Beruflich Dokumente
Kultur Dokumente
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13 May 2009
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Further
Center for Neural Science and Department of Psychology, New York University,
New York, New York 10003; Emotional Brain Institute Labs of the Nathan Kline Institute,
Orangeburg, New York 10962; email: ledoux@cns.nyu.edu
Key Words
Abstract
Fear arousal, initiated by an environmental threat, leads to activation of
the stress response, a state of alarm that promotes an array of autonomic
and endocrine changes designed to aid self-preservation. The stress response includes the release of glucocorticoids from the adrenal cortex
and catecholamines from the adrenal medulla and sympathetic nerves.
These stress hormones, in turn, provide feedback to the brain and inuence neural structures that control emotion and cognition. To illustrate
this inuence, we focus on how it impacts fear conditioning, a behavioral
paradigm widely used to study the neural mechanisms underlying the
acquisition, expression, consolidation, reconsolidation, and extinction
of emotional memories. We also discuss how stress and the endocrine
mediators of the stress response inuence the morphological and electrophysiological properties of neurons in brain areas that are crucial
for fear-conditioning processes, including the amygdala, hippocampus,
and prefrontal cortex. The information in this review illuminates the
behavioral and cellular events that underlie the feedforward and feedback networks that mediate states of fear and stress and their interaction
in the brain.
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Contents
INTRODUCTION . . . . . . . . . . . . . . . . . .
WHAT IS FEAR, AND HOW IS IT
ORGANIZED IN THE BRAIN? . .
Studying Fear in the Laboratory
with Fear Conditioning . . . . . . . . .
Phases of Fear Conditioning . . . . . . . .
Neural Circuitry Underlying
Fear Conditioning . . . . . . . . . . . . . .
FEAR AROUSAL AND THE
STRESS RESPONSE:
OVERVIEW OF THIS
FEEDFORWARD AND
FEEDBACK NETWORK . . . . . . . . .
HOW DO STRESS,
NOREPINEPHRINE, AND
GLUCOCORTICOIDS
INFLUENCE DIFFERENT
PHASES OF FEAR
CONDITIONING? . . . . . . . . . . . . . . .
ACQUISITION OF FEAR
CONDITIONING . . . . . . . . . . . . . . . .
The Effects of Stress on the
Acquisition of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
The Effects of NE on the
Acquisition of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
The Effects of GCs on the
Acquisition of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
CONSOLIDATION OF
LONG-TERM MEMORY . . . . . . . .
The Effects of Stress on the
Consolidation of LTM of
Fear Conditioning . . . . . . . . . . . . . .
The Effects of NE on the
Consolidation of LTM
of Fear Conditioning . . . . . . . . . . . .
The Effects of GCs on the
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Consolidation of LTM
of Fear Conditioning . . . . . . . . . . . .
RECONSOLIDATION . . . . . . . . . . . . . .
The Effects of Stress on the
Reconsolidation of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
The Effects of NE Manipulation
on the Reconsolidation of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
The Effects of GC Manipulation
on the Reconsolidation
of Fear Conditioning . . . . . . . . . . . .
EXTINCTION . . . . . . . . . . . . . . . . . . . . . .
The Effects of Stress on the
Extinction of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
Involvement of NE in the Extinction
of Fear Conditioning . . . . . . . . . . . .
Involvement of GCs in the
Extinction of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
SUMMARY OF THE EFFECTS
ON FEAR CONDITIONING . . . .
HOW STRESS AFFECTS
FEAR CIRCUITRY ON
A CELLULAR LEVEL. . . . . . . . . . . .
The Inuence of Stress on
the Morphology of Neurons
in Fear Circuitry . . . . . . . . . . . . . . . .
The Inuence of Stress on the
Electrophysiological Properties
of Neurons in Fear Circuitry . . . .
The Inuence of NE on the
Electrophysiological Properties
of Neurons in Fear Circuitry . . . .
The Inuence of GCs on the
Electrophysiological Properties
of Neurons in Fear Circuitry . . . .
CONCLUSIONS . . . . . . . . . . . . . . . . . . . .
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INTRODUCTION
Evolution has endowed each species with an array of instinctual defense mechanisms to help
organisms cope with environmental threats
and other challenges to safety and well-being.
Skunks spray offensive odors, blowsh inate to
look bigger than they actually are, and roaches
scurry away into crevices for safety. Although
humans in modern societies usually have the
luxury of not having to worry about escaping
from predators (except for the odd shark, bear,
or axe murderer), the emotion of fear and the
defensive behaviors connected with it help to
save us from peril both in everyday situations
as well as under rare but hazardous conditions:
We duck for cover, slam on the brakes, run for
the hills, or scream for help.
Fear arousal is one of the most reliable
routes for activating the stress response (LaBar
& LeDoux 2001), an array of peripheral autonomic and neuroendocrine changes that aid
survival (McEwen 2003, Sapolsky et al. 2000).
At the same time, the peripheral changes induced by fear impact the brain, altering the
way emotional and cognitive systems process
information. Although such responses enhance
survival in the short run, chronic activation
of stress responses contributes to the development of pathological states such as anxiety,
phobias, depression, and post-traumatic stress
disorder (PTSD), as well as a host of physical ailments, including compromised immune
function, hypertension, and insulin resistance
(McEwen 2003, Sapolsky et al. 2000).
The aim of this article is to explore how
fear arousal, manifested on the neurobiological
level, leads to activation of peripheral stress responses and how stress responses, in turn, alter
brain systems that control emotion and cognition. In the interest of space, we cannot cover
some important topics, including how early-life
experiences, genetics, or gender might interact with stress in altering fear (DeRijk & de
Kloet 2005, Kalin & Shelton 2003, Luine 2002,
Lyons & Parker 2007, Meaney 2001, Weinstock
2007).
