Amygdala

Joseph E. LeDoux (2008), revision #137109 [link

Scholarpedia, 3(4):2698. doi:10.4249/scholarpedia.2698 to/cite this article]
Post-publication activity

Curator: Joseph E. LeDoux

Dr. Joseph E. LeDoux, Center for Neural Science, NYU, New York, NY

Figure 1: Location of amygdala in the brain (reproduced from Wikipedia under GFDL).

The amygdaloid region of the brain (i.e. the amygdala) is a complex structure involved
in a wide range of normal behavioral functions and psychiatric conditions. Not so long
ago it was an obscure region of the brain that attracted relatively little scientific interest.
Today it is one of the most heavily studied brain areas, and practically a household
word. This article will summarize the anatomical organization of the amygdala and its
functions.

Contents
[hide]
1 Anatomical organization
2 Function
o 2.1 Fear conditioning
o 2.2 Reward processing
o 2.3 Other Functions
3 Conclusion
4 References

5 See Also

Anatomical organization
The existence of the amygdala was first formally recognized in the early 19th century.
The name, derived from the Greek, was meant to denote the almond-like shape of this
region in the medial temporal lobe. Much debate has since ensued, and continues today,
about how the amygdala should be subdivided. Also controversial is how the
subdivisions relate to other major regions of the brain.

One long-standing idea is that the amygdala consists of an evolutionarily primitive

division associated with the olfactory system (cortical, medial and central nuclei) and an
evolutionarily newer division associated with the neocortex (lateral, basal, and
accessory basal nuclei). The areas of the older division are sometimes grouped as the
cortico-medial region (cortical and medial nuclei) and sometimes as the centro-medial
region (the central and medial nuclei). In contrast, the newer structures related to the
neocortex are often referred to as the basolateral region. The almond shaped structure
that originally defined the amygdala included the basolateral region rather than the
whole structure now considered to be the amygdala.

In recent years, there have been a number of attempts to reclassify the amygdala and its
relation to other areas. For example, Heimer and colleagues have argued for the concept
of an extended amygdala. In this view, the central and medial amygdala form
continuous structures with the lateral and medial divisions of the bed nucleus of the stria
terminalis. A more radical notion comes from Swanson and Petrovich, who propose that
idea that the amygdala, whether extended or not, does not exist as a structural unit.
Instead, they argue that the amygdala consist of regions that belong to other regions or
systems of the brain and that the designation the amygdala is not necessary. For
example, in this scheme, the lateral and basal amygdala are viewed as nuclear
extensions of the neocortex (rather than amygdala regions related to the neocortex), the
central and medial amygdala are said to be ventral extensions of the striatum, and the
cortical nucleus is associated with the olfactory system. While this scheme has some
merit, the present review focuses on the organization and function of nuclei and
subnuclei that, while traditionally said to be part of the amygdala, nevertheless perform
their functions regardless of whether the amygdala itself exists, or whether it is
extended.

It is easy to be confused by the terminology used to describe the amygdala nuclei, as

different sets of terms are used. This problem is especially acute with regards to the
basolateral region of the amygdala. One popular scheme refers to the basolateral region
as consisting of the lateral, basal and accessory basal nuclei. Another scheme uses the
terms basolateral and basomedial nuclei to refer to the regions named as the basal and
accessory basal nuclei in the first scheme. Particularly confusing is the use of the term
basolateral to refer to both a specific nucleus (the basal or basolateral nucleus) and to
the larger region that includes the lateral, basal and accessory basal nuclei (the
basolateral complex). Another confusing point involves the cortical nucleus. Being a
cortical structure, albeit a primitive olfactory one, it is sometimes associated with the
basolateral region, but is also often grouped with the medial nucleus to form the cortico-
medial amygdala. The major nuclei of the amygdala are shown in sections from the rat
brain in Figure 2.
Figure 2: Some areas of the amygdala, as shown in the rat brain. The same
nuclei are present in primates, including humans. Different staining methods
show amygdala nuclei from different perspectives. Left panel: Nissl cell body
stain. Middle panel: acetylcholinesterase stain. Right panel, silver fiber stain. Figure 3: Some of the m
Abbreviations of amygdala areas: AB, accessory basal; B, basal nucleus; Ce, the amygdala. Sensory
central nucleus; itc, intercalated cells; La: lateral nucleus; M, medial nucleus; visual; somato, somato
CO, cortical nucleus. Non-amygdala areas: AST, amygdalo-striatal transition olfactory. Modulatory a
area; CPu, caudate putamen; CTX, cortex. norepinephrine, DA, do
serotonin).

