The Neural Bases of Emotions
24
Tamara B. Franklin and Isabelle M. Mansuy
The term “emotion” is understood intuitively but is
difficult to define, and currently there is no real con-
sensus in the literature as to its meaning. It is com-
monly described as a mental state, associated with
bodily changes, which arise spontaneously but are
consciously felt. Thus, emotions can encompass a
wide range of personal states accompanied by a num-
ber of observable behaviors and physiological changes.
Great progress in the understanding of the neural bases
for emotion has been made in the past decades.
However, several fundamental questions related to
emotions and the processing of emotional information
remain unanswered. The field of affective neurosci-
ence addresses these questions by investigating how
emotions and mood are represented in the brain.
Currently research interests lie in delineating which
neural structures and networks are required for emo-
tional responses, and further identifying the molecular
mechanisms acting in these brain areas. Other impor-
tant questions include how emotional events are
learned and stored, and how changes in the functioning
of the mechanisms and networks engaged during emo-
tional processing lead to mood disorders such as
depression and anxiety disorders. This chapter will
T.B. Franklin(*)
European Molecular Biology Laboratory Monterotondo,
Via Ramarini 32, Monterotondo, IT-00015 Rome, Italy
e-mail: tamara.franklin@embl.it
I.M. Mansuy
Brain Research Institute,
Medical Faculty of the University Zürich,
Zürich, Switzerland
Department of Health Sciences and
Technology of the ETH Zürich, Neuroscience Center Zürich,
Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
C.G. Galizia, P.-M. Lledo (eds.), Neurosciences - From Molecule to Behavior: A University Textbook,
DOI 10.1007/978-3-642-10769-6_24, © Springer-Verlag Berlin Heidelberg 2013
address past and present theories on the question of
“What is emotion?” and will outline our current
understanding of the neural mechanisms involved in
emotional processing.
24.1 Theories of Emotion
24.1.1 Charles Darwin
Thirteen years after publishing On the Origin of
Species in 1859, Charles Darwin (1809–1882) pub-
lished another seminal book entitled The Expression
of Emotions in Man and Animals. In this publication,
he presented three major principles for the origin of
emotions [15]. First, the Principle of Serviceable
Associated Habits proposed that some emotions help
to deal with emotional stimuli and, thus, are beneficial
to the organism. Second, the Principle of Antithesis
proposed that some emotions are just the opposite
emotions to the aforementioned beneficial emotions,
and they, themselves, have no beneficial attributes.
Last, the Principle of the Direct Action of the Nervous
System proposed that physiological changes that occur
as the result of emotional stimuli make up the final
part of emotional states.
He further developed two additional theories that
have become an integral part of how we think about
and research emotions today [13]. Importantly, he
drew parallels between animal and human emotions,
and explored cross-species similarities in emotional
states. This concept has justified the use of animals in
research aimed at understanding human emotions. A
second significant claim was that there are a certain
number of basic emotions, including anger, fear,
525
526
emotional state
sensory cortex cingulate cortex
3 2
hippocampus anterior thalamus
4 1
thalamus hypothalamus
bodily response
emotional stimulus
Fig. 24.1 The Papez circuit. The Papez circuit theory of the
functional neuroanatomy of emotion consists of two separate
streams: “thought” and “feeling”. Sensory messages containing
information about emotional stimuli are processed by the thala-
mus and then transmitted to the cortex (stream of thinking, red
arrows) and the hypothalamus (stream of feeling, green arrows).
The stream of feeling carries emotional information through
pathways from the hypothalamus to the anterior thalamus (1)
and then to the cingulate cortex (2). The stream of thought cor-
responds to top-down cortical control of emotional processes;
output pathways from the cingulate cortex to the hippocampus
(3) and then to the hypothalamus (4). Feelings or emotional
experiences are proposed to be the result of the integration of
signals from the hypothalamus with information from the sen-
sory cortex. While this theory is now outdated, many of the path-
ways proposed do exist and are key components of the emotional
response (Adapted from Dalgleish [13] with permission)
surprise, and sadness, that are present across species
and culture. This claim formed the basis for today’s
belief that different basic emotions have distinct under-
lying brain circuits and mechanisms.
24.1.2 The James-Lange Theory
Soon after Darwin’s publication containing his con-
cepts of emotion, a pioneering essay by William James
(1842–1910) entitled What is an Emotion? proposed that
emotion is the experience of physiological changes in
the body which occur on exposure to emotional stimuli
in our external environment [14, 25]. That is, when we
see a snake, our muscles contract and our breathing rate
increases in preparation for flight. According to James,
it is these instinctive bodily changes experienced when
seeing a snake that we perceive as fear of the snake.
Consequently, it is not because we feel afraid that we
prepare to run, but rather that we prepare to run, and
so we feel afraid. Similarly, it is not that we feel sad so
we cry, but rather we cry so we feel sad. This concept
was further developed by Carl Lange (1834–1900),
T.B. Franklin and I.M. Mansuy
who claimed that different emotions are encoded by
different patterns of physiological changes [13]. Thus,
the concept that sets of physiological changes are the
reason for emotional states is now termed the James-
Lange theory of emotions. One of the major caveats
for this theory is that it cannot explain the difference
between similar but differing emotions such as shame
and embarrassment, or fear and anxiety. Additionally,
this theory does not explain why emotion often per-
sists after the physiological response has subsided.
However, this theory was the first to compile scientific
knowledge of the time into a comprehensive theory of
emotion.
24.1.3 The Cannon-Bard Theory
Walter B. Cannon (1871–1945) criticized the James-
Lange theory for several reasons. One criticism was that
several studies undertaken in light of James’ theory
demonstrated that the same set of physiological changes
can be associated with both different emotional and non-
emotional states [10, 13]. A collaboration between
Cannon and Philip Bard (1898–1977) further opposed
the James-Lange theory [7, 13]. Bard studied the effect
of brain lesions on emotional behaviors in cats, and
found inappropriate anger responses in decorticated cats,
i.e., cats where the neocortex had been removed. Cannon
and Bard argued that this was not in accordance with the
James-Lange theory, as sensory and motor cortices
would need to be intact if emotions were indeed the per-
ception of bodily changes [13]. Instead, they argued that
the hypothalamus elicits emotional responses, and
that emotional responses are inhibited by neocortical
regions. This would explain why decorticated animals
display a lack of behavioral control and irrational emo-
tional responses. Thus, Cannon and Bard were the first
to propose a specific brain mechanism for emotion
and, importantly, advocated the use of surgical lesion
studies as a means to understand brain processes.
24.1.4 The Papez Circuit
The Papez circuit was first suggested in 1937 [13]
(Fig. 24.1). Papez (1883–1958) believed that the brain
has two separate streams: “thought” and “feeling”. In
his theory, sensory input of an emotional stimulus is
processed by the thalamus, and then transmitted to the
24 The Neural Bases of Emotions
sensory cortices, to either the cingulate cortex
(the thought stream) or the mamillary bodies of the
hypothalamus (the feeling stream). The thought stream
continues from the cingulate cortex through the cingu-
lum pathway to the hippocampus, through the fornix,
to the mamillary bodies of the hypothalamus, and back
to the anterior thalamus through the mamillothalamic
tract. The feeling stream continues from the mamillary
bodies, through the anterior thalamus up to the cingu-
late cortex. Thus, the cingulate cortex acts to integrate
information from the hypothalamus and the sensory
cortex to produce emotional states. Additionally,
Papez’s theory allowed for cortical regulation of emo-
tions as a result of projections from the cingulate cor-
tex to the hypothalamus. While it is now known that
not all regions named in Papez’s circuit are required
for the activation of emotional states, many of the pro-
posed pathways do exist, and several regions including
the hypothalamus and cingulate cortex are indeed key
contributors to emotional processing.
24.1.5 The Limbic System
In 1949, Paul MacLean (1913–2007) proposed an
anatomical model of the brain regions involved in
emotional processing. This model took components
of both the Papez circuit and Cannon-Bard theory
and integrated them with the findings of Kluver and
Bucy published in 1939 which demonstrated that
bilateral removal of the temporal lobes in monkeys
resulted in a particular set of behaviors, including
reduced emotional reactivity, increased exploratory
behavior, and hypersexuality [27]. Based on these
findings, structures within the temporal lobe became
an important component in MacLean’s theory of the
limbic system [13].
MacLean viewed the brain in three parts. The first
consists of the evolutionary primitive reptilian brain
and includes the basal ganglia, a group of nuclei com-
posed of the striatum, the globus pallidus, the substan-
tia nigra, and the subthalamic nucleus. He suggested
that these regions are responsible for primitive emo-
tions like fear and aggression. The second part consists
of the visceral brain, and includes several parts of the
Papez circuit such as the thalamus, hypothalamus, hip-
pocampus, and cingulate cortex, as well as the
amygdala and prefrontal cortex. He suggested that
these regions were responsible for augmenting the
527
primitive responses controlled by the ancient reptilian
brain, and for social emotions. The third part consists
of the new mammalian brain, which mostly includes
the neocortex. He proposed that these regions act as an
interface between emotions and cognition, and are
responsible for administering top-down control (con-
trol by brain structures responsible for higher level
functions) over all emotional responses.
Like James, MacLean proposed that external events
lead to physiological changes which, when recog-
nized by the brain and integrated with perceived
events in the outside world, result in emotional expe-
rience [13]. In his view, this integration occurred within
the visceral brain, which he later termed “the limbic
system”. While the concept of the limbic system has
since dominated theories on the neural basis of emo-
tion, it has come under criticism and some have even
suggested to drop the term altogether. One of the rea-
sons is that some regions of the limbic system may be
less important for emotional experiences than MacLean
supposed. For instance, MacLean suggested the hip-
pocampus as a key region in the integration of stimuli
that generate emotional experience. However, damage
to the hippocampus does not alter emotional respon-
sivity, or result in clinical changes in emotional pro-
cesses. Instead, the hippocampus is now believed to
play a much larger role in cognitive aspects of emo-
tional tasks. Further, regions suggested to play a larger
cognitive rather than emotional role are now known to
be key in mediating emotional processes. One
significant example of this is the amygdala, a region
now known to be a major component in emotional pro-
cessing (see Sect. 24.2). More generally, no criteria
have been established for inclusion of a particular
structure in the limbic system. Thus, while the limbic
system is arguably one of the most well-known neural
systems of the twentieth century, its relevance in cur-
rent neuroscience is under scrutiny.
24.1.6 Modern Theories of Emotion
24.1.6.1 Damasio and the Somatic
Marker Hypothesis
Antonio R. Damasio, a modern neurobiologist with a
distinctly pro-Jamesian theory of emotion, suggests
that an emotion is the collection of bodily changes in
response to visual or auditory mental images [14].
He further distinguishes between an emotion, and the
528
feeling of an emotion. For Damasio, feeling an emo-
tion is a cognitive response to the image or thought that
stimulated the emotion, combined with the realization
of this causal relationship between the thought and the
resulting bodily changes.
Damasio further theorizes that emotions can guide
decision-making. He suggests that a physiological
reaction tags previous events with emotionally relevant
stimuli, and has termed this phenomenon, a somatic
marker. A negative somatic marker acts as an alarm
bell, while a positive somatic marker is an incentive.
The somatic marker hypothesis suggests that somatic
responses to thought(s) increase the accuracy and
efficiency of decision-making, and implies that deci-
sion processing is not only the result of logical reason-
ing, but also includes a “gut reaction” which is essential
for appropriate and rational behavior.
24.1.6.2 The Schachter-Singer Theory
The Schachter-Singer theory of emotion (sometimes
called the two-component theory of emotion) pro-
poses that there are two main parts in emotion: a part
composed of Jamesian bodily factors, and a cognitive
component that allows us to properly label and dissoci-
ate emotions [45]. This theory was based on a series of
experiments that manipulated both the level of physi-
ological arousal through injections of epinephrine, and
the cognitive state of the individual by alteration of
social environments. These experiments demonstrated
that people do identify emotions based on bodily cues
stemming from arousal levels, and cognitive determi-
nants resulting from the circumstance in which they
are placed.
24.1.6.3 Edmund Rolls and Emotion
Another two-system approach to emotion is taken by
Rolls, who proposed that emotions are elicited by
either positive/rewarding, or negative/punishing
instrumental reinforcers [9, 43] (Fig. 24.2). Emotional
states are produced by delivery of a reward or punish-
ment, or omission or termination of a reward or
punishment. Thus, it is due to the fact that instrumen-
tal reinforcers have a goal-related aspect (delivery of a
reward/termination or omission of a punishment) that
they elicit emotions. For example, sweet taste when
T.B. Franklin and I.M. Mansuy
Fig. 24.2 Rolls’ theory of emotion. According to Rolls, emo-
tions are states resulting from positive (rewarding) and negative
(punishing) instrumental reinforcers. The vertical axis of the
graph is emotions elicited by presentation of a reward (S+) or
punishment (S−). Termination (or omission) of a reward (S+or
S+!) or punishment (S− or S−!) is placed on the horizontal axis.
The intensity of the emotion increases as distance from the mid-
point increases. The possibility of an active or passive behav-
ioral response is also accounted for. An example of this is that a
termination (or omission) of a positive reinforcer may result in
anger (an active response), but if this is not possible, in sadness/
grief (a passive response) (Reproduced from Calder [9] with
permission)
hungry is an instrumental reinforcer that will produce
physiological responses, such as salivation. However,
the neural processes required for producing salivation
can be distinct from those specifying this stimulus as a
goal for action, and inducing goal-directed instrumen-
tal learning. Thus, Rolls’ theory greatly differs from
the Damasio/Jamesian view by minimizing the role of
physiological responses, and instead defining emotion
as states induced by instrumental reinforcers.
24.2 Neuroanatomy of Emotion
Findings from human imaging and animal studies have
identified the amygdala, prefrontal cortex, anterior
cingulate cortex, and hypothalamus (Fig. 24.3), as
four main structures involved in emotional processing.
The following is a brief discussion of these brain areas
and their known function in terms of emotions [13].
24 The Neural Bases of Emotions 529