CS: neutral
conditioned stimulus
US: aversive
unconditioned
stimulus
NE: norepinephrine
GC: glucocorticoid
CR: conditioned
response
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CS sensory processing to the CR motor control systems. A key link in this circuitry is the
amygdala, which sits between the sensory input systems on one hand and the motor output
systems on the other (Fanselow & Poulos 2005;
Lang & Davis 2006; LeDoux 1995, 1996, 2007;
Maren 2001, 2005; Pare et al. 2004; Rodrigues
et al. 2004). However, other brain structures
also contribute to fear conditioning.
Amygdala contributions to fear conditioning. The amygdala contains a heterogeneity of
distinct nuclei, differing by cell type, density,
neurochemical composition, and connectivity
(LeDoux 2007, Pitkanen et al. 2000, Swanson
2003).
The lateral nucleus (LA) is typically viewed
as the sensory gateway to the amygdala because it receives auditory, visual, gustatory,
olfactory, and somatosensory (including pain)
information from the thalamus and the cortex (olfactory and taste information is transmitted to other nuclei, as well). The LA receives
sensory information about the CS from thalamic and cortical projections. The thalamoamygdala pathway is a shortcut of sorts, transmitting rapid and crude information about the
fear-eliciting stimulus without the opportunity for ltering by conscious control (LeDoux
1995, 1996). The cortico-amygdala pathway, in
contrast, provides slower, but more detailed and
sophisticated sensory information. Neurons in
the LA respond to both the CS and the US,
and damage to, or a disruption of, the LA prevents fear conditioning. It appears that the convergence takes place in the dorsal half of the
LA (Romanski et al. 1993), and indeed singleunit recordings show that cellular plasticity occurs in the dorsal LA during fear conditioning
(LeDoux 2007, Maren & Quirk 2004). Moreover, molecular changes in the LA consolidate
the fear memory, converting STM into LTM
traces (Dudai 2004, Rodrigues et al. 2004).
The central nucleus (CE), in contrast, is
viewed as the major output region of the
amygdala. The CE controls the expression
of the fear reaction, including behavioral,
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autonomic, and endocrine responses via projections to downstream areas, including hypothalamus, central gray, and the dorsal motor nucleus of the vagus (Fanselow & Poulos 2005;
Lang & Davis 2006; LeDoux 1995, 1996, 2007;
Maren 2001, 2005; Pare et al. 2004; Rodrigues
et al. 2004). Plasticity also occurs in the CE
(Pare et al. 2004, Wilensky et al. 2006), but this
is likely based on LA plasticity.
The LA communicates with the CE directly,
but the connections between these two nuclei
are somewhat modest and other amygdaloid
nuclei also help mediate between these two.
For instance, the LA projects to the basal nucleus (B), which in turn projects to CE (LeDoux
2000, Pitkanen et al. 1997). The LA and B also
project to the intercalated region (ITC), an inhibitory network that connects with the CE
(Likhtik et al. 2008, Pare et al. 2004). Projection neurons in the CE tend to be inhibitory,
thus LA and B projections to the ITC may
stimulate the ITCs inhibition of CE neurons
to allow the expression fear responses (LeDoux
2007). In addition, the B projects to the striatum
(McDonald 1991) to orchestrate instrumental
behaviors, such as escape to safety (LeDoux
2007). Furthermore, CE neurons project to the
medial peri-locus coeruleus dendritic region,
resulting in increased NE release (Aston-Jones
2004), as well as to other monoamine systems in
the brainstem and forebrain (Fudge & Emiliano
2003, Gray 1993, Pare 2003).
Information about the context of a fearful situation is conveyed to the LA and
B by the hippocampus ( Ji & Maren 2007,
Kim & Fanselow 1992, Phillips & LeDoux
1992, Pitkanen et al. 2000). Thus, although
fear conditioning to discrete sensory cues,
such as a tone or a light, are hippocampal independent, conditioning to contextual information, including details about the
environment, are hippocampal dependent. The
LA and B are also interconnected to a variety of
cortical areas, such as the prefrontal and polymodal association cortices (Amaral & Insausti
1992, McDonald 1998, McDonald et al. 1996,
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Sensory thalamus
and cortex
(auditory, visual,
somatosensory,
gustatory, olfactory)
Viscero-sensory
cortex
ITC
CE
LA
Hippocampus and
entorhinal cortex
Sensory brainstem
(pain, viscera)
Prefrontal cortex
(medial)
Polymodal
association cortex
Annu. Rev. Neurosci. 2009.32:289-313. Downloaded from arjournals.annualreviews.org
by OREGON STATE UNIVERSITY on 09/30/09. For personal use only.
HPA axis
(hypothalamus)
Freezing
(central gray)
ITC
CE
LA
Prefrontal cortex
(regulation)
B
Ventral striatum
(instrumental behaviors)
Polymodal association
cortex (cognition)
Modulatory systems:
NE, 5HT, DA, ACh
(cell groups in
forebrain and/or
brainstem)
Sympathetic and
parasympathetic NS
(hypothalamus,
brainstem)
Figure 1
(Top) Inputs to some specic amygdala nuclei. Asterisk ( ) denotes species difference in connectivity. (Bottom)
Outputs of some specic amygdala nuclei. 5HT, serotonin; Ach, acetylcholine; B, basal nucleus; CE, central
nucleus; DA, dopamine; ITC, intercalated cells; LA, lateral nucleus; NE, norepinephrine; NS, nervous
system.
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brain and the body that support the fear reaction. In the brain, monoaminergic systems are
activated, resulting in the release of neurotransmitters such as NE, acetylcholine, serotonin,
and dopamine throughout the brain. These
neurotransmitters lead to an increase in arousal
and vigilance and, in general, an enhancement
in the processing of external cues (Aston-Jones
& Cohen 2005, LeDoux 2007, Ramos &
Arnsten 2007, Talarovicova et al. 2007).
