1. Learning about Danger: The Neurobiology of Fear Memories

2. The Concept of a Behavioral System
Behavioral systems are designed to enable organisms to solve fundamental problems associated with survival.
There are specialized behavioral systems designed to support such activities as:
Reproduction
Feeding
Avoidance and escape from dangerous situations

3. The Concept of Fear as a Defensive Behavioral System
FIGURE 19.1 This figure illustrates a defensive behavioral system. This system organizes the expression of a variety of behaviors that have evolved to protect us from danger. It can be activated by innate danger signals, and experience allows this system to also be activated by learned danger signals.
The fear system organizes the expression of a variety of behaviors that have evolved to protect us from danger. It can be activated by innate danger signals, and experience allows this system to also be activated by learned danger signals.

4. The Concept of Fear as a Defensive Behavioral System
Robert Bolles developed the concept of species specific defense responses. Michael Fanselow developed the concept of a predatory imminence gradient.
FIGURE 19.1 This figure illustrates a defensive behavioral system. This system organizes the expression of a variety of behaviors that have evolved to protect us from danger. It can be activated by innate danger signals, and experience allows this system to also be activated by learned danger signals.

5. The Concept of Fear as a Defensive Behavioral System
If something unexpected occurs—a loud noise or sudden movement—people tend to respond immediately … stop what they are doing … orient toward the stimulus, and try to identify its potential for actual danger. This happens very quickly, in a reflex-like sequence in which action precedes any voluntary or consciously intentioned behavior. A poorly localizable or identifiable threat source, such as sound in the night, may elicit an active immobility so profound that the frightened person can hardly speak or even breathe (i.e., freezing). However, if the danger source has been localized and an avenue for flight or concealment is plausible, the person will probably try to flee or hide. Actual contact with the threat source is likely to elicit thrashing, biting, scratching, and other potentially damaging activities by the terrified person. (Blanchard and Blanchard, 1989)

6. Key Components of the Neural System Supporting Fear Behaviors
The elements of the neural system that support learned fear. Sensory information representing an aversive experience comes into the system by way of the sensory thalamus. A subcortical pathway takes unprocessed information directly to the lateral and central nuclei of the amygdala. A cortical pathway brings this information to the neocortex and the hippocampus, where more detailed representations of experience are constructed. Projections from these regions converge on neurons located in the lateral nucleus of the amygdala (LA) and neurons in the lateral capsule of the central amygdala (CEc). Neurons in both the LA and CEc are believed to contain modifiable synapses. Thus, when a behavioral experience contains an aversive event, synapses linking inputs from the sensory thalamus, neocortex, and hippocampus to neurons in these regions are strengthened. After the experience with an aversive event, a re-encounter with the surrounding stimuli will drive neurons in the LA and CEc to a point where they will activate the output region of the central amygdala—the medial nucleus (CEm)—to generate defensive behaviors by activating neurons in the lateral hypothalamus (LH) and the periacqueductal gray (PAG) in the midbrain.

7. Key Components of the Neural System Supporting Fear Behaviors
FIGURE 19.2 This figure illustrates the basic components of the fear system that can be modified by experience. The lateral nucleus receives sensory input from the sensory thalamus, perirhinal cortex, and hippocampus that provides information about the current state of the environment. The basal nucleus contains both fear and extinction neurons. Neurons in the central amygdala control midbrain structures that support the expression of fear behaviors. When neurons in the central amygdala depolarize they activate the midbrain nuclei to generate defensive behaviors. An ITC-b cluster normally inhibits central amygdala neurons. Arrows indicate excitatory connections, and round endings indicate inhibitory connections. PL = prelimbic; IF = infralimbic; F = fear; E = extinction.
The fear system is organized to receive sensory information about the environment and to decide if fear behaviors should be generated. The basolateral region is organized to receive sensory information about the environment. The central amygdala regulates the expression of fear.