a 24.2.1 The Amygdala

The amygdala is an almond-shaped structure in the

medial temporal lobe important for the processing of
emotional information. It is a heterogeneous area of
the brain, containing several distinct subnuclei with
differing cell types and density, neurochemical com-
position, and functional connectivity. Although it was
first characterized as a brain region already in the early
nineteenth century, there is continuing debate about
the appropriate divisions of subnuclei due to the het-
erogeneity of the structure. Currently, the most com-
monly used division is based on the evolutionary
origins of two different regions of the amygdala: the
primitive division, associated with the olfactory sys-
tem (the cortico-medial region, including the cortical,
b medial, and central nuclei), and an evolutionarily
newer division associated with the neocortex (the
basolateral region, including the lateral, basal, and
basal accessory).
The lateral amygdala, often referred to as the gate-
keeper of the amygdala, receives input from sensory
systems, including the visual, auditory, somatosensory,
olfactory, and taste systems [32, 42]. These sensory
inputs generally terminate in the dorsal subnucleus of
the lateral amygdala, which in turn is connected with
the ventrolateral and medial areas of the lateral
amygdala. The central nucleus is known as the out-
put region for the expression of innate emotional and
physiological responses. Connections from the central
nucleus to the brainstem act to control both behaviors
and physiological responses. While the connections
c between lateral amygdala and the central nucleus are
minimal, there are many connections between the