Detection of threat by the amygdala also has
endocrine consequences. Amygdaloid signaling
causes secretion of corticotropin-releasing hormone (CRH) from the periventricular nucleus
of the hypothalamus. CRH, along with other
hypothalamic secretagogs, causes the release of
adrenocorticotropic hormone from the pituitary, which in turn stimulates the secretion of
GCs from the adrenal cortex. Circulating GCs
bind to the high-afnity mineralocorticoid
receptor (MR) and the low-afnity glucocorticoid receptor (GR) in tissues throughout the
body and the brain (de Kloet 2004, Korte 2001).
Finally, detection of threat by the amygdala has autonomic consequences. Connections
from the amygdala to the brainstem lead to
the activation of the sympathetic nervous system, involving the release of epinephrine and
NE from the adrenal medulla and NE from
the terminals of sympathetic nerves throughout the body. Adrenal medullary hormones and
sympathetic nerves produce an array of effects,
including increasing blood pressure and heart
rate, diverting stored energy to exercising muscle, and inhibiting digestion (Goldstein 2003,
McCarty & Gold 1996, Sapolsky 2004). Coming full circle, fear circuitry is profoundly inuenced by these endocrine and autonomic stress
responses. Thus, GCs travel in the circulation
to the brain and affect the amygdala and a variety of other structures. Although NE does not
cross the blood-brain barrier, it may affect the
brain indirectly by binding to visceral afferent
nerves, which transmit to the brain (McGaugh
2003). Thus, the detection of threat and the
consequent activation of the fear system elicit a
variety of effects that feed back onto the system
that initiates and modulates emotional processing (McEwen 2003, Pare 2003, Sapolsky 2003).
With this overview we now turn to a more detailed consideration of how the fear system interacts with stress.
GR: glucocorticoid
receptor
HOW DO STRESS,
NOREPINEPHRINE,
AND GLUCOCORTICOIDS
INFLUENCE DIFFERENT PHASES
OF FEAR CONDITIONING?
In the remainder of this review we examine
how stress and its biochemical concomitants
(Charmandari et al. 2005, Sapolsky 2004) inuence the acquisition, consolidation, reconsolidation, and extinction of conditioned fear,
as well as the underlying neural mechanisms
responsible for different elements of fear processing. Throughout, we compare animal and
human studies and their implications for stressinduced psychopathology. Instead of an exhaustive survey of all pertinent studies, we highlight
overarching trends in the literature. To distinguish effects on acquisition from consolidation,
it is necessary to compare pretraining manipulations with immediate posttraining manipulations (Rodrigues et al. 2004). This comparison
is necessary because the effects of stress or drugs
tend to last beyond the short training session
in such studies (sometimes only a single training trial). If pretraining manipulations disrupt
STM but posttraining manipulations do not,
the effect is said to be on acquisition (though
an effect on STM itself cannot be ruled out).
If posttraining manipulations leave STM intact
but disrupt LTM, then the effect is said to be on
LTM consolidation. Another important manipulation involves treatments given immediately
before testing LTM. This treatment is called an
expression test. However, many studies examine pretraining or postraining effects only on
LTM but not on STM or on acquisition. Similarly, relatively few studies observe effects on
expression. Therefore, more investigations are
needed to fully determine how stress, NE, and
GCs inuence different phases of fear learning
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and its expression in memory. Below we discuss what has been discovered so far. Although
variability in protocols makes it difcult to com-
pare stress manipulations directly across studies, we make distinctions between acute and
chronic stress throughout.
Functional connectivity
Environmental
threat
Sensory
thalamus
PFC
Sensory
thalamus
Sensory
cortex
Sensory
cortex
(fast)
(slow)
Amygdala
Hippocampus
Feedback loop
PVN
Pituitary
Adrenal
gland
ACTH
Adrenal
Ad
dren gland
Monoamine
systems
SNS
Kidney
Medulla
Cortex
NTS
Glucocorticoids
Epinephrine and
norepinephrine
Glucocorticoids
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Vagus
nerve
Sapolsky
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ACQUISITION OF FEAR
CONDITIONING
CONSOLIDATION OF
LONG-TERM MEMORY
Figure 2
Overview of fear arousal and the stress response. Upper left: Black arrows indicate the functional connectivity of brain structures
involved in fear conditioning. Upper right: Red arrows represent the activation of brain areas recruited during the processing of
threatening stimuli. Bottom Left: The stress response leads to the release of stress hormones. Bottom Right: Dashed lines indicate
feedback of the stress response to neural structures involved in fear conditioning. ACTH, adrenocorticotropic hormone; CRH,
corticotropin-releasing factor; GRs, glucocorticoid receptors; MRs, mineralocorticoid receptors; NTS: nucleus of the solitary tract;
PVN, periventricular nucleus of the hypothalamus; SNS, sympathetic nervous system.
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time-dependent role for GC-facilitated memory of the tone-shock association (Hui et al.
2004). In addition, elevation of GCs systemically or in the LA/B enhances the retrieval of fear memories in avoidance paradigms
(Izquierdo et al. 2002, Roozendaal & McGaugh
1997), and this enhancement can be effective
for memories acquired from one day to many
months before (Izquierdo et al. 2002). Finally,
in humans, high GC levels positively correlate
with fear memory consolidation (Zorawski et al.
2006).
be investigated. After reactivation, GR antagonism in the LA/B disrupts LTM but not STM
of auditory fear reconsolidation; this effect occurs if blockade is immediate, but not 6 hours,
after reactivation. Furthermore, this immediate postreactivation blockade is effective both
1 day and 10 days after conditioning ( Jin et al.
2007). Likewise, GR blockade in the LA/B immediately after retrieval blocks reconsolidation
in an avoidance paradigm (Tronel & Alberini
2007).
RECONSOLIDATION
EXTINCTION
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Rodrigues
LeDoux
Sapolsky
LTM
LTM
LTM
LTM
?