8. Cyril Henry Discovered Fear and Extinction Neurons in the Basal Nucleus
The basal nucleus contains two types of neurons: (1) fear neurons (F) that are active when fear behaviors are expressed and (2) extinction (E) neurons that are active when fear has been extinguished. The fear neurons provide excitatory projections to the central nucleus and to neurons in the prelimbic region of the prefrontal cortex. Extinction neurons project to ITC-b cells.

9. A Fear Conditioning Experience Alters Synaptic Connections Linking Cortical Inputs to Neurons in the Lateral Amygdala
When an aversive event occurs, synapses are strengthened that link the sensory content (context and CS) to neurons in the lateral amygdala and prelimbic cortex. As a consequence, a re- encounter with these stimulus conditions will activate the fear circuit (in red). The inhibitory influence of ITC-b neurons on central neurons will be removed and excitatory drive provided by fear neurons and prelimbic cortex neurons will increase. PL = prelimbic; IF = infralimbic; F = fear; E = extinction.

10. Post-traumatic stress disorder Phobias Panic Attacks
The Neurobiology of Fear Removal
Learned fears can be the source of many of the so-called anxiety disorders.
Post-traumatic stress disorder
Phobias
Panic Attacks
Thus, from a clinical perspective understanding how fears can be removed is very important.
The process known as extinction plays a central role in fear removal.
In this section the focus will be on understanding extinction and its neurobiological underpinnings.

11. The Acquisition and Extinction of a Pavlovian Conditioned Response
Figure 19.4 Paired presentations of the conditioned stimulus (CS) and unconditioned stimulus (US) produce acquisition. The CS acquires the ability to evoke the conditioned response (CR). If the CS is then presented alone, it will lose the ability to evoke the CR. This phenomenon is called extinction.
Extinction is a term that refers to both a procedure—the CS is presented without the US— and to an outcome—the CS loses it ability to evoke a conditioned response.

12. Two Theories of Extinction
The associative loss hypothesis assumes that extinction is due to a CS-alone presentation eliminating the original CS–US association. The competing memory hypothesis assumes that extinction produces a new association called a CS–noUS association. The original CS–US association that produced the CR remains intact. If the CS–noUS association occurs, it inhibits (–) the expression of the conditioned response.
FIGURE 19.5 This figure illustrates two theories of extinction. The associative loss hypothesis assumes that extinction is due to a CS-alone presentation eliminating the original CS–US association. The competing memory hypothesis assumes that extinction produces a new association called a CS–noUS association. The original CS–US association that produced the CR remains intact. If the CS–noUS association occurs, it inhibits (–) the expression of the conditioned response.

13. Three Findings Imply that Extinction Does Not Erase the Underlying Association
The associative loss hypothesis predicts that extinction should be permanent—because the underlying associative connections should be erased. However, the three findings below indicate that extinction is not permanent.
Spontaneous recovery
Renewal effect
Reinstatement effect

14. Extinction Does Not Erase the Underlying Association: Spontaneous Recovery
FIGURE 19.6 This figure illustrates three findings that indicate that extinction is not permanent. In each example the critical results are from the retention test where the CS is re-presented after extinction has taken place. (A) Spontaneous recovery can occur when there is a long retention interval between extinction and the test. (B) Renewal can occur when the context where extinction trials take place is different from the context in which training takes place, and the test occurs in the training context. (C) Reinstatement occurs if the US is re-presented without the CS. In all cases, recovery from extinction occurs even though the CS and US are never re-paired.
Spontaneous recovery can occur when there is a long retention interval between extinction and the test.

15. Extinction Does Not Erase the Underlying Association: Renewal Effect
FIGURE 19.6 This figure illustrates three findings that indicate that extinction is not permanent. In each example the critical results are from the retention test where the CS is re-presented after extinction has taken place. (A) Spontaneous recovery can occur when there is a long retention interval between extinction and the test. (B) Renewal can occur when the context where extinction trials take place is different from the context in which training takes place, and the test occurs in the training context. (C) Reinstatement occurs if the US is re-presented without the CS. In all cases, recovery from extinction occurs even though the CS and US are never re-paired.
Renewal can occur when the context where extinction trials occur is different from the context in which training occurs, and the test occurs in the training context.

