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19 Learning about Danger: The Neurobiology of Fear Memories 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 The Concept of Fear as a Defensive Behavioral System 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. 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. 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) Key Components of the Neural System Supporting Fear Behaviors Key Components of the Neural System Supporting Fear Behaviors 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. 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. 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 reencounter 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. 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. The Acquisition and Extinction of a Pavlovian Conditioned Response 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. 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. 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. 1. Spontaneous recovery 2. Renewal effect 3. Reinstatement effect Extinction Does Not Erase the Underlying Association: Spontaneous Recovery Spontaneous recovery can occur when there is a long retention interval between extinction and the test. Extinction Does Not Erase the Underlying Association: Renewal Effect 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. Extinction Does Not Erase the Underlying Association: Reinstatement Effect (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. 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. 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. 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. 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. Extinction Can Erase Fear Memories in Infant Rats Adult rats Infant rats Short Long interval interval Context Context A B No US US 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. 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.