The amygdala has a wide range of connections with other brain regions, allowing it to
participate in a wide variety of behavioral functions. Some of the major connections are
shown above in Figure 3.

Different nuclei of the amygdala have unique connections (Figure 4, Figure 5, and
Figure 6), which is why each nucleus makes unique contributions to functions. A
thorough discussion of all the connections is beyond the present scope. Therefore, a few
key examples will be given. The lateral amygdala is a major site receiving inputs from
visual, auditory, somatosensory (including pain) systems, the medial nucleus of the
amygdala is strongly connected with the olfactory system, and the central nucleus
connects with brainstem areas that control the expression of innate behaviors and
associated physiological responses. In many instances, the subnuclei of a given nucleus
also have distinct connections. The lateral nucleus, for example, includes dorsal, medial,
and ventrolateral subnuclei, while the central nucleus contains lateral, capsular, and
medial subnuclei. The dorsal subnucleus of the lateral nucleus receives much of the
direct sensory flow to the amygdala, while the medial division of the central nucleus is
the part that connects with response control regions.
Figure 4: Inputs to some specific amygdala nuclei.
Abbreviations of amygdala areas: basal; B, basal nucleus; Ce,
central nucleus; itc, intercalated cells; LA: lateral nucleus; M,
medial nucleus. Sensory abbreviations: aud, auditory; vis,
visual; somato, somatosensory; gust, gustatory (taste).
Figure 5: Outputs of some specific amygd
Abbreviations of amygdala areas: basal; B
central nucleus; itc, intercalated cells; LA
Modulatory arousal systems abbreviation
norepinephrine, DA, dopamine, ACh, ace
serotonin). Other abbreviations: parasym
nervous system; symp ns, sympathetic ne

Most of the inputs to the amygdala involve excitatory pathways that use glutamate as a
transmitter. These inputs form synaptic connections on the dendrites of excitatory
principal neurons that transit signals to other regions or subregions of the amygdala or
to extrinsic regions. Principal neurons are thus also called projection neurons since the
project out. However, axons of principal neurons also give rise to local connections to
inhibitory interneurons that then provide feedback inhibition to the principal neurons. In
addition to terminating on projection neurons, some of the excitatory inputs to the
amygdala terminate on local inhibitory interneurons that in turn connect with principal
neurons, giving rise to feedforward inhibition.

The scheme of connections just described applies to the neurons of the basolateral
complex more so than to neurons within the centro-medial group. For example, while
the projection neurons of the basolateral group are excitatory, the projection neurons in
the central nucleus tend to be inhibitory in nature. Thus, excitation of neurons in the
central nucleus leads to inhibition of target neurons, while inhibition of these projection
neurons gives rise to increased output of the target neurons. Whether central amygdala
cells are activated by excitatory projection neurons or by way of connections from
projection neurons to local interneurons thus influences the ultimate output state of the
central amygdala. These connections are consistent with the notion described above that
the basolateral group is closely associated with the cerebral cortex and the cortico-
medial group with the basal ganglia.