Fig. 24.3 Key structures involved in emotional processing

in the human brain. Location of key structures involved in
emotional processing, including the amygdala, prefrontal cor-
tex, hypothalamus, and cingulate cortex. The involvement of
these regions in aspects of emotional processing is discussed in
Sect. 24.2 (a Reproduced from Perry et al. [39] with permission,
(b, c) From http://uhpsych100.wikispaces.com/chapter+three).
Abbreviations: (OB) olfactory bulb; (Cb) cerebellum; (lfh) lon-
gitudinal fissure of hemisphere; (Oc) occipital cortex; (cc) cor-
pus callosum; (ox) optic chiasm; (Hy) hypothalamus; (py)
pyramidal tract; (po) pons
530
a b
a' b'
c' d'
e' f'
Fig. 24.4 Differential response to fearful and happy facial
expressions in the left amygdala of human subjects.
(a) Prototypical neutral and fearful facial expressions are shown
in faces a and f, respectively. Faces b–e are facial expressions
falling within this continuum. (b) Regional cerebral blood flow
(rCBF) as measured by positron-emission tomography (PET)
values. (c) Statistical parametric maps (SPM) showing activa-
tion in only the left amygdala is significantly greater (yellow)
medial part of the lateral nucleus to other amygdala
subnuclei, that in turn connect with the central nucleus.
Additionally, output connections from the basal
nucleus to striatal areas mediate the expression of
instrumental behaviors, such as running to safety in
response to a predator.
The amygdala is an important region for emotional
processing, known to be involved in the processing of
social signals of emotion, emotional learning, and in
the consolidation of emotional memory. Much of the
research on the role of the amygdala is associated with
fear, but the amygdala is activated by multiple nega-
tive stimuli. For example, fearful faces activate the left
amygdala, and increased amygdalar response
significantly correlates with images of increased inten-
sity of fearfulness, and decreased response with increas-
ing level of happiness (Fig. 24.4). Increased intensity
of sad facial expressions have also been demonstrated
to increase neuronal activity in the left amygdala,
confirming its role in appraisal of negative facial
expressions. In addition to imaging studies, patients
with bilateral amygdala damage have demonstrated the
T.B. Franklin and I.M. Mansuy
c
when viewing fearful pictures as opposed to those showing
happy expressions. SPM is representative of this contrast in
rCBF values and shows significant difference in activation in the
left amygdala. The z-score is representative of the deviation of
activation elicited from fearful faces compared to the mean acti-
vation elicited from happy faces (Reproduced from Morris et al.
[37] with permission)
importance of the amygdala in fear recognition, as rec-
ognition of fear in fearful faces is severely impaired in
these patients. Along with its role in emotional process-
ing, the amygdala has also been suggested to be
involved in reward processing, and the use of reward
signals in decision-making processes.
24.2.2 The Prefrontal Cortex
The participation of the prefrontal cortex in emotional
processing was first suggested by a tragic accident
occurring in 1848 to a construction site foreman,
Phineas Gage [13]. While tamping gunpowder in a
blast hole with an iron rod, the gunpowder exploded
and propelled the iron rod through his head. The rod
entered under his left eyebrow and exited through the
top of the skull, causing major damage and a significant
loss of brain tissue in the prefrontal cortex. Gage
recovered from his injury, but his personality was
greatly altered. Before the accident, Gage was person-
able and good-natured, but following the lesion he
24 The Neural Bases of Emotions
became impatient and quick to anger. These changes in
emotional behavior were the first to suggest that the
prefrontal cortex is important for establishing appro-
priate emotional behavior.
The prefrontal cortex is thought to influence emo-
tion by recognizing the emotional and motivational
saliency of stimuli. In particular, the orbitofrontal
region of the prefrontal cortex has been suggested to
work in concert with the amygdala to learn and rep-
resent associations between new stimuli and primary
or innate reinforcers such as food, drink and sex [13].
It has been proposed that the prefrontal cortex is
important for changing the reward value attached to
learned stimuli, and thereby altering associated
behavioral responses to these stimuli [43]. The ven-
tromedial prefrontal cortex has been suggested to
process the code of somatic markers important in
decision processing, as described by Damasio (see
24.1.6.1). In support of this, Damasio et al. [14]
described a patient with damage to the ventromedial
prefrontal cortex who had difficulties when the appli-
cation of subtle emotional values to multiple stimuli,
and not logical reasoning alone, were required to
make appropriate decisions. The involvement of the
ventromedial prefrontal cortex in the development of
somatic markers was further confirmed in studies
with patients with ventromedial prefrontal cortex
damage performing a card-sorting task. In this task,
patients and control subjects were asked to play a
card game in which they could win or lose a cash
amount. Participants were allowed to choose 100
cards from any of 4 decks, but were not told how
many cards they will be allowed to select ahead of
time. Two of the decks contained cards that gave
large rewards, but also large losses, while two of the
decks gave smaller rewards, but smaller losses. In the
long-term these latter two decks were advantageous.
Thus, to win this task it was required that immediate
rewards were ignored in order for delayed rewards to
be provided. Control subjects performed this task
based on intuitive decisions, and were unaware of
any particular strategy. However, skin conductance
response was increased in anticipation of poor
choices within the game. In contrast, patients with
ventromedial prefrontal cortex lesions performed
poorly in the task, and did not exhibit enhanced skin
conductance response in anticipation of poor deci-
sions. This suggests that while control subjects devel-
oped somatic markers enabling appropriate
531
decision-making, patients lacking ventromedial pre-
frontal cortex were unable to do this.
24.2.3 The Anterior Cingulate Cortex
First suggested to be involved in conscious emotional
experience by Papez, the current concept of the ante-
rior cingulate cortex is that it is divided into a dorsal
cognitive subdivision, and a rostral, ventral affective
subdivision [13]. The anterior cingulate cortex is
thought to incorporate visceral, attentional, and emo-
tional information and be a key brain area involved in
the top-down regulation of emotion. The current
hypothesis is that the anterior cingulate cortex moni-
tors for any differences between the ongoing functional
state of the organism and new incoming information
with emotional or motivational importance. If a conflict
between the current state and additional information is
identified, then information concerning this discrep-
ancy is projected to areas of the prefrontal cortex,
within which appropriate response options are weighed
(see Sect. 24.2.2 on prefrontal cortex above).
The anterior cingulate cortex is activated by a vari-
ety of emotional stimuli, as demonstrated by human
imaging studies. In particular, the anterior cingulate
cortex has been implicated in emotional tasks requir-
ing a cognitive aspect, and in emotional recall or imag-
ery. For example, increased neuronal responses to
increasing intensity of angry facial expression in the
anterior cingulate cortex have been observed.
24.2.4 The Hypothalamus
The role of the hypothalamus in emotional response
was first clearly suggested by Walter Hess’ experiments
in the 1920s [13]. Hess implanted electrodes into the
hypothalamus of cats and demonstrated that electrical
stimulation in one part of the hypothalamus results in
an “affective defense reaction”. This defense reaction
included increased heart rate, heightened levels of alert-
ness, and enhanced likelihood to attack. In the 1950s,
James Olds and Peter Milner performed similar electri-
cal stimulation studies in rats [13]. Here, the hypothala-
mus was observed to be involved in the processing of
reward signals, such that a rat continues to press a lever
to deliver an electrical self-stimulation to the hypothal-
amus. The drive to perform such behavior is so strong
532
Fig. 24.5 The hypothalamic-pituitary-adrenal axis. On acti-
vation of the stress response, corticotrophin-releasing hormone
(CRH) and arginine vasopressin (AVP) are released from the
medial parvocellular region of the paraventricular nucleus of the
hypothalamus. This leads to the release of adrenocortropic hor-
mone (ACTH) from the pituitary gland, which in turn, leads to
the production of glucocorticoids by the adrenal cortex. Binding
of glucorticoids to the glucocorticoid receptor (GR) and the min-
eralocorticoid receptor (MR) regulate the responsiveness of the
HPA axis to stressful stimuli by regulating ACTH and CRH
release. Following withdrawal of the stressor, feedback loops
from the adrenal gland to the hypothalamus, hippocampus, and
frontal cortex shut down the HPA axis and returns it to baseline
activity. The amygdala initiates the stress response by activating
the HPA axis (Modified from Lupien et al. [35] with
permission)
that a rat will self-stimulate continuously for 75 % of
the time, up to 4 h/day. Robert G. Heath further demon-
strated the role of the hypothalamus in reward signal-
ing by observing self-stimulation of the hypothalamus
through electrodes in humans. The hypothalamus, along
T.B. Franklin and I.M. Mansuy
with the prefrontal cortex, amygdala, and ventral stria-
tum, has now been identified as a key region in the
reward pathway in the brain. It has also been observed
to be involved in the motivation for basic behaviors like
sex and food-seeking (see Sect. 24.6).
24.3 Stress
The subjective state of perceiving adverse changes in
the environment, whether potential or actual, is termed
“stress” [26]. It is a precipitating factor for the devel-
opment of psychiatric disorders like depression and
anxiety disorders. In addition to stress, genetic varia-
tion may also predispose individuals to mental illness.
Stressful stimuli cause the brain to activate several
stress mediators, including neurotransmitters, pep-
tides, and steroid hormones. The following is a discus-
sion of the mechanisms associated with and underlying
the processing of stressful stimuli.
24.3.1 The Hypothalamic-Pituitary-
Adrenal Axis
One of the main systems activated when perceiving a
stressor is the hypothalamic-pituitary-adrenal (HPA)
axis, which regulates the hormonal aspects of the stress
response [16, 35]. Activation of this axis results in the
release of glucocorticoids from the adrenal gland
through several steps (Fig. 24.5). On activation of the
stress response, neurons in the medial parvocellular
region of the paraventricular nucleus of the hypothala-
mus release corticotropin-releasing hormone (CRH, also
known as corticotropin-releasing factor, CRF) and argin-
ine vasopressin (AVP) into the portal vessel system,
which activates the synthesis of pro-opiomelanocortin
(POMC) in the anterior pituitary. POMC is then pro-
cessed into adrenocorticotropic hormone (ACTH), and
opioid and melanocortin peptides. ACTH released from
the pituitary gland in turn stimulates the release of gluco-
corticoids (cortisol in humans, and corticosterone in
humans, rats, and mice) from the adrenal cortex.
Additionally, the adrenal medulla releases catecholamines
(adrenaline and noradrenaline). These hormones can
produce multiple effects including increased blood
pressure and heart rate, reduced digestive capacity, and
discharge of stored energy to facilitate muscle use.
The amygdala can act directly to activate the stress
response. This is thought to be predominantly due to
disinhibition of the PVN as a result of sequential GABA
24 The Neural Bases of Emotions
synapses (GABAergic neurons in the amygdala pro-
jecting to GABAergic neurons in PVN-projecting brain
areas). The HPA axis is also under negative feedback
control. On removal of the stressful stimulus, the HPA
axis returns to baseline via several negative feedback
loops. Circulating glucocorticoids negatively regulate
ACTH and CRH release by binding glucocorticoid
receptors (GRs) and mineralocorticoid receptors (MRs)
in several brain areas including the hippocampus, the
prefrontal cortex, and the hypothalamus. This occurs as
a result of direct inhibitory influence on the hypothala-
mus, and indirect inhibitory influence of the hippocam-
pus and prefrontal cortex as a result of excitation of
inhibitory PVN-projecting brain areas. Thus, effective
stress coping occurs when the stress response is acti-
vated on exposure to a stressful stimulus, but is quickly
turned off on removal of the stimulus. An alteration of
these circuits leading to an inadequate stress response,
or an extreme or prolonged response to stressful stimuli
is thought to underlie most stress-related mental disor-
ders, such as depression or anxiety disorders.
GRs are activated by cortisol, corticosterone, and
other glucocorticoids, and are expressed ubiquitously
throughout the body, with very high expression levels in
stress-related brain regions. MRs are activated by aldos-
terone, deoxycorticosterone, as well as glucocorticoids
and progestins, and are predominantly located in limbic
structures, including the hippocampus, amygdala, and
prefrontal cortex. When homo- or heterodimeric, these
receptors act as transcriptional regulators by interacting
with glucocorticoid response elements (GREs), and
recruiting corepressors or coactivators, thereby mediat-
ing the responsiveness of the system [16]. GR mono-
mers interact with stress-induced transcription factors
(TFs), such as nuclear factor-kB (NF-kB) and activator
protein 1 (AP1) to reduce transcriptional activity.
Perhaps due to the importance of appropriate corti-
costerone signaling, many different mechanisms exist
to mediate its availability. In the blood, corticosteroid-
binding globulin can act as a sink to bind corticoster-
one, making it unavailable as a signaling molecule
[16]. Additionally, the multidrug resistance (MDR)
P-glycoprotein, a protein present in the blood–brain
barrier (BBB), reduces the levels of glucocorticoids
entering into the brain. As well, factors like heat shock
proteins, can bind corticosterone to form a multimeric
receptor-protein complex, consequently changing the
conformation of the receptor. Steroid metabolism is
another important factor in mediating corticosteroid
signaling, for instance by converting the bioactive cor-
tisol to its inactive metabolite, 11-dehydrocortisol
533
(cortisone), or in contrast, by regenerating bioactive
cortisol in the brain. Signaling is further regulated by
interaction of GRs with transcription factors, and inter-
actions of MRs and GRs with coregulators, which can
act to repress or activate gene transcription [16].
24.3.2 The Binary Organization
of the Stress System
The stress system is binary in nature. It consists of a
fast response, involving the CRH-dependent sympa-
thetic fight-flight response, and a slow response
associated with adaptation and recovery, involving
the urocortin-dependent parasympathetic response
(Fig. 24.6) [16]. The sympathetic system is mediated
through CRHR1 activation, while the parasympa-
thetic system depends on CRHR2 activation.
Transgenic mice deficient in CRHR1 are less anxious
and display an impaired stress response, while mice
deficient in CRHR2 display increased anxiety, and a
more rapid stress response. However, pharmacological
studies administering either CRHR2 agonists or
antagonists into specific brain areas have suggested
that CRHR2 may have both an anxiolytic and anxio-
genic role [5].
Both CRHR1 and CRHR2 are seven-transmem-
brane G protein-coupled receptors, which signal
mainly by coupling to Gs, thereby activating adenylyl
cyclase and protein kinase A [5]. There are four known
ligands for CRHR1 and CRHR2: CRF, urocortin I,
urocortin II, also known as stresscopin-related peptide,
and urocortin III, also known as stresscopin. CRH has
a much higher affinity for CRHR1 than CRHR2, uro-
cortin I has equal affinity for both receptors, and uro-
cortin II and III appear to be selective for CRHR2.
CRHR1 is widely expressed throughout the brain with
high levels in the cerebral cortex, cerebellum,
amygdala, hippocampus, and olfactory bulb [51].
CRHR2 appears to be more discretely expressed in the
brain, with highest expression in the striatum (lateral
septal nucleus), pallidum (bed nucleus of stria termi-
nalis), ventromedial hypothalamus, olfactory bulb, and
midbrain raphe nuclei.
The binary nature of the stress response can also be
illustrated by the theorized role of GRs and MRs. The
GR:MR balance hypothesis is linked to the recent
discovery of membrane MRs. Corticosterone binds to
nuclear MRs with a ten-fold higher affinity than to
GRs. However, membrane MRs have a much lower
affinity for corticosterone than nuclear MRs. Therefore,
534
Fig. 24.6 Phases following exposure to a stressor. Both fast
nongenomic and slow genomic actions are required for encod-
ing the emotional experience, behavioral adaptation, and prepa-
ration for future events, in response to stressful stimuli. On
activation of the HPA response by a stressor, corticosterone lev-
els rise. Increased levels of corticosterone can result in nonge-
nomic actions on the excitability and activation of neurons that
can enhance the action of the initial stress mediators. In order to
prevent stress reactions from overshooting, gene-mediated path-
ways are activated that lessen the initial stress response.
