The fear memories are stored in the connections between neurons in the prefrontal cortex

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A remote fear memory is a memory of traumatic events that occurred in the distant past—a few months to decades ago. A University of California, Riverside, mouse study published in Nature Neuroscience has now spelled out the fundamental mechanisms by which the brain consolidates remote fear memories.

The study demonstrates that remote fear memories formed in the distant past are permanently stored in connections between memory neurons in the prefrontal cortex, or PFC.

“It is the prefrontal memory circuits that are progressively strengthened after traumatic events and this strengthening plays a critical role in how fear memories mature to stabilized forms in the cerebral cortex for permanent storage,” said Jun-Hyeong Cho, an associate professor of molecular, cell and systems biology, who led the study.

“Using a similar mechanism, other non-fear remote memories could also be permanently stored in the PFC.”

The brain uses distinct mechanisms to store recent versus remote fear memories. Previous studies have suggested that while the initial formation of fear memory involves the hippocampus, it progressively matures with time and becomes less dependent on the hippocampus. Much research now explains how recent fear memory is stored, but how the brain consolidates remote fear memories is not well understood.

The researchers focused on the PFC, a part of the cerebral cortex that has been implicated in remote memory consolidation in previous studies.

“We found a small group of nerve cells or neurons within the PFC, termed memory neurons, were active during the initial traumatic event and were reactivated during the recall of remote fear memory,” Cho said. “When we selectively inhibited these memory neurons in the PFC, it prevented the mice recalling remote but not recent fear memory, suggesting the critical role of PFC memory neurons in the recall of remote fear memories.”

In the experiments, the mice received an aversive stimulus in an environment called a context. They learned to associate the aversive stimulus with the context. When exposed to the same context a month later, the mice froze in response, indicating they could recall remote fear memories.

The researchers showed that connections (synapses) between memory neurons in the PFC, termed prefrontal memory circuits, were gradually strengthened with time after fear learning, and such strengthening helped the PFC permanently store remote fear memories.

Next, to extinguish the remote fear memory in the mice, the researchers repeatedly exposed the mice to the same fear-predictive context but without the aversive stimulus. The result was a reduced fear response to the context.

“Interestingly, the extinction of remote fear memory weakened the prefrontal memory circuits that were previously strengthened to store the remote fear memory,” Cho said. “Moreover, other manipulations that blocked the strengthening of the PFC memory circuits also prevented the recall of remote fear memory.”

Cho explained that a dysregulation of fear memory consolidation can lead to chronic maladaptive fear in PTSD, which affects about 6% of the population at some point in their lives.

“Considering that PTSD patients suffer from fear memories formed in the distant past, our study provides an important insight into developing therapeutic strategies to suppress chronic fear in PTSD patients,” he said.

Next, Cho’s team plans to selectively weaken the prefrontal memory circuits and examine whether this manipulation suppresses the recall of remote fear memories.

“We expect the results will contribute to developing a more effective intervention in PTSD and other fear-related disorders,” Cho said.

Cho was joined in the study by Ji-Hye Lee, Woong Bin Kim, and Eui Ho Park. The title of the paper is “Neocortical Synaptic Engrams for Remote Contextual Memories.”


Types of Fear

Some psychological theories propose that fear is a biologically basic emotion of all humans and many other animals [3], a view in line with most lay opinions as well. But several proposals beg to differ, arguing that emotions like fear should be replaced by a distinction between a fear and a panic system [12], or “survival circuits” related more broadly to adaptive behavior [13], or dimensional accounts such as reward and punishment [15]. A variety of evidence supports a view also in line with common usage: there are types fear.

The most common distinction is between fear and anxiety. Whereas fear is usually conceptualized as an adaptive but phasic (transient) state elicited through confrontation with a threatening stimulus, anxiety is a more tonic state related to prediction and preparedness– the distinction is similar to the one between emotions versus moods.

Some schemes have related fear and anxiety to dissociable neural structures for mediating their behavioral effects, for instance the central nucleus of the amygdala (for fear), and the nearby bed nucleus of the striaterminalis (for anxiety) [19]. However, the dense interconnectivity of these two structures makes it difficult to uniquely assign either of them to participation in only one of these processes.

A yet finer-grained classification makes distinctions between anxiety, fear, and panic, three varieties of fear that each are associated with particular packages of adaptive responses yet can all be mapped also onto a continuum of threat imminence (respectively, from more distal to more proximal [20]).

There is also evidence for multiple fear circuits in relation to the content of the threat. For instance, it has been argued that there are separate neural systems for fear of pain, predators, and aggressive conspecifics [21]. Each of these can be processed through a distinct sensory channel (e.g., somatosensory, olfactory, visual), engage distinct subnuclei in the amygdala and hypothalamus, and result in distinct responses mediated by particular parts of the periaqueductal gray (PAG) (respectively, ventrolateral, dorsolateral, and dorsomedial).

Some of these distinctions among putative fear-subsystems are also supported by distinct molecular markers. For example, the predator-related subsystem is marked by the expression of steroidogenic factor 1 across several species, and corticotropin releasing factor is expressed across a wide range of species and serves as a marker of the central amygdala in rodents (see Box 1 in [21]).