The flow of information through amygdala circuits is modulated by a variety of

neurotransmitter systems. Thus, norepinephrine, dopamine, serotonin, and acetylcholine
released in the amygdala influences how excitatory and inhibitory neurons interact.
Receptors for these various neuromodulators are differentially distributed in the various
amygdala nuclei. Also differentially distributed are receptors for various hormones,
including glucocorticoid and estrogen. Numerous peptides receptors are also present in
the amygdala, including receptors for opioid peptides, oxytocin, vasopressin,
corticotropin releasing factor, and neuropeptide Y, to name a few.

Function
In the late 1930s, researchers observed that damage to the temporal lobe resulted in
profound changes in fear reactivity, feeding, and sexual behavior. Around mid century, it
was determined that damage to the amygdala accounted for these changes in emotional
processing. Numerous studies subsequently attempted to understand the role of the
amygdala in emotional functions, especially fear. The result was a large and confusing
body of knowledge about the functions of the amygdala because much of the research
ignored the nuclear and subnuclear organization of the amygdala, which was not fully
appreciated, and partly because the functions measured by behavioral tasks were not
well understood.

Fear conditioning

The early studies of fear used avoidance conditioning tasks. These measure fear in terms
of how well an animal leans to avoid shock. However, avoidance is a two stage process
in which Pavlovian conditioning establishes fear responses to stimuli that predict the
occurrence of the shock, and then new behaviors that allow escape from or avoidance of
the shock, and thus that reduce the fear elicited by the stimuli, are learned. In the 1980s,
researchers began to use tasks that isolated the Pavlovian from the instrumental
components of the task to study the brain mechanisms of fear. This strategy allowed a
focus on the fear reaction conditioned by the shock rather than on behaviors that avoid
the shock.
Figure 7: Auditory fear conditioning paradigm. Studies using this paradigm Figure 8: Auditory fear
have helped elaborate the functional role of amygdala nuclei. Rats are stimulus (CS) and soma
habituated to the chamber on day 1 (no stimulation). On day 2, the rat receives converge in the lateral a
a small number of training trials (typically 1-5) in which a tone CS is paired system via both thalam
with a footshock US. Controls receive unpaired presentations of the CS and synaptic plasticity in LA
US. On day 3, the CS is presented in a novel chamber with a unique odor LA to activate the centr
(peppermint) and fear responses (freezing) to the CS assessed. Animals in turn controls the exp
receiving pairings on day 2 show high levels of freezing but animals receiving endocrine responses tha
unpaired training show little freezing. abbreviations: B, basal
ITC, intercalated cells o
hypothalamus.

In Pavlovian fear conditioning a neutral conditioned stimulus (CS) that is paired with a
painful shock unconditioned stimulus (US) comes to elicit fear responses such as
freezing behavior and related physiological changes (Figure 7). Studies in rodents have
mapped the inputs to and outputs of amygdala nuclei and subnuclei that mediate fear
conditioning. In particular, it is widely accepted that convergence of the CS and US
leads to synaptic plasticity in the dorsal subregion of the lateral amygdala. When the CS
then occurs alone later, it flows through these potentiated synapses to the other
amygdala targets and ultimately to the medial part of the central nucleus, outputs of
which control conditioned fear responses (Figure 8). Much has been learned about the
cellular and molecular mechanisms within lateral amygdala cells that underlie the
plastic changes. In brief, convergence of the strong US inputs to cells that also receive
CS inputs results in an elevation of intracellular calcium, and event that triggers a host
of molecular responses leading to protein synthesis (Figure 9). The proteins then help
strengthen stabilize the CS input synapses, allowing them to respond more strongly to
the CS after conditioning. As a result, the CS flows through the amygdala circuits to
elicit the fear responses controlled by the central nucleus. Amygdala areas, together with
the prefrontal cortex and hippocampus, is involved in the reduction of learned fear
through extinction and cognitive regulatory processes.

Figure 9: Intracellular signal transduction pathways underlying auditory fear

conditioning in LA cells.