Structural and functional changes promoting homeostatic recov-
ery, replenishment of depleted energy resources, and emotional
memory also occur (Reproduced from de Kloet et al. [17] with
permission)
GRs and membrane MRs are only occupied at pulsa-
tile peaks of basal corticosteroid secretion resulting
from stressful conditions. Thus, while nuclear MRs
can regulate gene expression, resulting in slow and
persistent changes in the conductance of the plasma
membrane, membrane MRs can have rapid effects on
the cell. They promote presynaptic glutamate release,
and thereby increase both pre- and postsynaptic excit-
atory transmission (see Chap. 8). Thus, low-affinity
membrane MRs are thought to increase excitability
and facilitate a fast corticosteroid feed-forward
response, thereby enhancing attention, vigilance, and
risk-assessment responses. Nongenomic and genomic
actions of GRs subsequently stop the initial stress reac-
tion by suppressing the enhancement in excitability.
Activation of GRs is suggested to promote mecha-
nisms that prepare for future situations by not only
facilitating recovery from the stress reaction, but also
promoting memory storage, and mobilizing energy
stores.
T.B. Franklin and I.M. Mansuy
24.3.3 The Effects of Chronic Stress
Chronic stress has detrimental consequences on the
brain and can severely alter neuronal structures, but
differently depending on the brain structure. It has
region-specific effects on dendritic organization in the
CA3 subregion of the hippocampus, prefrontal cortex,
and amygdala [52]. Animals exposed to chronic stress
have decreased dendritic branching, shorter CA3 pyra-
midal apical dendrites, and fewer synaptic contacts on
these neurons. Similarly, chronic corticosterone admin-
istration or chronic stress results in decreased dendritic
length and spine density in the layer II/III neurons of
the prefrontal cortex. In the prefrontal cortex, mush-
room-shaped spines, thought to be important in the
establishment of synaptic connections, are most sus-
ceptible to the effects of chronic stress. Contrary to
effects seen in the hippocampus and prefrontal cortex,
chronic immobilization stress increases dendritic
arborization, spine formation, and synaptic connectiv-
ity in the basolateral amygdala [52], but not in the cen-
tral nucleus. While both, acute and chronic stress
increase spine density in basolateral amygdala, only
chronic stress increases dendritic arborization. A period
without stress reverses the stress-induced atrophy of
hippocampal and prefrontal cortex neurons but fails to
reverse the hypertrophy of pyramidal neurons in the
amygdala [12, 40, 53].
Both chronic overexposure to stress hormones and
chronic stress treatments also have a negative impact
on cell proliferation and neurogenesis in the adult
brain. Overexposure to corticosteroids reduces the
proliferation and survival of progenitor cells in the
subgranular zone of the dentate gyrus. However, this
effect is not permanent, and the reduction in progenitor
cell proliferation and survival is partially corrected
after several weeks of recovery. Two models that paral-
lel high levels of corticosteroids and reliably induce
depression-like behaviors in rodents are unpredictable
chronic mild stress and chronic social defeat stress.
Both models also affect neurogenesis and prolifera-
tion; chronic mild stress reduces survival of new brain
cells in the hippocampus and subventricular zone, and
chronic social defeat stress reduces cell proliferation in
the medial prefrontal cortex and neurogenesis in the
dentate gyrus. Additionally, chronic, but not acute,
restraint stress reduces neurogenesis in both the den-
tate gyrus and the dorsal vagal complex, an integrative
area of the brainstem that relays the autonomic neural
24 The Neural Bases of Emotions
responses to stress. Interestingly, both antidepressant
administration and treatment with CRH or vasopressin
antagonists can prevent the reduction in proliferation
of progenitor cells induced by chronic exposure to
high levels of corticosteroid or exposure to a chronic
stress situation. Thus, the deficit in neurogenesis result-
ing from chronic stress conditions is not irreversible
further emphasizing the ability of the hippocampus to
be plastic even in the adult.
24.4 Disorders of Emotional State:
Depression and Anxiety Disorders
Mental illnesses can be classified into thought disorders,
which result from a disturbance in cognitive functions, or
mood disorders, reflecting a perturbed emotional state
[29]. While normal emotional responses such as eupho-
ria, depression, and anxiety can have a beneficial outcome
for an individual, these emotions can be persistently dis-
ordered, thereby developing into a disease state.
24.4.1 Depression
Depression is a common chronic mental disease affect-
ing approximately 5 % of the U.S. population [49]. It
is very difficult to treat, and currently only half of
depressed patients show complete remission. Presently,
depression can be classified into two main types: uni-
polar and bipolar. Unipolar depression is character-
ized by dysphoria (a state of feeling discontent or
unhappy) most of the day, the inability to experience
pleasure (anhedonia), and reduced motivation [4].
Additionally, at least three of the following symptoms
are also present: disturbed sleep, diminished appetite
and weight loss, decreased energy, decreased sex drive,
restlessness, reduced speed of thoughts and actions,
difficulty concentrating, indecisiveness, feelings of
worthlessness, guilt, pessimistic thoughts, and thoughts
about dying and suicide. An episode of depression
typically lasts 4–12 months if untreated.
Bipolar depression occurs in patients who demon-
strate both depressive and manic episodes. About a
quarter of all patients with major depression will
experience a manic episode at some point [2].
Depressive episodes in patients with bipolar disorder
are similar to that seen in unipolar depression. The
manic episodes are characterized by a heightened or
535
irritable mood lasting for a minimum of 1 week,
expressed with a combination of the following symp-
toms: hyperactivity, over-talkativeness, social intru-
siveness, increased energy and libido, flight of ideas,
grandiosity, distractibility, reduced need for sleep, and
reckless spending [4]. Delusions and hallucinations
are also observed in patients with severe cases.
Both post-mortem and neuroimaging studies have
reported decreased gray-matter volume, small cell
bodies, and glial density in the prefrontal cortex and
hippocampus in depressed patients compared to con-
trol subjects [24, 30]. These brain regions are critical
because they are thought to be involved in cognitive
aspects of depression, including feelings of worthless-
ness and guilt. However, due to comorbid diagnoses
and medication history of patients, their involvement
has been difficult to prove, and obvious cause-effect
relationship between the pathology and the diagnosis
of depression is difficult to observe.
Functional studies using fMRI or PET have also
demonstrated that depressed patients have chronically
increased activity in the amygdala, a brain area where
transient sadness results in increased activation in
healthy subjects, and chronically decreased activity in
the cingulate cortex. Following successful treatment of
depression, normal activity in these brain regions was
restored. Additionally, deep brain stimulation of the
cingulate cortex (implantation of a device that sends
electrical impulses to proximal brain areas) was suc-
cessfully used to treat depressive symptoms in a
selected cohort of treatment-resistant patients. It also
successfully ameliorated depressive symptoms when
applied to the nucleus accumbens, a subregion of the
striatum important in the reward pathway and thought
to be responsible for anhedonic behaviors often exhib-
ited by depressed patients.
Although the neurobiological basis of depression is
still not fully understood, two hypotheses have been
proposed: a monoamine hypothesis and a neurotrophin
hypothesis [30]. The monoamine hypothesis is based
on early findings that two drugs developed for unre-
lated conditions, iproniazid and imipramine, have anti-
depressant effects in humans. Both drugs were also
shown to enhance neurotransmission of the monoam-
ines serotonin or noradrenaline. More selective agents
have now been designed to increase monoamine trans-
mission, through two main mechanisms: inhibiting
neuronal uptake of a monoamine (e.g., selective sero-
tonin reuptake inhibitors (SSRIs)) or inhibiting the
536
breakdown of monoamines (e.g., monoamine oxidase
inhibitors (MAOIs)). While SSRIs and MAOIs have
immediate effects on neurotransmission, their antide-
pressant properties are not observed until several
weeks of treatment. It is therefore now hypothesized
that antidepressant medications initially increase the
level of synaptic monoamines, then induce secondary
effects. These secondary effects are thought to take
time to develop, because they involve transcriptional
and translational changes.
The neurotrophin hypothesis emerged from evi-
dence that brain regions involved in emotional pro-
cessing often have decreased volume in depressed
patients compared to healthy controls [30]. However,
imaging studies of depressed patients have shown that
such reduction in volume can be reversed at least in the
hippocampus, by antidepressant treatment. The mech-
anisms underlying such reduction are suggested to
involve an alteration in the level of neurotrophic fac-
tors, a group of proteins known as growth factors
involved in synaptic plasticity in the adult brain. Much
of the research has focused on brain-derived neu-
rotrophic factor (BDNF), a neurotrophin highly
expressed in adult brain areas involved in emotional
processing. BDNF-mediated signaling is reduced by
stress in the hippocampus, but increased by antidepres-
sant treatment [30]. Additionally, lower BDNF expres-
sion has been observed in the brain of depressed
patients post-mortem. Because neurotrophins such as
BDNF are involved in adult neurogenesis, it was theo-
rized that their reduction in depressed patients could
contribute to reduced hippocampal volume by altering
neurogenesis. Thus, in the neurotrophin hypothesis the
mechanism of action of some antidepressants is postu-
lated to be increased neurotrophin signaling and neu-
rogenesis in depressed patients.
Because current antidepressants have a slow onset
of action and patients have a high rate of remission,
new targets for the pharmacological treatment of
depression have been sought. Recently, a subset of
depression that is associated with weight gain, has
suggested a link between pathways involved in mood
and those involved in feeding and metabolism. One of
these pathways involves melanin-concentrating hor-
mone (MCH), a hormone secreted from neurons pro-
jecting from the lateral hypothalamus to several brain
regions involved in emotion and motivation [30].
Antidepressant-like effects have been demonstrated by
decreasing MCH-mediated signaling either globally or
T.B. Franklin and I.M. Mansuy
locally within the nucleus accumbens. Additionally,
orexin and ghrelin, two peptides known to promote
food intake, have been proposed to have an antidepres-
sant effect, particularly during periods of caloric
restriction [30]. Thus, the interaction between meta-
bolic pathways and depression may provide new tar-
gets for antidepressant medication.
Another mechanism potentially underlying the
slow onset of treatment and amelioration of symp-
toms is epigenetic dysregulation. Posttranslational
modifications (PTMs) of histone proteins and DNA
methylation, mechanisms known to modulate gene
transcription, have been suggested as targets of anti-
depressant treatment. Recent studies in animals have
examined the link between histone PTMs and depres-
sion using the chronic social defeat model. Chronic
social defeat is a rodent model of chronic stress that
induces behavioral abnormalities that can be reversed
by chronic, but not acute antidepressant treatment. In
mice, chronic social defeat alters gene expression and
histone (H) methylation. It decreases the expression of
two splice variants of BDNF (BDNF III and BDNF IV)
in the hippocampus, and the dimethylation of H3
lysine (K) 27, a mark of transcriptional repression
(Fig. 24.7). The behavioral abnormalities induced by
chronic social defeat can be reversed by chronic anti-
depressant treatment, but H3K27 dimethylation is not
affected. However, two marks of transcriptional activa-
tion, H3 acetylation and H3K4 methylation, increase
at the same promoters after antidepressant treatment,
suggesting a potential mechanism for the action of
chronic antidepressant treatment.
DNA methylation has also been shown to be a target
of antidepressant treatment. Chronic treatment
increases methyl CpG binding protein 2 (MeCP2) and
methyl binding domain protein 1 (MBD1), two pro-
teins that bind methylated CpG dinucleotides and act
as either transcriptional activators or repressors in the
rodent brain. The increase in MeCP2 is specific to
g-aminobutyric acid (GABA)ergic interneurons, which
is particularly significant because altered GABAergic
transmission has been linked to major depression and
suicide. Further, depressed patients who committed
suicide have higher levels of methylation in the
GABA-A a1 receptor subunit promoter in the prefrontal
cortex when compared to control individuals who died
of other causes. Thus, antidepressant treatments may
specifically target factors affecting epigenetic
modifications in cell types important in depression.
24 The Neural Bases of Emotions
24.4.2 Anxiety Disorders
Anxiety disorders are extremely common in the gen-
eral population, and their lifetime prevalence is cur-
rently almost 30 % [46]. Anxiety disorders thus
represent a significant problem for our communities.
They are characterized by excessive fear, and are
expressed by avoidance of situations, people, or objects
that are usually no threat to the individual. These dis-
orders have been investigated in several functional
neuroimaging studies, which are summarized in
Table 24.1.
24.4.2.1 Specific Phobias
Specific phobia is a relatively common disorder, with a
lifetime prevalence of 7–11 % [46]. Patients with
specific phobia have excessive and persistent fear and
avoidance of specific situations or objects such as
flying, small animals, enclosed places, or height. These
situations or objects cause marked distress and deficits
in social, occupational, and academic performance.
Anatomically, specific phobias are associated with the
amygdala and insular cortex. Increased responses in
the amygdala, and enhanced functional connectivity
between the right amygdala and periamygdaloid area,
fusiform gyrus and motor cortex has been observed
when patients were presented with images of the pho-
bia. Such images also result in decreased activity in the
prefrontal, orbitofrontal, and ventromedial cortex. This
suggests that phobic reactions deactivate areas of the
prefrontal cortex which are involved in top-down con-
trol over emotion-related areas like the amygdala,
which results in preparation of motor responsiveness
for fight-or-flight behaviors. Increased activation of
the prefrontal, insular, and posterior cingulate cortex
on presentation of phobia-related versus phobia-
unrelated words was also observed in patients with
specific phobia compared to control subjects.
24.4.2.2 Social Anxiety Disorder
Similar to specific phobia, patients with social anxiety
disorder, also known as social phobia, have a marked
and persistent fear of social situations or performance
that involve the judgement of others [46]. This fear of
embarrassment causes significant distress and deficits
in social, occupational, and academic performance.
Patients with social anxiety disorder display a recogni-
tion bias towards negative voices; they are better at
identifying sad or fearful prosodies, but show impair-
537
a
b
c
Fig. 24.7 The role of posttranslational histone modifications
in a rodent model of depression. (a) Under basal conditions,
the promoter region of the BDNF gene has moderate levels of
H3 acetylation and H3K27 dimethylation, and is bound by the
histone deacetylase HDAC5. (b) Following chronic social defeat
stress, H3K27 dimethylation is increased. This results in
increased condensation of the BDNF promoter, which leads
to decreased BDNF gene expression. (c) Following chronic
antidepressant (imipramine) treatment, HDAC5 levels are
reduced, which leads to increased H3 acetylation. However,
H3K27 dimethylation is not changed. Despite this, the increase
in H3 acetylation is sufficient to reinstate normal levels of BDNF
gene expression. A acetyl, BDNF brain-derived neurotrophic
factor, H histone, HDAC histone deacetylase, K lysine, M methyl
(Reproduced from Tsankova et al. [49] with permission)
ments in identifying happy prosodies versus control
subjects.
Increased amygdalar response in patients with
social anxiety disorder is observed during and in antic-
ipation of public speaking, and on presentation of neg-
ative comments or emotional facial expressions. This
exaggerated amygdalar response during public speak-
ing is decreased in patients successfully treated for
social phobia. Similarly, the insular cortex displays
heightened activation in response to emotional facial
expressions, and in anticipation of public speaking in
patients with social anxiety disorder [34].
There are conflicting reports about the role of the
dorsal and anterior cingulate cortex in social anxiety
disorder. Increased rostral anterior cingulate cortex
activation was elicited by facial expressions of fear and
disgust in patients with social anxiety disorder.
Additionally, orbitofrontal cortex activation increases
538 T.B. Franklin and I.M. Mansuy