A recent comparison between humans and mice revealed that copy number variations at specific genetic loci can influence remarkably specific types of fear: duplications of the GTF2I gene are associated with increased separation anxiety in both species [22].

Are these findings of multiple fear systems a problem for a concept of “fear” as a central state? Of course, partly different sets of individual neurons will no doubt be involved in processing different fear stimuli, or for that matter even the identical fear stimulus but on different occasions.

This no more shows that there are distinct fear systems than does the fact that different visual images evoke somewhat different patterns of neural response in visual parts of the brain: nobody would conclude from this that there are many different visual systems. To demonstrate distinct fear systems, we would need to be able reliably to trace processing streams, and we would need to decide on the level of grain at which such processing streams are implemented in the brain.

If we do find more than one such parallel processing stream for fear, then this could show that there are neurobiologically distinct types of fear that all share a common ecological theme (they are about threat, but different types of threat). But unless the number of such parallel systems gets very large, this would seem like progress in understanding the microstructure of fear, rather than an obstacle to using the term. In this respect, the data so far would seem to indicate that “fear” is quite a cohesive concept with likely fewer subtypes than, say, “memory”.

Fear and the Amygdala
The basolateral amygdala receives most of the sensory inputs that specify fear associations (with the exception of olfactory input, which comes into the medial nucleus) and selective optogenetic activation of neurons within this nucleus is sufficient to associate the incoming sensory information with unconditioned fear responses [33] (Figure 2). The central nucleus of the amygdala is widely considered the main output regulator for mediating fear responses, and these are in turn mediated by distinct subdivisions of the central nucleus. Whereas some of these neurons can inhibit cholinergic targets mediating cortical arousal (in the substantiainnominata, diagonal band of Broca, nucleus basalis), they can at the same time promote freezing through projections to the periaqueductal gray [34]. The flexible modulation of different downstream fear components by the central amygdala depends on an intricate inhibitory control balance internal to the amygdala [35, 36].

Studies of the amygdala in humans have implicated this structure in the recognition [37], expression [38], and experience [39] of fear. However, in human neuroimaging studies it is activated not only in anxiety and phobia [40] but by a broad range of unpleasant or pleasant stimuli [41–43], including highly arousing appetitive stimuli such as sexual stimuli or one’s favorite music [44, 45]. The enormous range of stimulus properties that have been reported to activate the amygdala has given way to views that try to provide a more unified picture. Such accounts typically acknowledge that the amygdala plays an important role in fear, but stop short of endorsing the claim that this is a basic function. Instead, they propose that it is merely one example of a broader and more abstract function, such as processing arousal, value, preference, relevance, impact, vigilance, surprise, unsigned prediction error, associability, ambiguity or unpredictability. The extent to which any of these functions are domain-specific (notably, in regard to processing social stimuli) remains an open question [46].

Much of this literature has interacted with the amygdala’s well-known role in memory [47] and attention [48], with the emerging possibility that the amygdala may play a more modulatory [49], developmental [50], and learning-related role [51], rather than a principal role in the on-line processing of fear. Somewhat relatedly, there has been a shift towards more network-based views of fear processing, in which structures such as the amygdala are nodes in an anatomically much more extended collection of structures [52]. This shift emphasizes the fact that the initial question was simply ill-posed: “what does the amygdala do?” is not a sensical query in the first place, because the amygdala in isolation does nothing; it all depends on the particular network in which it participates. This also points us towards a different view on the search for neuroimaging activation patterns specific to certain emotions: the circuits responsible may simply be too distributed to resolve using techniques such as fMRI.

As important as moving from the amygdala outwards to include it in larger networks is moving inwards to consider its internal components. Earlier work in rodents began to show that different amygdala nuclei are involved in different types of fear-related behaviors, such as innate responses to conditioned stimuli or actions to avoid them (e.g., [53, 54]). However, whereas the earlier studies investigated these issues using bulk lesions of tissue (and generated some conflicting findings), it is now clear that the level of resolution required is at the level of specific neuronal subpopulations, often intermingled even within a single nucleus.

Such subpopulations are distinguishable by a number of criteria, including the set of genes they express, their morphology, and most importantly their connectivity and electrophysiological properties whereby they subserve particular functions in processing fear. Current investigations of this issue use optogenetics to address this issue. In this technique, light-activated ion channels are expressed in specific neuronal subpopulations through their coupling to a promotor specific to that subtype (alternatively, one can also engineer ion channels gated by exogenous drugs that can then be administered experimentally).

This is achieved best in transgenic mice, although it also possible to do it through focal injection of viruses, opening the door to such manipulations in monkeys as well. Optogenetic studies have demonstrated a tightly regulated network of inhibitory interneurons within the central nucleus that controls how sensory input (coming into the basolateral amygdala) can influence outputs to structures such as the hypothalamus and periaqueductal gray (e.g., [35, 36]).

