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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.