STM
LTM
Contextual
STM
Cued
STM
Contextual
STM
Cued
STM
Postreactivation
Reconsolidation
Prereactivation
Preconditioning
Extinction
Preextinction
training
Postextinction
training
Abbreviations: LA/B, lateral/basal nucleus of the amygdala; GC, glucocorticoids; LTM, long-term memory; mPFC, medial prefrontal cortex; NE, norepinephrine; STM, short-term memory.
Key:
, Stress, NE, or GCs facilitate fear memory here.
, Stress or GCs impair fear memory here.
, Stress, NE, or GCs manipulations produce no inuences at this time.
?, Effects unknown.
, conicting reports.
, effectively disrupts consolidation of avoidance learning, but not fear conditioning.
GCs
LTM
Contextual
STM
Cued
Pretesting
13 May 2009
NE
STRESS
Posttraining
Conditioning
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Pretraining
Table 1 Localization of manipulations: systemic/brain-wide (black), LA/B (red), hippocampus (blue), and mPFC (green)a,b . Postshock freezing findings
included in contextual STM results
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Control
Stress
Amygdala (LA/B)
500 nm
Hippocampus (CA3)
500 nm
500 nm
Figure 3
Inuences of stress on the morphology of neurons in fear circuitry. LA/B,
lateral/basal nucleus of the amygdala; CA3, cornu ammonis subeld of the
hippocampus; IL, infralimbic subregion of the medial prefrontal cortex.
Reconstructed Golgi-impregnated neuron images reproduced with permission
from Vyas et al. (2002) and Izquierdo et al. (2006).
Rodrigues
LeDoux
Sapolsky
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Dendrite
GABA
Cl-
Axon
Enhancement of neuronal
responses and excitability
GABA-A
receptor
Percent of control
200
100
LTP induction
0
Time (min)
50
LA/B neuron
cell body
Figure 4
Inuence of stress, norepinephrine (NE), and glucocorticoids (GCs) on the electrophysiological properties
of lateral (LA)/basal nucleus (B) neurons of the amygdala. Representative traces and long-term potentiation
(LTP) data reproduced with permission from Tully et al. (2007).
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know how GCs directly inuence the electrophysiological proles of mPFC neurons.
Therefore, more data are needed to illustrate
how GCs interact with other factors to inuence plasticity in structures that modulate fear
conditioning.
CONCLUSIONS
An extensive literature has demonstrated the
ways in which stress, and the endocrine mediators of the stress response, can impact explicit,
declarative memory processes (McEwen 1999).
Though based on a smaller literature, this review highlights the ability of stress and arousaltriggered fear to impact emotional learning
and memory, as assessed by fear conditioning. Indeed, stressful experiences, NE, and GCs
alter the morphological and electrophysiological characteristics of neurons in areas that play a
vital role in fear processing, including the amygdala (LA/B), hippocampus, and PFC. As a result, they can have a powerful inuence on fear
conditioning.
In the laboratory, investigators use a number of models to induce stress, including
exposure to predator odor, restraint, foot shock,
forced swimming, saline injections, and cold
temperatures. Furthermore, the duration of
stress manipulations can be acute, moderate, or
chronic. Although these differences make direct
comparisons between studies difcult, stereotypical responses to these various stressors do
occur and activate the brains fear system,
thus initiating the stress response in both the
body and the brain. Nonetheless, because stress
magnitude and duration differentially impact
the morphological and electrophysiological
properties of fear circuitry neurons, it would
be important for future studies to compare
and contrast the inuence of different stress
protocols.
Existing studies show that stress before or
after training boosts LTM of fear conditioning. In addition, stress before, but not after,
reactivation enhances reconsolidation. Finally,
stress before fear conditioning, but not before
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DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, or nancial holdings that
might be perceived as affecting the objectivity of this review.
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ACKNOWLEDGMENTS
We apologize to all the investigators whose research could not be appropriately cited owing
to space limitations. We extend our sincere gratitude to our many wonderful collaborators for
thoughtful discussions pertaining to the topic and data of this review. Research by S.M.R. and
R.M.S. on this topic supported by NIH Grant 5R01 AG020633. J.E.L. supported by NIH Grants
P50 MH058911, R01 MH046516, R37 MH037884, and K05 MH067048.
LITERATURE CITED
Rodrigues
LeDoux
Sapolsky
ANRV379-NE32-13
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Cain CK, LeDoux JE. 2008. Emotional processing and motivation: in search of brain mechanisms. In Handbook
of Approach and Avoidance Motivation, ed. AJ Elliot, pp. 1734. New York: Psychology Press
Cardinal RN, Parkinson JA, Hall J, Everitt BJ. 2002. Emotion and motivation: the role of the amygdala, ventral
striatum, and prefrontal cortex. Neurosci. Biobehav. Rev. 26:32152
Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N. 2007. The prefrontal cortex as a key target of the
maladaptive response to stress. J. Neurosci. 27:278187
Charmandari E, Tsigos C, Chrousos G. 2005. Endocrinology of the stress response. Annu. Rev. Physiol. 67:259
84
Conrad CD, LeDoux JE, Magarinos AM, McEwen BS. 1999. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav. Neurosci. 113:90213
Conrad CD, MacMillan DD 2nd, Tsekhanov S, Wright RL, Baran SE, Fuchs RA. 2004. Inuence of chronic
corticosterone and glucocorticoid receptor antagonism in the amygdala on fear conditioning. Neurobiol.
Learn. Mem. 81:18599
Cook SC, Wellman CL. 2004. Chronic stress alters dendritic morphology in rat medial prefrontal cortex.