This level of grain is impossible to investigate in humans so far, and poses a major challenge for how to interpret results from functional neuroimaging studies, which pool changes in blood-oxygenation-related activation over voxels several millimeters in size (typically, 15–20 cubic millimeters) over a timecourse of a few seconds.

As with midbrain and brainstem structures, the amygdala’s role in fear processing is highly conserved across species ranging from humans [55], to monkeys [56, 57], rodents [58, 59], and even reptiles [60], mirroring its conserved pattern of connectivity [61]. Sorely needed are systematic comparative studies that focus on specific structures and networks, and that map out the similarities and differences in functional components. For instance, the role of the amygdala in associative learning of fear appears to be ubiquitous across species; the set of unconditioned stimuli that it processes vary to some extent; and its role in the conscious experience of fear has been investigated only in humans [39].

The Modulation of Fear

A key current challenge is to assemble our knowledge at the level of individual structures, nuclei, and neuronal populations, to knowledge at the level of distributed large-scale networks (a challenge that pervades all of emotional and social neuroscience [66]). An emerging theme from such network concepts is that there are structures more concerned with directly orchestrating fear-related responses (e.g., PAG and hypothalamus), and structures more concerned with context-dependent modulation. Of particular interest for the latter have been prefrontal cortices, which some schemes have partitioned into orbital and medial networks, subserving processing of emotionally salient sensory stimuli and orchestrating of visceral emotional responses, respectively [67]; and into ventromedial and dorsolateral networks related to reward processing and cognitive control [68]. Moreover, such networks can be related to specific neurotransmitters and levels of action for pharmacological intervention [69]. The amygdala plays a key role in mediating between brainstem and cortical levels, with specific nuclei participating in distinct networks that may be similar across species [61]. Dissecting these networks and understanding their pharmacology, constitutes one of the main research components towards treating phobias and anxiety disorders [70].

The context-dependency of fear is seen in terms of the eliciting circumstances (e.g., flight available or not, which will elicit escape vs. freezing; Figure 4a), type of threat (predator, conspecific, unknown), distance to the threat (and hence time; i.e., predatory imminence [20]), and time elapsed since a threat was encountered (resulting, in order, in behaviors such as active defense and flight, risk assessment, inhibition of movement, distancing). All of these have been described in some detail by ethologists working on fear in nonhuman animals [71, 72], and emphasize the temporally extended and dynamic nature of a fear state that we noted earlier. There are many examples that networks within the medial prefrontal cortex play a key role in the modulation of fear-related processing, by projecting to targets such as the amygdala, hypothalamus, and brainstem. For instance, prefrontal regions are implicated in the extinction of conditioned fear responses, and lesions to ventromedial sectors of the prefrontal cortex in humans may actually exert a protective role in the acquisition of disorders such as post-traumatic stress disorder [73].

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Figure 4

Fear, the amygdala, and distance

Physical distance (proximity) is one of the most basic stimulus cues to trigger fear. (A) Different adaptive types of fear behaviors can be elicited as a function of distance, ranging from freezing to fleeing to defensive attack. Adapted from [74], see also [20] for a similar scheme. (B) Lesions of the human amygdala reduce interpersonal distance and the sense of invasion of personal space. At the top are schematized the mean interpersonal distances from an experimenter for healthy controls (left) and a patient with bilateral amygdala lesions (patient SM, right). At the bottom is a plot of the data showing mean distance that people felt comfortable standing from the experimenter (at the origin), patient SM is the red bar and the rest are healthy controls. From [91]. (C) Approach or retreat of a threatening stimulus (a tarantula) in a human fMRI study showed differential activation of the amygdala and bed nucleus of the striaterminalis. Participants lay inside the fMRI scanner while their foot was placed in compartments at varying distances from the tarantula, a procedure they observed through video (left panel). Subtraction of approach minus retreat (for the same distance, middle panel) resulted in the activation shown on the right panel. From [96].

Another example implicating the prefrontal cortex comes from studies of threat imminence: proximal predator threats require immediate flight; anticipations of dangerous future situations require long-term planning and control [20, 74] (cf. below). These distinctions are mirrored in the neural structures that have been emphasized: brainstem and midbrain structures on the one hand, and forebrain, in particular prefrontal cortex, on the other [27, 58]. Yet a strict dichotomy is probably inaccurate, and a better model may be to think of all “lower” structures as involved in both immediate and delayed responses, with the latter including more forebrain modulation; it has also become apparent that loops involving forebrain processing can be remarkably rapid [75].

An interesting line of work that ties together the themes of specific neurotransmitters (serotonin), prefrontal networks, and particular subtypes of fear comes from analyses of an animal’s control over a stressor. Uncontrollable stress has long been known to lead to more severe health consequences, and to specific behavioral adaptations such as “learned helplessness”. This behavior depends in part on serotonergic modulation via the dorsal raphe nucleus, but also requires input to the dorsal raphe from the ventromedial prefrontal cortex to signal that a stressor is uncontrollable [76].

reference link:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595162/


Original Research: Open access.
Neocortical Synaptic Engrams for Remote Contextual Memories” by Jun-Hyeong Cho et al. Nature Neuroscience

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