Table 24.1 Summary of Amygdala rACC dACC Hippocampus Insular cortex

altered activity in functional
Posttraumatic stress ↑ ↓ ↑* ↑↓ ↑↓
neuroimaging studies
disorder
of anxiety disorders.
Panic disorder ↑↓* ↑* – ↑↓ –
Social phobia ↑ ↑↓* ↑↓ – ↑
Specific phobia ↑ ↑↓* ↑ – ↑
Generalized anxiety ↑↓* ↑* ↑* – –
disorder
Reproduced with permission from Shin and Liberzon [46]
rACC rostral anterior cingulated cortex, dACC dorsal anterior cingulated cortex
↑ increased function in the disorder (relative to control groups)
↓ decreased function in the disorder (relative to control groups)
↑↓ mixed findings
* based on a very small number of studies
– too little information available

on presentation of angry versus neutral voices.
However, decreased activation on provocation by a
social anxiety-inducing stimulus [50], and decreased
rate of glucose metabolism were demonstrated in the
ventromedial prefrontal cortex of patients with social
anxiety disorder. Increased dorsal anterior cingulate
activation has been demonstrated as a result of nega-
tive comments and harsh or disgusted facial expres-
sions. In contrast, decreased dorsal anterior cingulate
cortex activation has been reported in response to
angry faces, in anticipation of public speaking, and
decreased glucose metabolism has been demonstrated
in patients with social anxiety disorder [20]. Thus, the
role of the cingulate cortex in social anxiety disorder
still requires further clarification.
Social anxiety disorder has been associated with
abnormal serotonergic and dopaminergic signaling.
Patients with social anxiety disorder display reduced
serotonin 1a receptor binding in the amygdala and
insular cortex. Additionally, reduced D2 receptor (a
dopamine receptor) binding and dopamine transporter
densities have been found in the striatum of patients
with social anxiety disorder, although one study has
failed to replicate this.
24.4.2.3 Panic Disorder
Patients with panic disorder experience unexpected
panic attacks, accompanied by a persistent worry about
having future attacks or concern for the implications of
the attacks [46]. These panic attacks recur over a period
of at least several months. Panic attacks themselves
tend to be brief periods of terror (usually 10–15 min but
lasting up to an hour in rare circumstances) during
occasions which should not normally induce a fear
response or, additionally, during times of social stress
when the patients feel as if they were the focus of atten-
tion. A key feature of panic disorder is that panic attacks
are unexpected and unpredictable. Panic attacks are
accompanied by overactivation of the sympathetic ner-
vous system, and result in increased heart rate, short-
ness of breath, dizziness, and chest pain. Panic disorders
are often first diagnosed during adolescence.
Panic disorder has been associated with enhanced
sensitivity of brain structures involved in fear pathways,
including the amygdala, hippocampus, thalamus, and
brain stem [46]. Additionally, failure of the frontal cor-
tex to provide inhibitory input to the amygdala, thereby
enhancing amygdalar output, has been suggested as an
underlying mechanism. Increased gray matter volume
in the midbrain and pons and reduced serotonin trans-
porter and receptor binding, have been observed in
patients with panic disorder [22]. The periaqueductal
gray (PAG) is a key midbrain structure involved in the
defensive reaction that is also affected. Both electrical
and chemical stimulations of the PAG cause behavioral
reactions including freezing, fight or flight, similar to
responses elicited by a proximal threat, such as a preda-
tor. Thus, it has been suggested that structural changes
and alterations in serotonergic signaling in the PAG are
a key component in the neurobiology of panic disorder.
24.4.2.4 Generalized Anxiety Disorder
Generalized anxiety disorder (GAD) is characterized by
uncontrollable and excessive anxiety and worry [4].
Symptoms of GAD include restlessness, fatigue, irrita-
bility, muscle tension, and sleep and concentration
difficulties. The lifetime occurrence rate for GAD is
approximately 5 % [3]. It is rare in children and adoles-
24 The Neural Bases of Emotions 539

cents and, in contrast to the majority of anxiety disor-

ders, it is unlikely to occur prior to the age of 25 years
old. However, it is twice as likely to occur in women
than men, and is increasingly likely as women age; in
women over 45, the incidence rate is approximately
10 %, while in men it remains at approximately 3–4 %.
GAD has not been well studied up to this point, per-
haps due to its relatively new classification; it was first
classified as a distinct disorder in 1980 and was fully
considered independent from panic disorder in 1994
[3]. Currently, both the amygdala and medial prefron-
tal cortex have been suggested to play a role in GAD
by neuroimaging studies in human patients [46].
Patients with GAD display enhanced amygdalar and
prefrontal activation in response to fearful and angry
facial expressions, and enhanced amygdalar activation
in anticipation of aversive photographs. Amygdala
activation has also been positively correlated with
GAD symptom severity. At present, such neuroimag-
ing studies have been limited and it is still unclear
exactly to what extent these structures contribute to the
pathophysiology of GAD.

24.4.2.5 Posttraumatic Stress Disorder
Posttraumatic stress disorder (PTSD) occurs as a conse-
quence of a stressful or traumatic event, making it one
of the few mental illnesses that require a stressor for its
occurrence [4]. In order for PTSD to be diagnosed, a
traumatic event, defined as actual or threatened death
or serious injury, or a threat to the physical integrity
of self or others, must occur, followed by intense fear,
helplessness, or horror. Following this, the traumatic
event is persistently reexperienced, and there is contin-
uous avoidance of stimuli associated with the trauma.
Traumatic events include combat situations experienced
by soldiers, childhood abuse, rape, assault, and serious
accidents. However, while the large majority of indi-
viduals are exposed to a traumatic event in their life-
time, only a minority of individuals are unable to cope
with the stressor, and exhibit prolonged, abnormal
behavioral and bodily responses due to the traumatic
experience; approximately 7–12 % of the U.S. popula-
tion will develop PTSD.
Dysregulation of the HPA axis has been implicated
in the neurobiological mechanism underlying this dis-
order. A hallmark endocrinological marker of PTSD is
hypocortisolism, distinguishing it endocrinologically
from depression, a comorbid but distinct disorder. The
neuroendocrinology suggests that patients with PTSD
Fig. 24.8 Direct and indirect pathways within cortico-basal-
ganglia-thalamo-cortical loops. The direct (excitatory) path-
way (green) leads from the cortex to the striatum, then to the
internal segment of the globus pallidus (GPi), and substantia
nigra pars reticulata (SNr), to the thalamus, and back to the cor-
tex. The direct pathway, referred to as a positive feedback loop,
contains two inhibitory GABAergic connections (filled circles)
making its net effect from the cortex back to the cortex excit-
atory. The indirect (inhibitory) pathway (red), a negative feed-
back loop, leads from the cortex to the striatum, to the external
segment of the globus pallidus (GPe), the subthalamic nucleus,
the GPi/SNr, the thalamus, then back to the cortex. It contains
three inhibitory GABAergic connections, making its net effect
from the cortex back to the cortex inhibitory. Excitatory connec-
tions are represented by arrows and inhibitory GABAergic con-
nections are represented by filled circles
have increased sensitivity of the HPA axis to negative
glucocorticoid feedback, as a result of increased GR
binding and function. Additionally, in PTSD patients,
there is a downregulation of pituitary CRF receptors
that result in a blunted ACTH response to CRF stimu-
lation. The downregulation of pituitary CRF receptors
is the result of increased hypothalamic CRF activity
resulting from increased CRF concentrations, found
present in cerebrospinal fluid of PTSD patients. PTSD
patients also have structural changes in the brain,
including reduced hippocampal volume similar to that
540
seen in depressed patients. Thus, PTSD is thought to
result in hypersensitivity of the HPA axis to stressful
stimuli. Several polymorphisms have been identified
as possible risk factors for the development of PTSD,
including a genetic variation of the glucocorticoid
receptor cochaperone FKBP5 that reduces the risk of
developing PTSD in the case of childhood abuse, but
not in adulthood trauma. Hypocortisolism is suggested
to be a preexisting risk factor for the development of
PTSD, as low cortisol levels at the time of exposure to
a particular trauma predicts the development of PTSD.
This is supported by studies demonstrating that hydro-
cortisone treatment immediately following exposure to
a psychological trauma can effectively treat PTSD.
24.4.2.6 Obsessive-Compulsive Disorder
Obsessive-compulsive disorder (OCD) is a condition
characterized by recurrent obsessions and compulsions
[4]. Obsessions are persistent, inappropriate, and intru-
sive thoughts, impulses, or images that cause anxiety
and distress. To reduce this anxiety or distress, patients
do repetitive behaviors or mental acts termed compul-
sions. These compulsions are excessive, inflexible, and
are not realistically linked with the obsessions they are
intended to prevent or counteract (i.e., neutralizing an
obsession of germs by counting). The most common
compulsions are cleaning and decontamination rituals,
checking, counting, repeating actions, ordering, hoard-
ing, confessing, and praying. Diagnosis of OCD occurs
when obsessions or compulsions cause evident distress,
consume more than 1 h/day for a month or more, or
significantly interferes with life’s normal routines.
Symptoms of OCD include fears of contamination,
worries about harm to self or others, the need for sym-
metry or order, and religious preoccupations.
OCD has a bimodal distribution and can thus be dif-
ferentiated as childhood-onset and adult-onset. It is
one of the most common psychiatric disorders
affecting children and adolescents with an average
age of onset of pediatric OCD at 7.5–12.5 years of age.
In adults the age of onset generally occurs between 22
and 35 years of age. Childhood-onset OCD differs
from adult-onset OCD, in that it is more familial and is
also more highly associated with tic disorders.
Additionally, OCD with a prepubertal onset is more
likely to affect males with a ratio of 3:2, but this pre-
dominance in males is no longer present in adoles-
cence. OCD affects 1–4 % of children and adolescents
and 1–3 % of adults. Approximately 40 % of patients
T.B. Franklin and I.M. Mansuy
with OCD onset during childhood still struggle with
OCD in adulthood.
The neurobiological basis of OCD has yet to be eluci-
dated. However, neuroimaging studies have consistently
identified hyperactivity of the orbitofrontal cortex, ante-
rior cingulate cortex, and the head of the caudate nucleus
in patients that have not been treated for OCD, that is not
present in OCD patients who have received treatment.
OCD has been hypothesized to be the result of an imbal-
ance between the “direct” and “indirect” pathways through
the basal ganglia (Fig. 24.8). The “direct” pathway is
excitatory and the “indirect” pathway is inhibitory. These
opposing pathways are thought to be involved in both
OCD, and in hyperkinetic and hypokinetic movement dis-
orders. In movement disorders, it has been hypothesized
that when the balance between these two pathways shifts
towards “excitatory”, cortical motor programs are disin-
hibited resulting in hyperkinetic symptoms, such as is
observed in Huntington’s disease. When the balance shifts
to the indirect pathway this inhibits cortical motor pro-
grams, resulting in hypokinetic symptoms, such as is
observed in Parkinson’s disease. While these symptoms
are motor related, it has been suggested that imbalance in
these two pathways in nonmotor loops may result in OCD.
Increased relative activity in the direct pathway in the
OFC/ACC loops may result in a positive feedback loop
that results in obsessive thoughts becoming “trapped”.
This is consistent with findings that the symptoms of
obsessive-compulsive disorder are greater in patients with
Huntington’s disease than in the regular population.
24.4.3 Stress Is a Precipitating Factor
for Mental Illness
An adverse early environment, or traumatic events
occurring during early development, may alter devel-
opmental pathways in such a way that it predisposes
the individual to abnormal stress responses and stress
coping in later life. Increased vulnerability to stress
and other forms of pathological stress-coping behav-
iors is strongly influenced by early life experiences
during both pre- and postnatal periods.
Both acute and chronic exposure to stress or gluco-
corticoids during pregnancy increase maternal
glucocorticoid secretion [35]. Since the placenta allows
a certain proportion of these glucocorticoids to pass
through to the fetus, this results in increased fetal HPA
axis activity and altered fetal brain development. This
24 The Neural Bases of Emotions 541

