Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

2022, vol. 31, nr 3, March, p. 217–221

doi: 10.17219/acem/146756

Publication type: editorial

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Battaglia S. Neurobiological advances of learned fear in humans. Adv Clin Exp Med. 2022;31(3):217–221. doi:10.17219/acem/146756

Neurobiological advances of learned fear in humans

Simone Battaglia1,A,D,E,F

1 Center for Studies and Research in Cognitive Neuroscience, Department of Psychology, University of Bologna, Italy


In the whole animal kingdom, fear learning is an essential process that allows living beings to survive. Therefore, revealing the neurophysiological processes that govern the expression of emotional fear memory and exploring its neurobiological underpinnings are the imperatives of affective neuroscience. Learned fear memories activate defensive behaviors in anticipation of harm, thus minimizing the impact of the threat. However, despite a century of research, the neural circuitry underlying fear learning in humans is still a matter of debate. This editorial will discuss recent evidence of the neural and behavioral correlates of fear learning in humans, with an emphasis on the role of the human prefrontal cortex (PFC).

Key words: prefrontal cortex, amygdala, hippocampus, fear conditioning, fear neural network

The state of art

Learning to recognize and respond to certain stimuli or external contingencies that signal imminent threats is a widely useful and adaptable function for both animals and humans.1 Fear conditioning is the most frequently adopted experimental design to investigate this circumstance that produces both behaviorally and physiologically conditioned responses.2 From an evolutionary perspective, it is highly advantageous to preserve clear memories of the main significant experiences in life. Nonetheless, the so-called indissoluble nature of emotional memory can be extremely damaging and have negative consequences for those individuals who have experienced traumatic events and may endure dreadful memories and severe anxiety. For these reasons, fear conditioning is broadly acknowledged to be a model for translational framework of psychiatric disorders.3, 4, 5, 6 Thus, to further understand mechanisms of fear learning, many new techniques that allow studying physiological responses of fear conditioning are being developed. These techniques might be applied as measures for dysfunctional and altered fear learning and may help in identifying the individuals who are at risk for developing psychiatric disorders.5 In fact, human fear conditioning is generally investigated on different levels: as subjective verbal reports about the experienced fear, as well as behavioral, physiological and neurobiological changes.7, 8 Among these, physiological changes are the most frequently used measures in the study of human acquired fear memories, as a consequence of their benefit of being unaffected by the participant itself, as well as because of the possibility of a direct comparison with animal research.

Pavlovian fear conditioning is one of the most widely investigated fear-induced behavioral models in the history of cognitive psychology and behavioral neuroscience. It was developed upon the appetitive conditioning paradigm utilized by Pavlov in animals (1903/1928). Its effect occurs as a consequence of repetitive association of an initially innocuous stimulus (i.e., a tone) with an innately aversive stimulus (i.e., a shock pulse). By associating cue to consequence, stimulus presentation usually induces different types of psychophysiological reactions indicating fear. This simple procedure is a fundamental paradigm not only for behavioral and cognitive sciences, but also for medicine, since its application is useful in both psychiatry and neurology. It has taken almost a century of scientific investigation to utilize the classic fear conditioning paradigm in both animals and humans9 in order to gain a broad and thorough knowledge of learned fear and its associated processes, such as learning mechanisms, memorization and retrieval. This experimental and clinical paradigm has been extremely effective and valuable in defining the psychological processes governing the genesis and expression of fear and the functioning of emotional and general memory, together with uncovering the neurobiological basis of emotion and learning in healthy subjects and psychiatric populations.6, 10, 11

The neurobiological model

Currently, the fear conditioning framework has moved beyond the realm of associative learning theory and has become a framework of substantial interest in the neuroscience of learning, memory and emotion.12, 13 Neural circuits have been mapped, synaptic plasticity in these circuits has been identified, and biochemical and genetic investigations have begun disentangling the mechanisms of fear memories.3, 14, 15, 16, 17 However, despite a century of research, the neural circuitry underlying fear learning in humans is still a matter of debate. Modern neuroimaging technologies have made a significant contribution to the understanding of neuroanatomical brain circuits of human fear conditioning.18 Specifically, amygdala plays a key role in the acquisition of fear learning, while the prefrontal cortex (PFC) and hippocampus are 2 other crucial neural structures that contribute to this process, representing together the neural network of fear conditioning.19, 20, 21 It is broadly assumed that connections between these regions govern the acquisition, storage, retrieval, expression, and contextual modulation of fear conditioning (for a review, see the paper by Milad and Quirk22). In accordance to animal model research, functional neuroimaging, ad hoc lesion studies, and morphology, extinction of previously learned fear is dependent on the integrated functioning of this network, indicating that the brain mechanisms underlying fear acquisition and extinction are phylogenetically maintained throughout species.23

Over the last century, ad hoc surgical lesions, pharmacological drug administration and physiological data from animal and human studies have established a comprehensive framework of the neural network that supports fear conditioning. Among all, when the amygdala involvement in fear conditioning was recognized, it was acknowledged as the key structure of this network.2 Precisely, this brain region is commonly recognized as ‘the locus of fear conditioning’.15 Furthermore, anatomical studies highlighted the interactions between the central nucleus of the amygdala and downstream structures involved in the expression of fear conditioned responses, namely the hypothalamus, periaqueductal gray, pons, and other brainstem regions.24 Other studies reported the inhibitory mechanisms within the amygdala that have been involved in fear extinction as well, including the lateral division of the central nucleus,25 and inhibitory cells within the lateral and basolateral nuclei.26