16. Extinction Does Not Erase the Underlying Association: Reinstatement Effect
FIGURE 19.6 This figure illustrates three findings that indicate that extinction is not permanent. In each example the critical results are from the retention test where the CS is re-presented after extinction has taken place. (A) Spontaneous recovery can occur when there is a long retention interval between extinction and the test. (B) Renewal can occur when the context where extinction trials take place is different from the context in which training takes place, and the test occurs in the training context. (C) Reinstatement occurs if the US is re-presented without the CS. In all cases, recovery from extinction occurs even though the CS and US are never re-paired.
(C) Reinstatement occurs if the US is re-presented without the CS. In all cases, recovery from extinction occurs even though the CS and US are never re-paired.

17. Key Components of the Neural System that Support the Extinction of Fear: Intercalated Inhibitory Neurons
Intercalated neurons
Denis Paré and his colleagues identified clusters of intercalated cells (ITCs) located between the basolateral complex and the central amygdala. These neurons receive CS information from the basolateral amygdala and project to the central amygdala. When activated, these cells release the inhibitory neurotransmitter GABA and thus prevent their target neurons from depolarizing. In this way, they prevent neurons in the central amygdala from generating defensive behavior. BL = basolateral amygdala; LA = lateral amygdala; AB = accessory basal nucleus.

18. Neural Basis of Fear Extinction: A CS-noUS Neural Circuit
Extinction training reconfigures the fear circuit (black arrows) so that the CS activates intercalated clusters that inhibit neurons in the central amygdala. To accomplish this, extinction training strengthens synaptic connections linking the context and CS input to extinction neurons in the basal nucleus to ITCs and to neurons in the infralimbic prefrontal cortex that also projects to ITCs. Thus, when the CS is presented, ITCs are activated and neurons in the central amygdala are inhibited.
Figure This figure illustrates how extinction training reconfigures the neural system to support extinction. The red arrows indicate how fear conditioning organizes the system to produce fear. The black arrows indicate how extinction training modifies the system to support no fear. The fundamental outcome produced by extinction training is to change synaptic connections that will increase inhibitory control over neurons in the central amygdala. This is accomplished by strengthening synapses linking the CS to extinction neurons in the basal region and to neurons in the infralimbic cortex. Both extinction and infralimbic cortex neurons project to ITCs that inhibit neurons in the central amygdala. The result is that the CS can now activate the new extinction circuit or the fear circuit and prevent neurons in the central amygdala from depolarizing and generating fear behaviors. Arrows indicate excitatory connections; round endings indicate inhibitory connections. PL = prelimbic; IF = infralimbic; F = fear; E = extinction.

19. Why Fear Renews—A Role for the Hippocampus
In this experiment, rats are conditioned to the CS in one context (context A) but extinguished in a different context (context B). Normal rats display renewed fear of the CS if they are tested in context A, but display no fear if tested in context B. In contrast, rats with damage to the hippocampus do not display renewed fear to the CS when tested in context A.

20. it facilitates the processes that produce extinction.
Extinction Learning Depends on NMDA Receptors
NMDA receptors have two binding sites, one for glutamate and one for glycine. APV
antagonizes the glutamate binding site and interferes with extinction. D-cycloserine (DCS) is an agonist for the glycine site. When it is given before or after extinction training,
it facilitates the processes that produce extinction.

21. Extinction Can Erase Fear Memories in Infant Rats
Short Long interval interval
Context Context
A B
No US US
Adult rats Infant rats
When infant rats experience extinction training, they do not exhibit either spontaneous recovery, renewal, or reinstatement. These findings suggest that extinction erases the underlying association.

22. Infant Rats Lack a Well-Developed Perineuronal Net
(A) Early in development, perineuronal nets that surround spines are immature. During this period extinction training can erase the fear memory. (B) When these nets are mature, extinction training does not erase the fear memory and extinction is due to new learning. However, by degrading these nets the infant state can be reinstated and extinction training can again erase the fear memory.