J. Neurobiol. 60:23648
Cordero MI, Kruyt ND, Merino JJ, Sandi C. 2002. Glucocorticoid involvement in memory formation in a
rat model for traumatic memory. Stress 5:7379
Cordero MI, Kruyt ND, Sandi C. 2003a. Modulation of contextual fear conditioning by chronic stress in rats
is related to individual differences in behavioral reactivity to novelty. Brain Res. 970:24245
Cordero MI, Venero C, Kruyt ND, Sandi C. 2003b. Prior exposure to a single stress session facilitates
subsequent contextual fear conditioning in rats. Evidence for a role of corticosterone. Horm. Behav.
44:33845
Corodimas KP, LeDoux JE, Gold PW, Schulkin J. 1994. Corticosterone potentiation of conditioned fear in
rats. Ann. NY Acad. Sci. 746:39293
Czeh B, Perez-Cruz C, Fuchs E, Flugge G. 2008. Chronic stress-induced cellular changes in the medial
prefrontal cortex and their potential clinical implications: Does hemisphere location matter? Behav. Brain
Res. 190:113
Debiec J, Ledoux JE. 2004. Disruption of reconsolidation but not consolidation of auditory fear conditioning
by noradrenergic blockade in the amygdala. Neuroscience 129:26772
de Kloet ER, Oitzl MS, Joels M. 1999. Stress and cognition: Are corticosteroids good or bad guys? Trends
Neurosci. 22:42226
de Kloet ER. 2004. Hormones and the stressed brain. Ann. NY Acad. Sci. 1018:115
de Quervain DJ. 2008. Glucocorticoid-induced reduction of traumatic memories: implications for the treatment of PTSD. Prog. Brain Res. 167:23947
DeRijk R, de Kloet ER. 2005. Corticosteroid receptor genetic polymorphisms and stress responsivity. Endocrine
28:26370
Diamond DM, Campbell AM, Park CR, Halonen J, Zoladz PR. 2007. The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, ashbulb
and traumatic memories, and the Yerkes-Dodson law. Neural Plast. 2007:133, Art. 60803
Donley MP, Schulkin J, Rosen JB. 2005. Glucocorticoid receptor antagonism in the basolateral amygdala and
ventral hippocampus interferes with long-term memory of contextual fear. Behav. Brain Res. 164:197205
Dudai Y. 2004. The neurobiology of consolidations, or, how stable is the engram? Annu. Rev. Psychol. 55:5186
Dudai Y. 2006. Reconsolidation: the advantage of being refocused. Curr. Opin. Neurobiol. 16:17478
Duvarci S, Pare D. 2007. Glucocorticoids enhance the excitability of principal basolateral amygdala neurons.
J. Neurosci. 27:448291
Fanselow MS, Poulos AM. 2005. The neuroscience of mammalian associative learning. Annu. Rev. Psychol.
56:20734
Feenstra MG, Vogel M, Botterblom MH, Joosten RN, de Bruin JP. 2001. Dopamine and noradrenaline
efux in the rat prefrontal cortex after classical aversive conditioning to an auditory cue. Eur. J. Neurosci.
13:105154
Fendt M, Fanselow MS. 1999. The neuroanatomical and neurochemical basis of conditioned fear.
Neurosci. Biobehav. Rev. 23:74360
www.annualreviews.org Stress Hormones and Fear Circuitry
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ARI
13 May 2009
8:31
Ferry B, McGaugh JL. 1999. Clenbuterol administration into the basolateral amygdala post-training enhances
retention in an inhibitory avoidance task. Neurobiol. Learn. Mem. 72:812
Frankland PW, Josselyn SA, Anagnostaras SG, Kogan JH, Takahashi E, Silva AJ. 2004. Consolidation of CS
and US representations in associative fear conditioning. Hippocampus 14:55769
Fudge JL, Emiliano AB. 2003. The extended amygdala and the dopamine system: another piece of the
dopamine puzzle. J. Neuropsychiatry Clin. Neurosci. 15:30616
Gabriel M, Burhans L, Kashef A. 2003. Consideration of a unied model of amygdalar associative functions.
Ann. NY Acad. Sci. 985:20617
Gallagher M, Kapp BS, Musty RE, Driscoll PA. 1977. Memory formation: evidence for a specic neurochemical system in the amygdala. Science 198:42325
Garcia R, Paquereau J, Vouimba RM, Jaffard R. 1998. Footshock stress but not contextual fear conditioning
induces long-term enhancement of auditory-evoked potentials in the basolateral amygdala of the freely
behaving rat. Eur. J. Neurosci. 10:45763
Garcia R, Spennato G, Nilsson-Todd L, Moreau JL, Deschaux O. 2008. Hippocampal low-frequency stimulation and chronic mild stress similarly disrupt fear extinction memory in rats. Neurobiol. Learn. Mem.
89:56066
Goldstein DS. 2003. Catecholamines and stress. Endocr. Regul. 37:6980
Gourley SL, Kedves AT, Olausson P, Taylor JR. 2008. A history of corticosterone exposure regulates fear
extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacology 34:70716
Gray TS. 1993. Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to
stress. Ann. NY Acad. Sci. 697:5360
Grillon C, Cordova J, Morgan CA, Charney DS, Davis M. 2004. Effects of the beta-blocker propranolol on
cued and contextual fear conditioning in humans. Psychopharmacology 175:34252
Harley CW. 2007. Norepinephrine and the dentate gyrus. Prog. Brain Res. 163:299318
Hu H, Real E, Takamiya K, Kang MG, Ledoux J, et al. 2007. Emotion enhances learning via norepinephrine
regulation of AMPA-receptor trafcking. Cell 131:16073
Huang YY, Martin KC, Kandel ER. 2000. Both protein kinase A and mitogen-activated protein kinase are required in the amygdala for the macromolecular synthesis-dependent late phase of long-term potentiation.
J. Neurosci. 20:631725
Hui GK, Figueroa IR, Poytress BS, Roozendaal B, McGaugh JL, Weinberger NM. 2004. Memory enhancement of classical fear conditioning by post-training injections of corticosterone in rats. Neurobiol. Learn.
