Remembering the fear that arose during a dangerous experience is important as it teaches us to avoid similar circumstances in the future. The intensity of the initial experience will often influence the strength of the memory. Milder memories often lead to responses that protect individuals from harm (known as adaptive behaviors). However, stronger memories of more traumatic experiences can sometimes trigger disproportionate responses to a situation (known as maladaptive behaviors), such as in individuals with phobias or post-traumatic stress disorder (PTSD).

Forming and retrieving fear memories requires different parts of the brain to work together and send signals to one another. At the core of this network is the amygdala (also known as the fear center of the brain), which other brain regions then feed into to modulate the fear response to ensure it is appropriate and manageable. However, it remained unclear whether neurons in these brain regions wire together differently when recalling mild or more severe fear memories. Identifying these differences may help explain why certain fear memories lead to adaptive behaviors, while others result in maladaptive ones.

To investigate this question, Haubrich and Nader generated fear memories in rats that triggered either mild fear responses or strong responses akin to trauma. Imaging tools were then used to measure the activity and connections between neurons across 12 regions of the brain known to be involved in remembering fearful experiences.

This revealed that recalling mild fear memories resulted in a well-coordinated network of neurons which could effectively send information between the different brain regions. In contrast, severe fear memories led to disrupted overall connectivity, with the amygdala becoming disconnected from the other brain regions.

The results reveal stark contrasts in the pattern of neuronal connections formed by mild and severe fear memories. Investigating the specific pathways involved in these differences will allow scientists to gain a better understanding of why memories of traumatic experiences can lead to maladaptive behaviors, including those formed as a result of PTSD.

Whether a fear memory leads to adaptive or maladaptive behavior can be determined by the intensity of the initial aversive experience. A deeper understanding of fear memory requires identifying changes in the neural mechanisms engaged by fear memories of varying levels of aversiveness. Research on rodent fear conditioning has been mostly conducted in mild protocols and comparisons with strong protocols are scarce. While this approach advances our understanding of normal fear memories, it leaves open questions about specific mechanisms in disorders of fear dysregulation, such as post-traumatic stress disorder (PTSD) (Flores et al., 2018).

Normal fear memories are critical to survival. These memories trigger appropriate responses that are cue-specific and can be attenuated by extinction (Fanselow, 2018; Homan et al., 2019; Alexandra Kredlow et al., 2022). These adaptive representations are flexible and their content may be updated upon recall through reconsolidation (Arellano Pérez et al., 2020; Forcato et al., 2010; Haubrich et al., 2015; Monfils et al., 2009). Importantly, these fear memories can be disrupted by pharmacological interventions targeting their reconsolidation (Haubrich et al., 2020a; Haubrich et al., 2017; Nader et al., 2000; Pigeon et al., 2022), offering a wealth of clinical possibilities (Phelps and Hofmann, 2019). However, severe aversive events can lead to the formation of strong, maladaptive fear memories that trigger disproportionate and generalized fear responses (Baldi et al., 2004; Corchs and Schiller, 2019; Morey et al., 2015) and tend to be resistant to extinction (Sangha et al., 2020) and to undergo reconsolidation (Haubrich and Nader, 2018a; Holehonnur et al., 2016; Kindt, 2018; Wang et al., 2009).

The formation and expression of fear memories are believed to rely on the coordinated activity of a network of brain structures. The amygdala is an integral structure in all aspects of fear memory formation and expression (Sears et al., 2014; Zhang et al., 2021). Subsequent to severe fear learning, it has been shown that changes take place in the composition of glutamate receptors in the amygdala that are linked to maladaptive memories (Holehonnur et al., 2016; Wang et al., 2009; Conoscenti et al., 2022; Haubrich et al., 2020b). In the case of contextual fear memories, the involvement of the hippocampus also becomes critical given its role in the processing of context-related information (Frankland et al., 2019; Suzuki et al., 2004; Topolnik and Tamboli, 2022). Other regions, such as the retrosplenial, infralimbic, prelimbic, and cingulate cortices, and the reuniens and paraventricular nuclei of the thalamus, also play important roles in modulating fear memories (Alexandra Kredlow et al., 2022; Barchiesi et al., 2022; de Oliveira Alvares and Do-Monte, 2021; Levy and Schiller, 2021; Milton, 2019). Importantly, the action of stress hormones and the locus coeruleus-noradrenaline system plays a key role in the formation of maladaptive-like fear memories (Haubrich et al., 2020b; Dębiec et al., 2011; Gazarini et al., 2014). It is not clear how the coordinated activity between these regions changes with the severity of fear memories but basic and clinical findings suggest it may be dysregulated (Ressler et al., 2022).