increase in HPA activity is persistent into adulthood in a b

rodents. Additionally, prenatal stress results in a persis-
tent decrease in levels of MRs and GRs in the hip-
pocampus, as well as decreased dendritic spine density
in the anterior cingulate gyrus and orbitofrontal cortex
in adult animals [35]. Behavioral effects of prenatal
stress include learning impairments, increased sensitiv-
ity to drugs of abuse, and increased anxiety- and depres-
sion-like behaviors in adults. These behavioral effects
are thought to be the result of developmental changes in
the brain. Specifically, learning impairments are thought
to be due to persistent alterations in hippocampal func-
tion, anxiety, and depression-like behaviors, the result
of effects on amygdalar function, and increased sensi-
tivity to drugs, the result of alterations in the developing
dopaminergic system, a system known to be involved in
reward-seeking behaviors (see also Sect. 24.6).
In mammals, the quality of early life is primarily
defined by nutrition and maternal care. In rodents,
maternal care is expressed by arched-back nursing
(ABN) and licking and grooming (LG) behaviors.
These two behavioral traits influence the offspring’s Fig. 24.9 Poor early environment can cause persistent
overall anxiety and stress-related behaviors. Anxiety alterations in stress responsiveness. Female rat dams demon-
strate a range of maternal behaviors, with some dams providing
and stress-related behaviors are in part regulated via low levels of licking and grooming and some dams providing
glucocorticoids and GRs, such that high levels of GR high levels. (a) Low levels of licking and grooming during post-
in forebrain areas such as the hippocampus provide a natal development result in increased methylation of the pro-
negative feedback to the brain to reduce the production moter region of the glucocorticoid receptor (GR) in the
hippocampus of the adult brain. This is associated with reduced
of glucocorticoids and thereby dampen the stress binding of the transcription factor nerve growth factor-inducible
response (Fig. 24.5) Offspring of high-LG-ABN moth- protein A (NGFI-A) and decreased expression of GR. Lower
ers show increased GR expression and reduced reac- levels of hippocampal GR result in higher levels of baseline and
tivity to stress, whereas offspring of low-LG-ABN corticosterone secretion following a stressor, increased anxiety-
like behavior, and reduced maternal behaviors in females. (b)
mothers have decreased GR expression and increased High levels of licking and grooming during postnatal develop-
stress reactivity (Fig. 24.9). In addition to reduced ment result in reduced methylation of the GR gene, increased
stress responsivity, mice provided with high levels of binding of NGFI-A to the GR promoter, and increased GR
maternal care have greater dendritic length and spine expression in the adult hippocampus. This is associated with
reduced levels of baseline corticosteroid, increased corticoster-
density in neurons in the CA1 region of the hippocam- oid following a stressor, reduced anxiety-like behavior and
pus and increased dendritic arborization and spine increased maternal care in females when adult (Reproduced
density in the dentate gyrus, as well as increased syn- from Feder et al. [21] with permission)
aptic plasticity compared to mice raised with low lev-
els of maternal care [35]. Interestingly, if corticosterone Abnormal levels of circulating corticosteroids have
is present, mice receiving poor maternal care show been linked to a variety of disorders in the human pop-
enhanced synaptic plasticity. Similarly, in a hippocam- ulation [16]. Hypercortisolemia, or the hypersecre-
pal-dependent fear learning task, mice raised with poor tion of corticosteroids, is a risk factor for a variety of
levels of maternal care perform better than mice raised conditions including depression, obesity, osteoporosis,
with high levels of maternal care. This suggests that and cardiovascular conditions. This can occur during
certain forms of adverse early environments while det- chronic stress conditions and results in an inability to
rimental at basal conditions, may better prepare the coordinate adaptation on release of neuropeptides like
animal to perform under stressful conditions as an CRF. In contrast, hypocortisolemia has been strongly
adult. linked with PTSD.
542
Several hypotheses have been put forward in regard
to the persistent effects of stress exposure and its link
with mental illness. The neurotoxicity hypothesis,
formerly known as the glucocorticoid cascade
hypothesis, suggests that chronic overexposure to glu-
cocorticoids makes neurons unable to withstand insults
occurring either during toxic challenges, or normally
across development [35]. This results in cell death that
manifests itself in the reduction in hippocampal vol-
ume often seen following chronic exposure to stress,
depression or PTSD. The major caveat to this hypoth-
esis is that it cannot account for the hyposecretion of
glucocorticoids present in PTSD patients.
In contrast to the neurotoxicity hypothesis, the vul-
nerability hypothesis claims that reduced hippocam-
pal volume is not the result of chronic stress conditions,
but rather is a predisposing factor for the development
of stress-related disorders [35]. This hypothesis
includes the possibility that reduced hippocampal vol-
ume can be the result of either genetic factors or early
life stress.
A third hypothesis, called the life cycle model of
stress, takes aspects of both the neurotoxicity and
vulnerability hypotheses, and suggests that there are
windows of vulnerability when the developing brain is
more or less sensitive to environmental factors causing
neurotoxicity [35]. Thus, stressful conditions during
the time of hippocampal development could lead to
different emotional disorders than those resulting from
stressful events during the time of frontal cortex devel-
opment (Fig. 24.10). In line with this hypothesis, it has
been shown that women who experience trauma before
the age of 12 have increased risk of major depression,
while those who experience trauma between 12 and
18, are at increased risk of PTSD. Similarly, repeated
sexual abuse occurring before the age of 12 is associ-
ated with reduced hippocampal volume, but the same
trauma during adolescence, was associated with
reduced prefrontal cortex volume [47].
24.4.4 Genetic Variation May Predispose
Individuals for Mental Illness
Many of the genetic variants linked with emotional
processing are in the serotonergic system. Here we
will focus on three genes encoding for enzymes, as
examples of how genetic variation can predispose
T.B. Franklin and I.M. Mansuy
individuals for psychological disorders: catechol-O-
methyltransferase gene (COMT), the serotonin
transporter gene (5-HTT), and the tryptophan
hydroxylase 2 gene (TPH2).
The gene for COMT, an enzyme that degrades
catecholamine neurotransmitters (dopamine, epineph-
rine, norepinephrine), contains a functional polymo-
rphism that results in a Met–Val substitution at codon
158 [1]. The methionine (Met) allele is associated
with low enzymatic activity, and the valine (Val) allele
is associated with high enzymatic activity. The
Met allele has been associated with increased levels of
tonic dopamine and decreased phasic dopamine activ-
ity. This polymorphism has been suggested to play a
role in a wide range of emotional and cognitive pro-
cessing. While the Met allele is beneficial for working
memory and attentional processing, the Val allele is
beneficial for emotional recognition of negative stim-
uli; healthy Val/Val carriers recognize negative facial
expressions faster and better than healthy Met/Met
carriers. Met/Met carriers also exhibit increased reac-
tivity to emotional stimuli in brain areas associated
with emotional processing, including the hippocam-
pus, amygdala, and thalamus, as well as areas of the
prefrontal cortex, compared to Val/Val carriers. Thus,
it has been suggested that overactivation of these con-
tribute to emotional dysregulation present in Met/Met
individuals. Additionally, COMT Val158Met genotype
may contribute to the emergence of particular person-
ality traits. Alexithymia is a personality trait that is
characterized by difficulties in identifying or verbal-
izing ones feelings [1]. Val/Val carriers have higher
alexithymia scores than Met/Met or Met/Val carriers,
further suggesting a role for COMT in affective
processing.
5-HTT is important in serotonergic signaling, as it
removes serotonin released into the synaptic cleft [1].
The 5-HTTLPR (serotonin-transporter-linked poly-
morphic region) is a relatively common polymorphism
present in the promoter region of the 5-HTT gene
(SLC6A4). It consists of a 22-base-pair repeat with a
short (S) and long (L) version that results in differen-
tial 5-HTT expression; the short produces less 5-HTT
mRNA and protein than the long variant, resulting in
increased serotonin in the synaptic cleft. The S allele
has been associated with increased amygdala reactiv-
ity, neuroticism, social anxiety disorder, and the
increased risk for the development of PTSD, especially
24 The Neural Bases of Emotions
Fig. 24.10 The life cycle model of stress. The effects of an
exposure to stress, either acute or chronic, are dependent on the
stage of life and the stage of brain development during which it
occurs. Exposure to a stressor during the prenatal period affects
the development of the hippocampus, frontal cortex, and the
amygdala, brain areas involved in the HPA axis (programming
effects). Exposure to a stressor during postnatal development
has variable effects, including increased secretion of glucocorti-
coids, as in the case of exposure to maternal separation during
childhood, or decreased levels of glucocorticoids, in the case of
severe abuse. Thus, the environment during childhood induces
differential glucocorticoid production (differentiation effects).
After the prenatal period, stress hormones can affect all develop-
ing brain areas (broken blue bars). Some brain areas may be
more susceptible to the effects of stress hormones during periods
when they undergo rapid growth (solid blue bars). For example,
when social support was limited. However, these asso-
ciations remain controversial, as many studies have
failed to replicate these findings.
Tyrptophan hydroxylase is the rate-limiting enzyme
for the synthesis of serotonin. A single-nucleotide
polymorphism (SNP) in the TPH2 gene (−703 G/T
SNP, rs4570625) has been associated with altered
serotonergic function and emotional processing.
A significantly higher proportion of T-allele carriers
are present in two separate cohorts of patients with
anxiety-related personality disorders compared to con-
trol subjects. Additionally, in healthy subjects, the
genetic variant of TPH2 is significantly associated
with anxiety-related traits defined by the TPQ Harm
Avoidance test, including emotional instability. Brain
imaging of T-allele carriers also displays heightened
responsiveness to emotional stimuli in the amygdala.
Thus, evidence suggests that T-allele carriers are at a
higher risk than G-allele carriers for the presence of
543
the hippocampus grows rapidly between birth and 2 years of
age, and therefore may be more vulnerable to the effects of
stressful stimuli during this time. This differs from the amygdala,
which continues to grow from birth until the late 20 s, and there-
fore may be susceptible to the effects of stressful stimuli occur-
ring during childhood. The frontal cortex undergoes a major
period of growth during adolescence. A prolonged glucocortio-
cid response to stress occurring during adolescence may persist
into adulthood (potentiation/incubation effects). Brain areas that
degenerate most quickly due to aging (red bars) are more vul-
nerable to the effects of stress hormone and this can result in the
manifestation of incubated effects of earlier adversity (manifes-
tation effects) or to maintenance of the effects of stressful stimuli
(maintenance effects). PTSD posttraumatic stress disorder
(Reproduced from Lupien et al. [35] with permission)
anxiety-related personality traits, and for the develop-
ment of anxiety-related personality disorders.
24.5 Fear Learning and Memory
Emotional memory is the acquisition and storage of
information concerning emotionally salient events
[32]. It recruits several brain areas depending on the
nature of the memory, but always requires the
amygdala. The hippocampus and associated cortical
areas can also be involved, in particular in the storage
of explicit or conscious memory that has an emo-
tional component. Thus, emotional events result in
the recruitment of both amygdala-based emotional
systems and hippocampal-based nonemotional sys-
tems. Here, we will focus on fear learning and mem-
ory as a basis for understanding emotional memory
processes.
544
24.5.1 Fear Conditioning Is a Behavioral
Model for Fear Learning and Memory
Fear refers to a psychological state and physiological
changes that occur as a result of an actual or perceived
threat [42]. Thus, the emotion of fear is associated with
the induction of a stress response and subsequent
defensive behaviors, on exposure to threatening situa-
tions. Fear conditioning is a common behavioral model
for emotional learning and memory. Pavlovian fear
conditioning is based on Ivan Pavlov’s discovery that a
neutral stimulus can acquire emotional properties
when paired with a biologically relevant stimulus [38]
(see Chap. 26). Since every species has innate defense
mechanisms that help cope with threat, fear condition-
ing is highly conserved across species [42].
Fear conditioning paradigms involve one or sev-
eral pairings of a neutral stimulus (the conditioned
stimulus; CS) such as a tone, light, or place (context)
with an intrinsically aversive stimulus (the uncondi-
tioned stimulus or US), most often a mild foot shock.
Following conditioning, animals are once again
exposed to the CS, in the absence of the US. In animals
that have learned and remember the CS-US associa-
tion, this elicits measurable behavioral, autonomic,
and endocrine fear responses such as freezing or
increased blood pressure (Fig. 24.11). Repeated expo-
sure of the CS without the US leads to extinction of the
conditioned response (CR) [42]. Cue conditioning
(i.e., association of the US with a tone or light) is
amygdala-dependent, while contextual conditioning
(i.e., association of the US with the environment)
involves both the amygdala and the hippocampus.
Accordingly, the hippocampus is not thought to be
involved specifically in forming the association
between the CS and the US, but rather in placing these
associations within the appropriate contexts.
In general, chronic stress enhances fear acquisition
and memory. Both cued and contextual fear condition-
ing can be enhanced by exposure to either acute or
chronic stress prior to training [44]. Pre-training stress
also increases the sensitivity of the animal to the stres-
sor, such that the same CRs can be elicited from a less
extreme stressful stimulus. This has been suggested to
mimic PTSD patients, who demonstrate abnormally
strong reactions to relatively mild stimuli. Acute stress
following training has also been demonstrated to
enhance long-term memory in a cued fear conditioning
paradigm.
T.B. Franklin and I.M. Mansuy
24.5.1.1 The Neuroanatomy of Fear
Conditioning
The circuitry underlying fear conditioning has been
well studied and is thought to be relatively simple.
Sensory information, including auditory, visual, gusta-
tory, olfactory, and somatosensory information, is sent
to the lateral amygdala through inputs from both corti-
cal and thalamic regions [32]. The cortico-amygdala
pathway provides slow and detailed sensory informa-
tion that is filtered by conscious control, while the thal-
amo-amygdala pathway provides rapid, but less detailed
information about the threatening stimulus [42]. Both
CS and US information converge in the lateral amygdala,
and this integrated information is then sent to the cen-
tral nucleus, either directly or indirectly via the basal,
accessory basal, and intercalated nuclei. The central
nucleus has many projections out of the amygdala.
From the central amygdala, there are projections to the
brainstem and hypothalamus, and it is these connec-
tions which control the expression of defensive behav-
iors, hormonal secretions, and autonomic responses
which are part of the behavioral fear response [32]
(Fig. 24.11). For example, projections to the hypothala-
mus can mediate autonomic responses like increased
blood pressure and pupil dilation [19]. Additionally,
projections to midbrain nuclei can mediate behavioral
responses such as freezing and vigilance.
There are direct connections between the lateral
amygdala and central amygdala, but these connections
are quite minimal [42]. However, there are several
indirect connections through other subnuclei of the
amygdala. For instance, both the lateral amygdala and
basal amygdala project to an inhibitory network of
cells, the intercalated region that, in turn, projects to
the central nucleus. Since the majority of neurons in
the central amygdala are also inhibitory, activation of
the neurons projecting from the intercalated region to
the central amygdala may act to reduce the inhibitory
actions of the central amygdala, and thereby increase
the fear-related behaviors.
In mice, neurons in the lateral amygdala are prefer-
entially activated by the expression of fear memories
[23]. When these neurons are deleted following acqui-
sition of a fear memory, the expression of this fear
memory is blocked. This memory loss is persistent,
suggesting that some or all of the fear memory can be
permanently erased by ablation of a subpopulation of
specific neurons within the lateral amygdala.
Importantly, following the erasure of the fear memory
24 The Neural Bases of Emotions 545