Reward processing

Although fear is the emotion best understood in terms of brain mechanisms, the
amygdala has also been implicated in a variety of other emotional functions. A relatively
large body of research has focused on the role of the amygdala in processing of rewards
and the use of rewards to motivate and reinforce behavior. As with aversive
conditioning, the lateral, basal, and central amygdala have been implicated in different
aspects of reward learning and motivation, though the involvement of these nuclei
differs somewhat from their role in fear. The amygdala has also been implicated in
emotional states associated with aggressive, maternal, sexual, and ingestive (eating and
drinking) behaviors. Less is known about the detailed circuitry involved in these
emotional states than is known about fear.

Other Functions

Because the amygdala learns and stores information about emotional events, it is said to
participate in emotional memory. Emotional memory is viewed as an implicit or
unconscious form of memory and contrasts with explicit or declarative memory
mediated by the hippocampus.

In addition to its role in emotion and unconscious emotional memory, the amygdala is
also involved in the regulation or modulation of a variety of cognitive functions, such as
attention, perception, and explicit memory. It is generally thought that these cognitive
functions are modulated by the amygdala's processing of the emotional significance of
external stimuli. Outputs of the amygdala then lead to the release of hormones and/or
neuromodulators in the brain that then alter cognitive processing in cortical areas. For
example, via amygdala outputs that ultimately affect the hippocampus, explicit
memories about emotional situations are enhanced. For example, glucocorticoid
hormone released into the blood stream via amygdala activity travels to the brain and
then binds to neurons in the basal amygdala. The latter then connects to the
hippocampus to enhance explicit memory. There is also evidence that the amygdala can,
through direct neural connections, modulate the function of cortical areas.

Over the past decade, interest in the human amygdala has grown considerably, spurred
on by the progress in animal studies and by the development of functional imaging
techniques. As in the animal brain, damage to the human amygdala interferes with fear
conditioning and functional activity changes in the human amygdala in response to fear
conditioning. Further, exposure to emotional faces potently activates the human
amygdala. Both conditioned stimuli and emotional faces produce strong amygdala
activation when presented unconsciously, emphasizing the importance of the amygdala
as an implicit information processor and its role in unconscious memory. Studies of
humans and non-human primates also implicate the amygdala in social behavior.
Findings regarding the human amygdala are mainly at the level of the whole region
rather than nuclei.

Structural and/or functional changes in the amygdala are associated with a wide variety
of psychiatric conditions in humans. Included are various anxiety disorders (PTSD,
phobia, and panic), depression, schizophrenia, and autism, to name a few. This does not
mean that amygdala causes these disorders. It simply means that in people who have
these disorders alterations occur in the amygdala. Because each of these disorders
involves fear and anxiety to some extent, the involvement of the amygdala in some of
these disorders may be related to the increased anxiety in these patients.

Conclusion
The rise in popularity of the amygdala as a research topic should not overshadow the
fact that much remains to be learned. Especially important for the future will be studies
that attempt to understand whether the importance of the amygdala in fear reflects the
importance of fear to the amygdala or whether fear is just the function that has been
studied most.

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Internal references

Peter Redgrave (2007) Basal ganglia. Scholarpedia, 2(6):1825.

Valentino Braitenberg (2007) Brain. Scholarpedia, 2(11):2918.

Nestor A. Schmajuk (2008) Classical conditioning. Scholarpedia, 3(3):2316.

Joseph E. LeDoux (2007) Emotional memory. Scholarpedia, 2(7):1806.

William D. Penny and Karl J. Friston (2007) Functional imaging. Scholarpedia,

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Howard Eichenbaum (2008) Memory. Scholarpedia, 3(3):1747.

Peter Jonas and Gyorgy Buzsaki (2007) Neural inhibition. Scholarpedia,

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Wolfram Schultz (2007) Reward. Scholarpedia, 2(3):1652.

Marco M Picchioni and Robin Murray (2008) Schizophrenia. Scholarpedia,

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See Also
Memory, Emotional Memory, Medial Temporal Lobe, Fear Conditioning, Pavlovian
Conditioning