The distinctions between adaptive and maladaptive memories may not be solely attributed to changes within isolated structures or altered connectivity between pairs of structures, but rather to collective changes across multiple structures within the neural network. Combining the quantification of immediate-early genes expression linked to neural activation such as c-fos (Terstege and Epp, 2023) and network-based graph analysis (Bassett et al., 2018; Bullmore and Sporns, 2009; Roland et al., 2023), it is possible to reveal the brain functional connectivity during active cognitive experiences, such as memory recall (Silva et al., 2019; Takeuchi et al., 2022; Vetere et al., 2017; Wheeler et al., 2013). In network models of neural systems, brain regions are represented as nodes, and functional connections between nodes are represented as edges. Multiple measures can be computed to inform the relationship between nodes and the global characteristics of the network, which can elucidate changes in information processing across different conditions.

In this study, we aimed to shed light on the system mechanisms underlying the recall of mild and strong fear memories. First, we established the behavioral differences triggered by fear conditioning protocols of varying intensities. We then employed c-fos immunohistochemistry to measure brain activation in 12 brain areas critical for fear learning and memory during the recall of mild and strong fear. Subsequently, the interregional coordinated brain activity was computed and functional networks were generated. Our findings indicate that the system mechanisms of fear memories vary based on their intensity as a mild fear recall is supported by a well-connected network while the recall of strong fear is associated with disruptions in network connectivity.

This study investigated how functional connectivity during fear memory recall varies depending on fear memory intensity. Utilizing mild and strong fear protocols, we were able to generate memories that exhibit remarkable differences in their behavioral and neuronal signatures. Specifically, we found that mild memories triggered moderate and precise behavioral responses that were susceptible to extinction and reconsolidation, while strong memories triggered robust and generalized responses and were resistant to both extinction and reconsolidation. When comparing the brain activity across 12 regions implicated in fear memory, we found that recall resulted in changes in overall activity in only a subset of these regions. However, when we examined coordinated activity patterns, we discovered striking differences in the functional networks that underlie mild and strong fear memory recall. Mild memories displayed a well-connected network with the amygdala, which was well-positioned to interact with and be influenced by several regions. However, such connectivity was absent in the strong fear memory network, which may underlie the observed high and generalized fear responses that are resistant to attenuation. These findings suggest that abnormal functional connectivity may be a core factor in maladaptive, severe fear memories.

To study brain differences between mild and strong fear memories, we used conditioning protocols of different intensities that generated fear memories remarkably differently at the behavioral level. Conditioning with 2 shocks resulted in a fear memory eliciting mild and discriminative fear responses, which could be attenuated by extinction, and its recall triggered reconsolidation. In contrast, a 10-foot shock training generated a strong fear memory that can be seen as maladaptive; it elicited high and generalized fear expression, which was resistant to undergo both extinction and reconsolidation. Importantly, our control animals were exposed to the conditioning chamber for an equivalent duration without being subjected to shocks, thus encoding and recalling a nonfearful contextual memory (Figure 1). The recall of these distinct memories resulted in differential brain activation in some structures. In line with the role of the amygdala (Bernabo et al., 2021; Gründemann et al., 2019; Josselyn et al., 2015; Maddox et al., 2019) and paraventricular nucleus (Do-Monte et al., 2015b; Padilla-Coreano et al., 2012) in fear expression, we observed that c-fos counts in these structures increased as a function of the strength of the fear memory. Conversely, in the infralimbic cortex, c-fos expression was decreased in the 10S group, which is in line with its established role in safety learning and fear suppression (Bloodgood et al., 2018; Do-Monte et al., 2015a). Adding to the known involvement of the RSC (Todd et al., 2019; Trask et al., 2021) and the Re (Ramanathan et al., 2018; Sierra et al., 2017; Troyner et al., 2018) in modulating fear memory formation and expression, our results revealed neural activity in these structures was increased during mild memory recall, but not during strong memory recall, when compared to unshocked controls. Although the hippocampus (Gründemann et al., 2019; Josselyn et al., 2015; Guo et al., 2018; Haubrich and Nader, 2018b; Pedraza et al., 2016), prelimbic (da Silva et al., 2020; Dixsaut and Gräff, 2022; Fernandez-Leon et al., 2021), and cingulate cortex (Finnie et al., 2018; Haubrich et al., 2016; Ortiz et al., 2019) are critical to contextual fear memory-related processes, we found no differences in their activation between groups, suggesting that the role of these structures in modulating the expression of fear of different intensities may not reflect in changes in overall activation levels.

The amygdala is a central hub for the processing of fear memory and fear expression during recall. It receives input from sensory areas and integrates this information with several other brain regions, such as the hippocampus and the prefrontal cortex, to generate adaptive fear responses. The projections to the amygdala from these regions modulate the intensity of fear responses, extinction learning, and the induction of reconsolidation. Consequently, the functional connectivity of the amygdala within a memory network plays a crucial role in determining the level of fear expression. Our initial assessment of mean coordinated activity supports this concept. We found that, in comparison with unconditioned controls, the overall correlation values of the amygdala with other brain regions increase during the recall of a mild fear memory, but not during the recall of a strong fear memory.