Fig. 24.11 Autonomic and behavioral a b

responses following auditory fear
conditioning, and the brain pathways
involved. Fear conditioning occurs when
an animal associates an initially neutral
conditioned stimulus (CS), such as a tone,
with an aversive unconditioned stimulus
(US), such as a foot shock, after the CS
and US are paired in time. (a, b)
Following classical auditory fear
conditioning, a tone (CS) elicits both
autonomic and behavioral responses. The
conditioned group experienced 10-s CS
associated with a 0.5-s foot shock (US),
the random group was exposed to both
the CS and US but this exposure was
random, and the naïve group never
experienced the CS or the US. Twenty-
four hours following conditioning, the c
testing phase occurs. Here, three CS
trials, in the absence of the US, were
presented, and arterial pressure responses
were measured (a). Additionally, one
120-s CS alone trial was presented and
freezing was measured (b). (c) Auditory
inputs, associated with the CS, and
somatosensory inputs, associated with the
US, converge onto single neurons within
the lateral nucleus of the amygdala. The
LA projects, both directly and indirectly,
to the central nucleus of the amygdala.
Projections from the central amygdala to
the brainstem and hypothalamus regulate
the fear response, including behaviors
like freezing, autonomic responses
including increased blood pressure and
heart rate, and endocrine responses,
including increased pituitary-adrenal
hormones. PAG periaqueductal gray, LH
lateral hypothalamus, PVN
paraventricular nucleus (Reproduced
from LeDoux [32] with permission)