Mem. 81:6774
Hui IR, Hui GK, Roozendaal B, McGaugh JL, Weinberger NM. 2006. Posttraining handling facilitates
memory for auditory-cue fear conditioning in rats. Neurobiol. Learn. Mem. 86:16063
Izquierdo A, Wellman CL, Holmes A. 2006. Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J. Neurosci. 26:573338
Izquierdo LA, Barros DM, Medina JH, Izquierdo I. 2002. Stress hormones enhance retrieval of fear conditioning acquired either one day or many months before. Behav. Pharmacol. 13:20313
Jackson ME, Moghaddam B. 2006. Distinct patterns of plasticity in prefrontal cortex neurons that encode
slow and fast responses to stress. Eur. J. Neurosci. 24:170210
Ji J, Maren S. 2007. Hippocampal involvement in contextual modulation of fear extinction. Hippocampus
17:74958
Ji JZ, Wang XM, Li BM. 2003. Decit in long-term contextual fear memory induced by blockade of betaadrenoceptors in hippocampal CA1 region. Eur. J. Neurosci. 17:194752
Jin XC, Lu YF, Yang XF, Ma L, Li BM. 2007. Glucocorticoid receptors in the basolateral nucleus of amygdala
are required for postreactivation reconsolidation of auditory fear memory. Eur. J. Neurosci. 25:3702
12
Joels M, de Kloet ER. 1992. Control of neuronal excitability by corticosteroid hormones. Trends Neurosci.
15:2530
Kalin NH, Shelton SE. 2003. Nonhuman primate models to study anxiety, emotion regulation, and psychopathology. Ann. NY Acad. Sci. 1008:189200
Kavushansky A, Richter-Levin G. 2006. Effects of stress and corticosterone on activity and plasticity in the
amygdala. J. Neurosci. Res. 84:158087
ANRV379-NE32-13
308
Rodrigues
LeDoux
Sapolsky
ANRV379-NE32-13
ARI
13 May 2009
8:31
Kavushansky A, Vouimba RM, Cohen H, Richter-Levin G. 2006. Activity and plasticity in the CA1, the dentate
gyrus, and the amygdala following controllable vs. uncontrollable water stress. Hippocampus 16:3542
Kim JJ, Fanselow MS. 1992. Modality-specic retrograde amnesia of fear. Science 256:67577
Kohda K, Harada K, Kato K, Hoshino A, Motohashi J, et al. 2007. Glucocorticoid receptor activation is
involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic
stress disorder model. Neuroscience 148:2233
Korte SM. 2001. Corticosteroids in relation to fear, anxiety and psychopathology. Neurosci. Biobehav. Rev.
25:11742
LaBar KS, LeDoux JE. 2001. Coping with danger: the neural basis of defensive behaviors and fearful feelings.
In Handbook of Physiology, Section 7: The Endocrine System, Vol. IV: Coping with the Environment: Neural and
Endocrine Mechanisms, ed. BS McEwen, pp. 13954. New York: Oxford Univ. Press
Lang PJ, Davis M. 2006. Emotion, motivation, and the brain: reex foundations in animal and human research.
Prog. Brain Res. 156:329
LeDoux J. 2007. The amygdala. Curr. Biol. 17:R86874
LeDoux JE. 1995. Emotion: clues from the brain. Annu. Rev. Psychol. 46:20935
LeDoux JE. 1996. The Emotional Brain: The Mysterious Underpinnings of Emotional Life. New York: Simon &
Schuster. 384 pp.
LeDoux JE. 2000. Emotion circuits in the brain. Annu. Rev. Neurosci. 23:15584
LeDoux JE. 2002. Synaptic Self: How Our Brains Become Who We Are. New York: Viking. x. 406 pp.
Lee HJ, Berger SY, Stiedl O, Spiess J, Kim JJ. 2001. Post-training injections of catecholaminergic drugs do
not modulate fear conditioning in rats and mice. Neurosci. Lett. 303:12326
Lee JL, Dickinson A, Everitt BJ. 2005. Conditioned suppression and freezing as measures of aversive Pavlovian
conditioning: effects of discrete amygdala lesions and overtraining. Behav. Brain Res. 159:22133
Liang KC, Juler RG, McGaugh JL. 1986. Modulating effects of posttraining epinephrine on memory: involvement of the amygdala noradrenergic system. Brain Res. 368:12533
Likhtik E, Popa D, Apergis-Schoute J, Fidacaro GA, Pare D. 2008. Amygdala intercalated neurons are required
for expression of fear extinction. Nature 454:64245
Liu X, Lonart G, Sanford LD. 2007. Transient fear-induced alterations in evoked release of norepinephrine
and GABA in amygdala slices. Brain Res. 1142:4653
Luine V. 2002. Sex differences in chronic stress effects on memory in rats. Stress 5:20516
Lyons DM, Parker KJ. 2007. Stress inoculation-induced indications of resilience in monkeys. J. Trauma. Stress
20:42333
Maren S. 1999. Neurotoxic basolateral amygdala lesions impair learning and memory but not the performance
of conditional fear in rats. J. Neurosci. 19:8696703
Maren S. 2001. Neurobiology of Pavlovian fear conditioning. Annu. Rev. Neurosci. 24:897931
Maren S. 2005. Synaptic mechanisms of associative memory in the amygdala. Neuron 47:78386
Maren S, Quirk GJ. 2004. Neuronal signalling of fear memory. Nat. Rev. 5:84452
Maroun M, Richter-Levin G. 2003. Exposure to acute stress blocks the induction of long-term potentiation
of the amygdala-prefrontal cortex pathway in vivo. J. Neurosci. 23:44069
McCarty R, Gold PE. 1996. Catecholamines, stress, and disease: a psychobiological perspective. Psychosom.