The functional networks analysis further evaluated the system-level interactions of different brain regions during the recall of mild and severe fear memories. Centrality measures were computed to assess the number of functional connections, hub nodes, and information flow throughout the network. These measures were increased during the recall of mild fear memories compared to untrained controls, and such an increase was not observed during the recall of strong fear memories. Moreover, only the mild fear memory network displayed a small-world organization, which allows for both specialized and efficient information processing in the network. These findings suggest that the expression of moderate and flexible fear memories involves an efficient, integrated activation of specific brain regions, which is not present in the recall of strong fear memories.

Importantly, both the basolateral and the central amygdala ranked high across the centrality measures assessed. Of particular importance is the high nodal efficiency ranking of the amygdala, indicating that it was a main central mediator of information flow throughout the network. Notably, the infralimbic cortex, a region known to suppress fear responses by sending inhibitory projections to the amygdala (Bouton et al., 2021), displayed the highest betweenness centrality during mild memory recall. However, during the recall of severe fear memory, the amygdala displayed a considerably lower ranking across centrality measures, similar to what was observed in control unconditioned animals. These changes in the network-level integration of the amygdala are apparent in the model depicted in Figure 4F. In the 2S graph, the amygdala is at the center of a fully connected network and the IL is a critical bridge connecting the amygdalar module to the one containing the hippocampus and the retrosplenial cortex. In contrast, in the 10S graph, the amygdala is disconnected from the other regions. This indicates that the differences observed behaviorally during severe fear memory recall – high and generalized freezing and resistance to attenuation – coincided with a disruption in the functional connectivity of the amygdala with other regions that are important for regulating fear. To further elucidate the underlying mechanisms of fear memory strength in vivo, understanding the specific roles of individual network elements in fear regulation becomes essential. Future research will be important to probe the causal interplay among distinct nodes and edges, both individually and in combination, in shaping diverse aspects of fear expression.

To generate mild and strong fear memories, we based our conditioning parameters on methods that have shown distinct behavioral outcomes in prior studies (Holehonnur et al., 2016; Wang et al., 2009; Poulos et al., 2016). To ensure a focused comparative analysis, our conditioning protocols differed only in the number of foot shocks and maintained consistent shock intensities and session durations. Yet, the number of shocks is not the only factor that can affect the strength of fear memories (Gazarini et al., 2023). Other conditioning parameters, such as shock intensity, its predictability, and inter-shock intervals, can also play crucial roles. Moreover, different fear measures like freezing behavior, fear-potentiated startle, and inhibitory avoidance might manifest differently following varying conditioning protocols, adding another layer of complexity. A comprehensive understanding of fear memory strength will benefit from further studies scrutinizing these parameters and memory attributes. In addition, a growing body of evidence underscores the differences between males and females concerning fear memories (Fleischer and Frick, 2023). Given that our study was conducted only with male rats, future studies exploring sex differences will be instrumental in providing a more complete account of the network-level mechanisms underlying fear memory strength.

In summary, this study investigated the behavioral and neural differences during the recall of memories with varying levels of aversiveness. In contrast to memories formed with a 2-shock fear conditioning protocol, 10 shocks generate maladaptive memories with intense and generalized fear responses, resistance to extinction, and an inability to flexibly change through reconsolidation. The recall of these memories resulted in changes in brain activation across some, but not all, regions where c-fos was measured. Graph-based network analysis uncovered that moderate and flexible fear memory expression involves an efficient integrated activation of particular brain regions, which is absent in strong fear memories. These results provide a deeper understanding of fear memory by showing that functional connectivity during recall varies greatly depending on the level of aversiveness of the memory. It supports the notion that not only local synaptic mechanisms but also broader functional changes play a role in shaping fear memory strength. Moreover, these findings highlight the importance of studying the neural mechanisms involved with fear memory strength, as they may provide insight into the development of maladaptive memories and potential interventions for their treatment.

All data generated and analyzed during this study are available at https://doi.org/10.5061/dryad.280gb5mw3.

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Author details

1. Josue Haubrich

   1. Department of Psychology, McGill University, Montréal, Canada
   2. Department of Neurophysiology, Ruhr-University Bochum, Bochum, Germany

   Contribution

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

   For correspondence

   Josue.Haubrich@ruhr-uni-bochum.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3632-5566

2. Karim Nader

   Department of Psychology, McGill University, Montréal, Canada

   Contribution

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

   Competing interests

   No competing interests declared

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