Another structure, the hippocampus, is considered essential in contextual fear learning, along with the acquisition and the extinction of context conditioning: lesion studies have provided pivotal insights on the direct projections that the ventral hippocampus (vHPC) has with both infralimbic cortex (IL, in PFC) and the basolateral amygdala,27 suggesting a crucial role of this region in the modulation of contextual fear responses.28 In addition, the hippocampus is supposed to be necessary in monitoring the context-specific recall of extinction, both directly through connections with the amygdala and indirectly via projections to the ventromedial PFC (vmPFC) (for a review, see the paper by Maren et al.29). Moreover, it has been acknowledged that different hippocampal subregions are involved in different human behavior features – specifically, the dorsal part in spatial-related behaviors and the ventral region in anxiety-related behaviors (for a review, see the paper by Bannerman et al.30). Increasing evidence suggests that the hippocampus and its subregions are involved in several aspects of fear conditioning.15

Crucially, latest available evidence has identified the PFC as a critical core component in the neural circuit underlying fear conditioning, particularly for the ability of PFC to bidirectionally modulate the expression of previously learned fear. On one hand, the activation in the dorsomedial PFC (dmPFC) occurs for the long-term storage and retrieval of old memories31; on the other, the vmPFC forms strong reciprocal connections with the amygdala and other subcortical structures as well as with the lateral cortex. Thus, this subregion seems to be necessary for controlling fear relative to a stimulus that no longer predicts danger,32 representing a relay-station for “bottom-up” information from limbic and subcortical structures signaling emotion detection, as well as for information from lateral PFC (LPFC), conveying response selection and control.33 Furthermore, Harrison et al.34 have suggested different contributions of anterior and posterior subregions of the vmPFC to the fear learning processes, showing greater anterior vmPFC activity in response to a safety stimulus, as it is likely to compute the value or meaning of safety signals. Nonetheless, recent work suggests that vmPFC may also have a crucial role in fear acquisition, which is processed in its posterior subregion35: crucially, naturally occurring bilateral lesions in the human vmPFC were found to compromise fear conditioning (measured by skin conductance responses), proving that fear conditioning was impaired due to brain injury.36 These findings were supported in a recent meta-analysis21 that identified greater activation of the posterior vmPFC (BA11) during late fear conditioning, providing potential causal evidence of a crucial role of the mid-posterior vmPFC in the acquisition of fear.

Converging lines of research have also brought insight on the involvement of PFC in the extinction of fear learning: in concert with the animal studies, neuroimaging studies reported that, besides amygdala activation, vmPFC is particularly important for consolidation of the extinction memory and is especially involved in the recall of extinction in subsequent testing.37 In particular, this subregion may not simply inhibit the expression of amygdala-dependent conditioned threat responses, but signal a change in previously acquired contingencies in order to select the most appropriate response to the current situation.32 The extinction of conditioned fear appears to involve also dorsolateral PFC (dlPFC). This could be due to its capacity of shifting the attention from the stimulus to the context, but may also be a consequence of its role as a site of explicit short-term memory processes in humans, aimed at maintaining the trace interval.38

Importantly, consistently with signs of PFC functional impairment, it has been observed that patients with post-traumatic stress disorder (PTSD) show normal conditioned fear acquisition and extinction, but appear to be impaired in the recall of extinction memory the following day.39 Specifically, extinction recall was compromised due to the hypoactivation in the vmPFC and hyperactivation in the dorsal anterior cingulate cortex (dACC).40 Similar findings were also observed in schizophrenic patients with functionally damaged vmPFC.41 Taking everything into consideration, this evidence reveals that fear conditioning circuits may be altered in many different psychiatric disorders in humans.42

and future perspectives

In conclusion, functional alterations of the neural network underlying fear conditioning or in the emotional regulatory mechanisms might contribute to the etiology of anxiety-related disorders, including panic disorder, specific phobias and PTSD.43 These altered mechanisms are regarded as pivotal factors in the pathogenesis and development of psychiatric disorders characterized by anxiety.44, 45, 46 Hence, a deep understanding of the psychological and molecular mechanisms underlying such disorders is necessary, and fear conditioning paradigm appears to be the most effective for this purpose. Furthermore, a deeper understanding of fear learning neural networks may also contribute to the advancement of alternative, more precise and individualized treatments for psychiatric disorders.

On this note, some issues and questions come to mind. According to corroborated literature, the human PFC modulates the activity of the amygdala and hippocampus after fear conditioning (i.e., extinction learning) like in animals; however, such assumption is based on limited empirical data. Differently from the classical view,47 recent work suggests that the vmPFC may also play a major role in the acquisition of fear,21, 34, 35, 36, 48 as processed within its posterior subregion.49

Consequently, it is plausible to assume that there are differences between humans and animals in the functional neuroarchitecture of PFC. Thus, it is reasonable and timely relevant now to address this question: what exactly is the role of the prefrontal cortex in human fear conditioning?

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