by such selective ablation, a new fear memory trace
can be produced by retraining the animal.
There is some evidence that overtraining results in
fear conditioning which does not rely on the fear cir-
cuits involving the lateral amygdala, but rather on
weak connections to the central amygdala which are
normally not recruited [6]. The concept that the cen-
tral amygdala is involved in a conditioning indepen-
dent of the lateral amygdala has been theorized mainly
as a result of appetitive conditioning findings; its
presence in aversive conditioning requires further
study [42].
24.5.1.2 The Molecular Mechanisms
Underlying Fear Acquisition
and Consolidation
A model of fear conditioning at the molecular level is
shown in Fig. 24.12 [33]. Glutamate released as a
result of CS inputs, binds to glutamate receptors,
including AMPA receptors, NMDA receptors, and
metabotropic glutamate receptors, on lateral amygdala
cells [41]. At resting membrane potentials, NMDA
receptors are gated by magnesium. However, when
glutamate is bound to the receptor and the cell is
depolarized, the channel is opened and calcium is
546
Ca2+
mGluR5 from intracellular stores
nucleus
P CREB
MAPK
DNA
PKC CRE
NMDAR enhancer promoter
RNA
Ca2+ PKA
synthesis
AMPAR
αCaMKII
Na+ protein
Rho-GAP
structural remodeling synthesis
of dendrites and spines
L-VGCC
Fig. 24.12 Molecular mechanisms of fear learning and
memory in the lateral amygdala. On presentation of the audi-
tory conditioned stimulus, glutamate is released from presynap-
tic terminals in the lateral amygdala. Glutamate binds
postsynaptic NMDA, AMPA, and mGluR5 receptors. If a strong
unconditioned stimulus simultaneously activates the cell (not
shown), calcium can enter the cell through NMDA receptors and
L-type voltage-gated calciums channels (L-VGCC). This
increase in intracellular calcium leads to the activation (phos-
phorylation) of MAP kinase (MAPK), protein kinase C (PKC),
protein kinase A (PKA), and CaM kinase II (CamKII). On acti-
vation, MAPK is translocated to the nucleus, and activates tran-
scription factors (i.e., CREB), thereby leading to changes in
gene expression and protein translation. The new proteins can be
additional glutamate receptors for insertion into the cell mem-
brane, or proteins required for structural changes, a process
which is mediated in part by Rho-GAP (Reproduced from
LeDoux [33] with permission)
allowed to flow into the cell. Thus, NMDA receptors
are coincidence detectors, and are key mediators of
experience-dependent synaptic modification (see
Chaps. 6 and 26). Consequently, when the US depolar-
izes cells within the lateral amygdala while glutamate
released by CS inputs is bound to NMDA receptors,
calcium can enter into the cell. This increase in intrac-
ellular calcium leads to the activation of protein kinase
second messenger cascades that are necessary for
memory formation. The role of cyclic AMP-dependent
protein kinase (PKA) and the mitogen-activated pro-
tein kinase (MAPK) have been studied extensively in
relation to fear conditioning and the formation of long-
term memory. On activation of PKA and MAPK,
MAPK is translocated into the nucleus where it acts on
gene transcription factors and thereby mediates
changes in gene expression and, ultimately, protein
T.B. Franklin and I.M. Mansuy
levels. New proteins include additional glutamate
receptors for insertion into the cell membrane, and
proteins that alter actin and other cytoskeletal func-
tions, thereby contributing to structural changes
required for synaptic connectivity.
Calcium entry through voltage-gated calcium chan-
nels during training is also necessary for memory for-
mation [41]. It is believed that calcium entry via
L-type voltage-gated calcium channels, occurring as a
result of strong depolarization, is necessary not for
acquisition, but for consolidation of long-term mem-
ory. Blockade of L-type voltage-gated calcium chan-
nels prior to training results in specific impairment of
long-term memory, but leaves short-term memory
intact.
24.5.1.3 Reconsolidation and Extinction
of Fear Memories
After consolidation, fear memories can once again
become labile as a result of reactivation, termed recon-
solidation. A summary of the molecular signaling path-
ways involved in memory reconsolidation is provided in
Fig. 24.13 [48]. In rodents, infusion of a b-adrenergic
receptor antagonist, propanolol, into the amygdala
immediately after reactivation of a previously learned
fear association impairs subsequent recall. The effect of
propanolol is also seen in humans given an oral admin-
istration of propanolol before memory reactivation of a
previously learned fear response. This treatment pre-
vents the future behavioral expression of fear providing
a possible therapeutic option for those suffering with
PTSD. Similarly, animal studies have demonstrated
that glucocorticoid administration immediately after
reactivation of a contextual fear memory reduces subse-
quent recall, suggesting that glucocorticoids can act to
enhance fear memory extinction. This concept of
enhanced extinction resulting from glucocorticoid
administration has now been successfully used in
humans for the treatment of PTSD and anxiety disor-
ders [18].
Extinction of the conditioned response through
repeated exposure of the CS in the absence of US is not
thought to be the result of an erasure of the original
CS-US association, but rather the induction of a stron-
ger association between the CS and the absence of the
US [8]. A proposed mechanism for extinction involves
the downregulation of amygdala output by infralimbic
neurons in the medial prefrontal cortex. These neurons
activate GABAergic neurons within the basolateral
24 The Neural Bases of Emotions
Fig. 24.13 Molecular mechanisms of memory reconsolida-
tion. Activation of NMDA receptors result in an influx of calcium
that, in turn, activates small GTPases, like Ras, Raf, and Rap.
These activated GTPases result in the activation of the extracellu-
lar signal-regulated kinase pathway (ERK). Additionally, activa-
tion of adrenergic receptors result in increased levels of cyclic
AMP (cAMP), resulting in the activation of protein kinase
A (PKA). PKA can act directly or indirectly via ERK and ribo-
somal protein S6 kinase (RSK) to activate transcription factors
including camp response element-binding protein (CREB), zinc
finger 268 (ZIF268) and ELK1, thereby initiating gene transcrip-
tion. Memory reconsolidation activates the immediate-early genes
c-Fos and JunB. In addition, the CCAAT-enhancing binding pro-
tein-b (C/EBP) is necessary for memory reconsolidation. Although
not yet studied, NMDA receptor activation suggests that the cal-
cium/calmodulin (CaM)-CaM-dependent protein kinase kinase
(CamKK)-CaMKIV pathway is also involved in memory recon-
solidation. AP1 activator protein complex 1 (a complex of c-Fos
and c-JUN), CBP CREB-binding protein, MEK mitogen-activated
protein kinase/ERK kinase, SRE serine response element, SRF
serum response factor, TATA box required for transcription
(Reproduced from Tronson and Taylor [48] with permission)
amygdala or intercalated cells that, in turn, act to
inhibit output from the central nucleus (Fig. 24.14).
NMDA receptors play a role in extinction learn-
ing. When NMDA antagonists are infused in the
amygdala, extinction is blocked, while administration
of an NMDA partial agonist, d-cycloserine, facili-
tates extinction, whether administered systemically
or directly into the amygdala. These findings led to
the use of d-cycloserine in phobic patients. Patients
with a fear of heights (acrophobia) were administered
d-cycloserine while undergoing behavioral expo-
547
sure therapy. Administration of this NMDA agonist
resulted in a faster reduction in acrophobia symptoms
when compared to those taking placebo. This reduc-
tion in symptoms included both decreases in posttreat-
ment skin conductance responses (SCRs), and better
scores in scales measuring acrophobia symptoms, sug-
gesting that d-cycloserine also results in a facilitation
of extinction learning in humans.
24.5.1.4 Fear Conditioning in Human Studies
Imaging studies have demonstrated an important role
for the amygdala in fear learning in humans. In a fear
conditioning model similar to that used in animals,
neutral stimuli are paired with mild shocks. During
acquisition, subjects demonstrate increased bilateral
activation of the amygdala to the association between
CS and US. Additionally, in human studies, skin
conductance response (SCR) is often used as the CR
elicited by exposure to the CS. In the above-mentioned
study, the increase in amygdala activation to the US
was further correlated with the magnitude of SCR,
demonstrating a positive correlation between amygdala
activation and the conditioned fear response. Similarly,
when using white noise as the US, bilateral amygdala
a b
Fig. 24.14 Proposed mechanisms for the downregulation of
amygdala output by the medial prefrontal cortex (mPFC).
(a) In rat, infralimbic (IL) neurons in mPFC inhibit central
medial nucleus (CeM) projection neurons indirectly via
GABAergic intercalated cells (ITC). This reduces CeM responses
to inputs from the basolateral amygdala (BLA) or cortex. (b) A
second hypothesis is that the mPFC inhibits CeM output through
excitatory connections to BLA GABAergic interneurons. LA lat-
eral nucleus of the amygdala, CeL central lateral nucleus of the
amygdala, BS brain stem, Pu putamen, Glu excitatory gluta-
matergic projections, GABA inhibitory GABAergic projections
(Adapted from Bishop [8] with permission)
548
a b
Fig. 24.15 Dissociable role of amygdala and hippocampus
in conditioned fear learning in human subjects. (a) Healthy
control subjects have factual knowledge and exhibit a condi-
tioned response, increased skin conductance responses (SCR) to
conditioned fear stimuli (visual or auditory cues) paired with a
loud noise, relative to unpaired control stimuli (top). A patient
with selective amygdala damage (SM) has factual knowledge
about the conditioned association but does not acquire the appro-
activation was demonstrated in response to the CS,
particularly during initial learning phases but decreased
over time. In human fMRI studies, it was also demon-
strated that repeated CS-US associations are not
required for fear memory to occur, but rather verbal
instructions explaining CS-US associations are
sufficient. Thus, when participants are told that the CS
may be associated with an aversive shock, then activa-
tion of the left amygdala and associated SCRs are dis-
played. Similarly, patients with lesions in the left, but
not right, amygdala demonstrate deficits in the fear
response to a stimulus that had previously been associ-
ated with an aversive stimulus through a verbal
description.
The use of patients with specific lesions to the hip-
pocampus or amygdala has allowed researchers to
study the differential role of these two brain regions in
fear acquisition. Amnesic patients with damage to the
T.B. Franklin and I.M. Mansuy
priate conditioned response (middle). An amnesic patient with
selective hippocampal damage (WC) has no factual knowledge
but has intact conditioned fear responses (bottom). (b) Structural
MRIs displaying normal amygdala (top left, yellow arrow) and
normal hippocampus (top right, red arrow) compared to selec-
tive amygdala damage (bottom left, yellow arrows) and selective
hippocampal damage (bottom right, red arrows) (Adapted from
LaBar and Cabeza [31] with permission)
hippocampus, but not amygdala, are unable to verbally
report the relationship between CS and US, but still
display the appropriate conditioned response (increased
SCR) to the appropriate CS [31]. The opposite is seen
in patients with damage to the amygdala, but not hip-
pocampus; they can verbally report the association
between CS and US, but do not display increased SCR
to the CS (Fig. 24.15). Further, increased SCR is
observed even when the CS is masked to prevent con-
scious awareness.
24.5.2 Fear Learning and Memory Is the
Result of Changes in Synaptic
Strength in the Amygdala
Learning and memory are thought to be the result of
long-term changes in synaptic strength. Long-term
24 The Neural Bases of Emotions
potentiation (LTP), a model for the persistent
increase in synaptic strength resulting from coinci-
dent pre- and postsynaptic activity, is a mechanism
for fear learning (see also Chap. 26). Fear condition-
ing is thought to be the result of LTP-like synaptic
changes at sensory inputs to the lateral amygdala. It is
suggested that prior to conditioning, the CS inputs are
not strong enough to evoke fear responses. US inputs
are stronger, and therefore are capable of inducing
responses in lateral amygdala neurons. Since the lat-
eral amygdala receives inputs from both CS and US
during fear conditioning, the US induces strong post-
synaptic depolarization while the CS inputs are also
active. This results in increased synaptic strength
between CS inputs and lateral amygdala neurons,
which, in turn, can affect downstream structures that
regulate fear responses.
24.6 Motivation and Emotion
It is impossible to know whether animals experience
emotions in a similar way as humans. However,
humans experience the strongest emotions when they
are anticipating activation of the motivational systems,
or when this activation of the motivational systems is
completed. Motivational systems can be defined as
systems governing goal-relevant, reflexive behaviors.
Thus, motivation can be defined as the drive to obtain
a reward or to avoid a punishment and motivated
behavior is the result of appetitive and aversive
cues. These motivated behaviors are conserved across
species due to their importance in the promotion of
survival [11]. Thus, motivation may provide an impor-
tant means of understanding emotion in less complex
animals.
As the majority of research on motivational systems
has focused on the role of the dopaminergic system, a
brief description of dopaminergic projections is pro-
vided here [11, 54]. The mesolimbic and mesocortical
dopamine systems, arising from the ventral tegmental
area (VTA), are thought to be predominantly involved
in motivational function, whereas dopaminergic cells
arising from the substantia nigra (SNc) are thought to
be predominantly involved in motor function [54]. The
substantia nigra projects mainly to the caudate puta-
men. The mesolimbic dopamine system refers to the
dopaminergic projections from the VTA that mainly
innervate the nucleus accumbens and olfactory tuber-
549
Fig. 24.16 Dopaminergic pathways in the brain. Dopaminergic
cells present in the substantia nigra project to the striatum (cau-
date-putamen) and are involved primarily in motor function. The
mesocorticolimbic dopamine pathway arises from the ventral teg-
mental area (VTA) and projects to the nucleus accumbens,
amygdala, and hippocampus, as well as to frontal cortical areas
(Adapted from Knab and Lightfoot [28] with permission)
cle, but also the septum, amygdala, and hippocampus.
The mesocortical dopamine system refers to the dop-
aminergic projections from the VTA to the medial pre-
frontal, cingulate, and perirhinal cortices. Currently,
the two systems are often collectively referred to as the
mesocorticolimbic dopamine system, due to the sub-
stantial overlap between mesocortical and mesolimbic
sytems (Fig. 24.16).
Both primary rewards (like food, water, and sex),
and reward-associated stimuli have a drive-like
effect [54]. These stimuli cause an energizing effect
or motivational arousal, accompanied with an
increased likelihood of responses in anticipation of
a reward that has yet to be attained. For example,
after a reward signal, there is not only reinforcement
of the rewarding behavior, but also arousal of the
animal before and during the subsequent reward-
seeking behavior. This energizing or motivating
effect of the presence of a reward, prior to a reward-
driven act is known as priming. Priming has been
suggested as a mechanism underlying the increased
likelihood of depressed patients to make negative
associations, and as a reason why patients with anxi-
ety disorders respond more quickly to threatening
cues. The priming effect decays rather quickly, while
the reinforcing effect is stored in long-term mem-
ory. Dopamine is involved in both the priming and
reinforcing effect of rewarding stimuli and has been
550
a b
Fig. 24.17 Dopamine blockade, via administration of pimoz-
ide, reduces reward-seeking behaviors. Rats were trained for
2–3 weeks to press a lever for food under food deprivation condi-
tions prior to testing. (a–c) Testing of control and pimozide-treated
rats occurred on 4 days, separated by 2 days of retraining. On the
first day, nonrewarded and pimozide-treated animals (0.5 or
1.0 mg/kg 4 h prior to testing) responded similarly. Thus, pimoz-
ide-treatment does not affect performance capacity in this test. On
demonstrated to be important in brain self-stimulation
as well as food-, cocaine-, and heroin-seeking
behaviors (Fig. 24.17).
Learning the association between an emotional
value and a context, stimulus, or event is influenced
by motivational state [54]. Incentive motivation
refers mainly to the priming effects or the drive to
encounter a neutral stimulus with enhanced motiva-
tional importance as the result of previous pairing
with a primary reward. Thus, a previously neutral
stimulus can gain incentive value through its associa-
tion with a reward. Again, dopamine is the neurotrans-
mitter that has been most often speculated to be
important for both the establishment and maintenance
of incentive motivation.
Recent findings have suggested that a subgroup of
dopaminergic neurons encode both reward- and pun-
ishment-related signals; in monkeys, certain dopamin-
ergic neurons were both excited by reward-predicting
stimuli and inhibited by stimuli predicting an aversive
outcome [36]. However, the majority of dopaminergic
neurons were excited by stimuli predicting both appet-
itive and aversive outcomes. There was also a
neuroanatomical distribution of these neurons, with
those excited by the stimuli predicting an aversive out-
come located more dorsolaterally in the substantia
nigra pars compacta, but those inhibited by these stim-
uli located more ventromedially, with a portion of
these in the VTA [36] (Fig. 24.18).
T.B. Franklin and I.M. Mansuy
c d
subsequent testing sessions, responding decreased in pimozide-
treated groups, but not control. (d) This reduction in response to
reward on the fourth test day in pimozide-treated animals was not
due to accumulation of the drug, since rats given the first three
pimozide injections without the opportunity to receive food reward
(home cage (HC) transfer condition) had similar response levels
after their fourth injection as animals given their first injection in
the test box (Reproduced from Wise [54] with permission)
24.7 Summary and Outlook
There are still many unanswered questions concerning
the neural basis of emotions. However, an explosion of
research over recent years has contributed to a greater
understanding of the neural circuits underlying emo-
tional processing. From these findings, the hypothala-
mus, amygdala, and prefrontal cortex have emerged
as key structures in the regulation of emotions. The
persistent effects of stressful events on these, and other
brain areas involved in emotion, are thought to increase
the risk of developing psychiatric illnesses like depres-
sion, posttraumatic stress disorder, and obsessive-
compulsive disorder. In recent years, there have been a
growing number of treatments for these disorders.
However, due to the complexity of these illnesses, they
have been particularly difficult to treat and current
pharmacological interventions need to be improved.
Since it is not known to what extent emotions are con-
served across species, motivational systems may pro-
vide a means for understanding emotion-related
processes in less complex animals.
Insect models for emotion related conditions are
currently not well studied, and have not been covered
in this chapter. However, recent attempts have been
made to find models of emotional behaviors particu-
larly in Drosophila, where the role of genetic and epi-
genetic effects are easier to study. Importantly,
Drosophila express some behaviors that may be related
24 The Neural Bases of Emotions
Fig. 24.18 Location of dopamine neurons in relation to their
responses to punishment-predicting conditioned stimuli in
the monkey. Five coronal sections, shown rostrocaudally from
left to right (interval, 1 mm), showing recording sites of 68 dop-
amine neurons in the substantia nigra and ventral tegmental area
of a single monkey. Neurons significantly excited by all punish-
ment-related CS are shown in red, neurons significantly inhibited
by all punishment-related CS are shown in blue, and nonrespon-
sive neurons are shown in white. Electrode penetration tracks are
indicated by black lines. (b, c) Red, blue, and white circles indi-
cating neurons excited, inhibited, and nonresponsive to punish-
ment-related CS, respectively, in relation to recording depth for
two individual monkeys (right and left) (Reproduced from
Matsumoto and Hikosaka [36] with permission)
to emotions in mammals, including avoidance of aver-
sive areas and fear conditioning.
Finally, the critical question of the potential herita-
bility of defects in emotional processing induced by
stress has recently gained importance. Its study is
expected to reveal novel insight into the contribution
of epigenetic processes in the future [55].
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