Med. 58:59097
McDonald AJ. 1991. Topographical organization of amygdaloid projections to the caudatoputamen, nucleus
accumbens, and related striatal-like areas of the rat brain. Neuroscience 44:1533
McDonald AJ. 1998. Cortical pathways to the mammalian amygdala. Prog. Neurobiol. 55:257332
McDonald AJ, Mascagni F, Guo L. 1996. Projections of the medial and lateral prefrontal cortices to the
amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat. Neuroscience 71:5575
McEwen BS. 1999. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22:10522
McEwen BS. 2001. Plasticity of the hippocampus: adaptation to chronic stress and allostatic load. Ann. NY
Acad. Sci. 933:26577
McEwen BS. 2003. Mood disorders and allostatic load. Biol. Psychiatry 54:2007
McEwen BS, Magarinos AM. 2001. Stress and hippocampal plasticity: implications for the pathophysiology
of affective disorders. Hum. Psychopharmacol. 16:S719
www.annualreviews.org Stress Hormones and Fear Circuitry
309
ARI
13 May 2009
8:31
ANRV379-NE32-13
310
Rodrigues
LeDoux
Sapolsky
ANRV379-NE32-13
ARI
13 May 2009
8:31
Price JL. 2003. Comparative aspects of amygdala connectivity. Ann. NY Acad. Sci. 985:5058
Przybyslawski J, Roullet P, Sara SJ. 1999. Attenuation of emotional and nonemotional memories after their
reactivation: role of beta adrenergic receptors. J. Neurosci. 19:662328
Pugh CR, Fleshner M, Rudy JW. 1997a. Type II glucocorticoid receptor antagonists impair contextual but
not auditory-cue fear conditioning in juvenile rats. Neurobiol. Learn. Mem. 67:7579
Pugh CR, Tremblay D, Fleshner M, Rudy JW. 1997b. A selective role for corticosterone in contextual-fear
conditioning. Behav. Neurosci. 111:50311
Quirarte GL, Roozendaal B, McGaugh JL. 1997. Glucocorticoid enhancement of memory storage involves
noradrenergic activation in the basolateral amygdala. Proc. Natl. Acad. Sci. USA 94:1404853
Quirk GJ, Garcia R, Gonzalez-Lima F. 2006. Prefrontal mechanisms in extinction of conditioned fear. Biol.
Psychiatry 60:33743
Quirk GJ, Mueller D. 2008. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology
33:5672
Radley JJ, Rocher AB, Janssen WG, Hof PR, McEwen BS, Morrison JH. 2005. Reversibility of apical dendritic
retraction in the rat medial prefrontal cortex following repeated stress. Exp. Neurol. 196:199203
Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, et al. 2006. Repeated stress induces dendritic spine
loss in the rat medial prefrontal cortex. Cereb. Cortex 16:31320
Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, et al. 2008. Repeated stress alters dendritic
spine morphology in the rat medial prefrontal cortex. J. Comp. Neurol. 507:114150
Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, et al. 2004. Chronic behavioral stress induces apical
dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 125:16
Ramos BP, Arnsten AF. 2007. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol. Ther. 113:52336
Rau V, DeCola JP, Fanselow MS. 2005. Stress-induced enhancement of fear learning: an animal model of
posttraumatic stress disorder. Neurosci. Biobehav. Rev. 29:120723
Rau V, Fanselow MS. 2008. Exposure to a stressor produces a long lasting enhancement of fear learning in
rats. Stress 18:1
Richter-Levin G. 2004. The amygdala, the hippocampus, and emotional modulation of memory.
Neuroscientist 10:3139
Richter-Levin G, Akirav I. 2003. Emotional tagging of memory formationin the search for neural mechanisms. Brain Res. Brain Res. Rev. 43:24756
Rocher C, Spedding M, Munoz C, Jay TM. 2004. Acute stress-induced changes in hippocampal/prefrontal
circuits in rats: effects of antidepressants. Cereb. Cortex 14:22429
Rodrigues SM, Sapolsky RM. 2009. Disruption of fear memory through dual-hormone gene therapy. Biol.
Psychiatry 65:44144
Rodrigues SM, Schafe GE, LeDoux JE. 2004. Molecular mechanisms underlying emotional learning and
memory in the lateral amygdala. Neuron 44:7591
Rodrguez Manzanares PA, Isoardi NA, Carrer HF, Molina VA. 2005. Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala.
J. Neurosci. 25:872534
Romanski LM, Clugnet MC, Bordi F, LeDoux JE. 1993. Somatosensory and auditory convergence in the
lateral nucleus of the amygdala. Behav. Neurosci. 107:44450
Roozendaal B, Hui GK, Hui IR, Berlau DJ, McGaugh JL, Weinberger NM. 2006. Basolateral amygdala noradrenergic activity mediates corticosterone-induced enhancement of auditory fear conditioning. Neurobiol.
Learn. Mem. 86:24955
Roozendaal B, McGaugh JL. 1997. Glucocorticoid receptor agonist and antagonist administration into
the basolateral but not central amygdala modulates memory storage. Neurobiol. Learn. Mem. 67:176
79
Rosenkranz JA, Moore H, Grace AA. 2003. The prefrontal cortex regulates lateral amygdala neuronal plasticity
and responses to previously conditioned stimuli. J. Neurosci. 23:1105464
Santini E, Quirk GJ, Porter JT. 2008. Fear conditioning and extinction differentially modify the intrinsic
excitability of infralimbic neurons. J. Neurosci. 28:402836
www.annualreviews.org Stress Hormones and Fear Circuitry
311
ARI
13 May 2009
8:31
Sapolsky RM. 2003. Stress and plasticity in the limbic system. Neurochem. Res. 28:173542
Sapolsky RM. 2004. Why Zebras Dont Get Ulcers. New York: Owl Book/Henry Holt. xv. 539 pp.
