals will recall and extinguish fear memories that were formed only 1 day ago. As a result, stress-induced BLA hyperactivity will be manifested as stronger fear memories that are resistant to subsequent extinction (as evidenced by higher freezing during extinction recall in CIS rats, Figure 1e). Thus, now it is the sustained enhancement in BLA theta activity, not normal regulation of dmPFC activity, that is likely to drive higher freezing in stressed rats during extinction learning and extinction recall (Figure 4c). Further, the detrimental effects of stress will be compounded by the disruption of mPFC-BLA theta-frequency coherence and directional coupling, which is likely to impair the mPFC’s ability to regulate BLA hyperactivity. Interestingly, pre-conditioning stress has been shown to cause subsequent enhancement in fear learning that can last up to 90 days later (Rau and Fanselow, 2009). This naturally raises questions about the involvement of the BLA in the enhanced expression of conditioned fear at remote time points. Our preliminary findings (Figure 4—figure supplement 1), taken together with the study by Do-Monte et al. (2015), suggest that despite the effects of pre-conditioning stress on the encoding of fear memories, subsequent expression at later time points may no longer depend on BLA activity. This, in turn, raises the possibility that other brain areas that interact with the BLA in the regulation of fear, such as the dmPFC, may play a role in maintaining this expression at remote time points. Thus, a better understanding of the neural basis of earlier behavioral findings (Izquierdo et al., 2006; Meyer et al., 2014; Miracle et al., 2006; Noble et al., 2017; Rau and Fanselow, 2009) will require detailed in vivo electrophysiological analyses, coupled with targeted inactivation, to examine the role of other brain areas that are engaged in stress-induced changes of fear expression.

Finally, it is interesting to note that the chronic immobilization stress paradigm used in the present study was previously shown to strengthen functional connectivity from the amygdala to the hippocampus (Ghosh et al., 2013), which undergoes stress-induced deficits similar to the mPFC (Arnsten, 2015; Chattarji et al., 2015; McEwen and Morrison, 2013). In other words, although both the hippocampus and mPFC undergo similar forms of stress-induced deficits, the impact of stress on their individual interactions with the amygdala are strikingly different. A better understanding of these divergent features of aberrant interactions distributed across the amygdala-mPFC-hippocampal network, not just those confined within each area, may offer new insights into therapeutic interventions against the cognitive and emotional symptoms of stress-related psychiatric disorder.

Data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all the Figures.

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Author details

1. Mohammed Mostafizur Rahman

   National Centre for Biological Sciences, Bangalore, India

   Present address

   Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, 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:" 0000-0002-9355-4867

2. Ashutosh Shukla

   National Centre for Biological Sciences, Bangalore, India

   Contribution

   Formal analysis, Validation, Investigation

   Competing interests

   No competing interests declared

3. Sumantra Chattarji

   1. National Centre for Biological Sciences, Bangalore, India
   2. Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India
   3. Centre for Integrative Physiology, Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   shona@ncbs.res.in

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9962-3635

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