Sapolsky RM, Romero LM, Munck AU. 2000. How do glucocorticoids inuence stress responses? Integrating
permissive, suppressive, stimulatory, and preparative actions. Endocr. Rev. 21:5589
Sarter M, Markowitsch HJ. 1985. Involvement of the amygdala in learning and memory: a critical review, with
emphasis on anatomical relations. Behav. Neurosci. 99:34280
Schafe GE, Nader K, Blair HT, LeDoux JE. 2001. Memory consolidation of Pavlovian fear conditioning: a
cellular and molecular perspective. Trends Neurosci. 24:54046
Schelling G, Roozendaal B, De Quervain DJ. 2004. Can posttraumatic stress disorder be prevented with
glucocorticoids? Ann. NY Acad. Sci. 1032:15866
Segal M, Markram H, Richter-Levin G. 1991. Actions of norepinephrine in the rat hippocampus.
Prog. Brain Res. 88:32330
Selden NR, Robbins TW, Everitt BJ. 1990. Enhanced behavioral conditioning to context and impaired behavioral and neuroendocrine responses to conditioned stimuli following ceruleocortical noradrenergic
lesions: support for an attentional hypothesis of central noradrenergic function. J. Neurosci. 10:531
39
Shors TJ, Seib TB, Levine S, Thompson RF. 1989. Inescapable versus escapable shock modulates long-term
potentiation in the rat hippocampus. Science 244:22426
Soravia LM, Heinrichs M, Aerni A, Maroni C, Schelling G, et al. 2006. Glucocorticoids reduce phobic fear
in humans. Proc. Natl. Acad. Sci. USA 103:558590
Sotres-Bayon F, Bush DE, LeDoux JE. 2004. Emotional perseveration: an update on prefrontal-amygdala
interactions in fear extinction. Learn. Mem. 11:52535
Sousa N, Lukoyanov NV, Madeira MD, Almeida OFX, Paula-Barbosa MM. 2000. Reorganization of the
morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral
improvement. Neuroscience 97:25366
Stefanacci L, Amaral DG. 2002. Some observations on cortical inputs to the macaque monkey amygdala: an
anterograde tracing study. J. Comp. Neurol. 451:30123
Swanson LW. 2003. The amygdala and its place in the cerebral hemisphere. Ann. NY Acad. Sci. 985:17484
Talarovicova A, Krskova L, Kiss A. 2007. Some assessments of the amygdala role in suprahypothalamic neuroendocrine regulation: a minireview. Endocr. Regul. 41:15562
Tronel S, Alberini CM. 2007. Persistent disruption of a traumatic memory by postretrieval inactivation of
glucocorticoid receptors in the amygdala. Biol. Psychiatry 62:3339
Tully K, Li Y, Tsvetkov E, Bolshakov VY. 2007. Norepinephrine enables the induction of associative long-term
potentiation at thalamo-amygdala synapses. Proc. Natl. Acad. Sci. USA 104:1414650
Vidal-Gonzalez I, Vidal-Gonzalez B, Rauch SL, Quirk GJ. 2006. Microstimulation reveals opposing inuences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn. Mem. 13:728
33
Vouimba RM, Munoz C, Diamond DM. 2006. Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala. Stress 9:29
40
Vouimba RM, Yaniv D, Diamond D, Richter-Levin G. 2004. Effects of inescapable stress on LTP in the
amygdala versus the dentate gyrus of freely behaving rats. Eur. J. Neurosci. 19:188794
Vyas A, Bernal S, Chattarji S. 2003. Effects of chronic stress on dendritic arborization in the central and
extended amygdala. Brain Res. 965:29094
Vyas A, Chattarji S. 2004. Modulation of different states of anxiety-like behavior by chronic stress. Behav.
Neurosci. 118:145054
Vyas A, Jadhav S, Chattarji S. 2006. Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala. Neuroscience 143:38793
Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S. 2002. Chronic stress induces contrasting patterns of
dendritic remodeling in hippocampal and amygdaloid neurons. J. Neurosci. 22:681018
Vyas A, Pillai AG, Chattarji S. 2004. Recovery after chronic stress fails to reverse amygdaloid neuronal
hypertrophy and enhanced anxiety-like behavior. Neuroscience 128:66773
ANRV379-NE32-13
312
Rodrigues
LeDoux
Sapolsky
ANRV379-NE32-13
ARI
13 May 2009
8:31
Weinstock M. 2007. Gender differences in the effects of prenatal stress on brain development and behaviour.
Neurochem. Res. 32:173040
Wellman CL. 2001. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic
corticosterone administration. J. Neurobiol. 49:24553
Wessa M, Flor H. 2007. Failure of extinction of fear responses in posttraumatic stress disorder: evidence from
second-order conditioning. Am. J. Psychiatry 164:168492
Wilensky AE, Schafe GE, Kristensen MP, LeDoux JE. 2006. Rethinking the fear circuit: the central nucleus of
the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning.
J. Neurosci. 26:1238796
Yang YL, Chao PK, Lu KT. 2006. Systemic and intra-amygdala administration of glucocorticoid agonist and
antagonist modulate extinction of conditioned fear. Neuropsychopharmacology 31:91224
Zimmerman JM, Rabinak CA, McLachlan IG, Maren S. 2007. The central nucleus of the amygdala is essential
for acquiring and expressing conditional fear after overtraining. Learn. Mem. 14:63444
Zorawski M, Blanding NQ, Kuhn CM, LaBar KS. 2006. Effects of stress and sex on acquisition and consolidation of human fear conditioning. Learn. Mem. 13:44150
Zorawski M, Killcross S. 2002. Posttraining glucocorticoid receptor agonist enhances memory in appetitive
and aversive Pavlovian discrete-cue conditioning paradigms. Neurobiol. Learn. Mem. 78:45864
313
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ARI
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