The Influence of Stress Hormones on Fear Circuitry

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The Influence of Stress
Hormones on Fear Circuitry
Sarina M. Rodrigues,1 Joseph E. LeDoux,2,∗
and Robert M. Sapolsky3,∗
1
Institute of Personality and Social Research, University of California, Berkeley,
California 94720; Address correspondence to Department of Psychology, Oregon State
University, Corvallis, Oregon 97331; email: [email protected]
2
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: [email protected]
3
Departments of Biological Sciences and Neurology and Neurological Sciences,
Stanford Medical Center, Stanford, California 94305-5020; email: [email protected]
Annu. Rev. Neurosci. 2009. 32:289–313
Key Words
First published online as a Review in Advance on
March 24, 2009
fear conditioning, glucocorticoids, norepinephrine
The Annual Review of Neuroscience is online at
neuro.annualreviews.org
This article’s doi:
10.1146/annurev.neuro.051508.135620
c 2009 by Annual Reviews.
Copyright All rights reserved
0147-006X/09/0721-0289$20.00
∗
These authors contributed equally to this work.
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 influence neural structures that control emotion and cognition. To illustrate
this influence, 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 influence 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 . . . . . . . .
Consolidation of LTM of
Fear Conditioning . . . . . . . . . . . . . .
Consolidation of LTM
of Fear Conditioning . . . . . . . . . . . .
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“The oldest and strongest emotion of mankind is
fear.”
—H.P. Lovecraft
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RECONSOLIDATION . . . . . . . . . . . . . .
Reconsolidation of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
The Effects of NE Manipulation
on the Reconsolidation of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
The Effects of GC Manipulation
on the Reconsolidation
EXTINCTION . . . . . . . . . . . . . . . . . . . . . .
Extinction of Fear
Conditioning . . . . . . . . . . . . . . . . . . .
Involvement of NE in the Extinction
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 Influence of Stress on
the Morphology of Neurons
in Fear Circuitry . . . . . . . . . . . . . . . .
The Influence of Stress on the
Electrophysiological Properties
of Neurons in Fear Circuitry . . . .
The Influence of NE on the
The Influence of GCs on the
CONCLUSIONS . . . . . . . . . . . . . . . . . . . .
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“A crust eaten in peace is better than a banquet
eaten in fear.”
—Aesop
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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, blowfish inflate 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).
WHAT IS FEAR, AND HOW IS IT
ORGANIZED IN THE BRAIN?
The term fear refers to both a psychological
state and a set of bodily responses that occur
in response to threat (LeDoux 1996). Much
progress has been made in understanding how
fear is organized in the brain through studies
of Pavlovian fear conditioning, which we focus on here (Fanselow & Poulos 2005; Lang &
Davis 2006; LeDoux 1995, 1996, 2007; Maren
2001, 2005; Paré et al. 2004; Rodrigues et al.
2004). There are a variety of ways to assess
learned fear besides measuring Pavlovian conditioned response effects. For example, a number of studies have examined the role of brain areas in passive and active avoidance conditioning
(Gabriel et al. 2003, McGaugh 2003, Sarter &
Markowitsch 1985). In such studies, fear is
measured indirectly in terms of instrumental
behaviors that avoid danger. Because studies of
avoidance conditioning have not led to a coherent view of the neural system that mediates
avoidance (Cain & LeDoux 2008), we emphasize the effects of stress on fear conditioning in
this review. However, we mention some findings from other procedures where relevant.
CS: neutral
conditioned stimulus
US: aversive
unconditioned
stimulus
NE: norepinephrine
GC: glucocorticoid
CR: conditioned
response
Studying Fear in the Laboratory
with Fear Conditioning
Pavlovian fear conditioning is a behavioral procedure in which an emotionally neutral conditioned stimulus (CS), such as an auditory tone,
is paired with an aversive conditioned stimulus (US), typically a foot shock. After one or
several pairings, the CS comes to elicit defensive behaviors, including freezing behavior, as well as increased arousal in the brain
and secretion of norepinephrine (NE) and
glucocorticoids (GCs) peripherally. These
conditioned responses (CRs) are hard-wired
and occur in response to both innate and
learned threats. Thus, fear learning does not
create conditioned fear responses but allows
environmental stimuli to come to elicit such
responses.
www.annualreviews.org • Stress Hormones and Fear Circuitry
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Phases of Fear Conditioning
STM: short-term
memory
LTM: long-term
memory
LA: lateral nucleus of
the amygdala
CE: central nucleus of
the amygdala
In studies of fear conditioning, responses
elicited by the CS are often measured during
acquisition and retrieval tests. Acquisition is initial learning of the association between the CS
and US during the training portion of fear conditioning, when the animal first learns to pair
the two. Retrieval involves a test of the CS-US
association in which the CS is presented alone.
Retrieval tests that occur within a few hours
after acquisition measure short-term memory
(STM), whereas those that occur later (typically 24 hours after learning) measure longterm memory (LTM). STM and LTM tests are
used to study memory consolidation, the process through which an unstable STM is converted into a more stable and enduring LTM
trace (Dudai 2004, McGaugh 2000, Rodrigues
et al. 2004).
Retrieval tests are also used to study reconsolidation. Reconsolidation occurs when fear
memories are retrieved and enter a new labile state that requires stabilization via protein
synthesis to persist as an enduring LTM trace
(Dudai 2006, Nader 2003, Nader et al. 2000). In
addition, retrieval tests are utilized to measure
extinction, which is the gradual reduction in the
ability of the CS to elicit fear CRs that occur
when the CS is presented repeatedly in the absence of the US (Quirk & Mueller 2008, SotresBayon et al. 2004). Unlike the disruption of reconsolidation, which is robust and long lasting,
extinction involves a new learning process. As
a result, after extinction training, the CS can
spontaneously produce CRs again after the animal is reexposed to the US or is placed in a
novel context (Bouton et al. 2006, Ji & Maren
2007).
Neural Circuitry Underlying
Fear Conditioning
Fear conditioning is especially useful for studying the neural basis of fear because the circuit can be described in terms of pathways
processing the CS and controlling the CRs. Indeed, the pathways have been mapped from the
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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; Paré 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 filtering 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; Paré et al. 2004; Rodrigues
et al. 2004). Plasticity also occurs in the CE
(Paré 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, Paré et al. 2004). Projection neurons in the CE tend to be inhibitory,
thus LA and B projections to the ITC may
stimulate the ITC’s 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, Paré 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,
Pitkanen et al 2000, Price 2003, Stefanacci &
Amaral 2002). These connections allow higherorder cognitive processes, such as emotion regulation, complex associations, imagination, and
reactions to the news of an abstract state, to
influence amygdala functions.
The LA, B, and accessory basal nuclei are
sometimes grouped together as the BLA (basolateral amygdala). It is important to keep these
nuclei separate when possible.
Although the LA is required for fear conditioning under standard training conditions,
it appears that, with overtraining, fear conditioning can be mediated by circuits that do not
depend on the LA (Lee et al. 2005, Maren
1999). With overtraining, weak connections
to the CE appear to induce fear conditioning
(Zimmerman et al. 2007), but such pathways
are not normally used. Moreover, although the
B is not required for conditioning, it nevertheless appears to contribute to the appearance of
the fear response (Anglada-Figueroa & Quirk
2005). Some authors suggest that under some
conditions, especially those involving the use
of instrumental responses to assess Pavlovian
conditioning, the CE can mediate conditioning independent of LA (Balleine & Killcross
2006, Cardinal et al. 2002). However, this conclusion is extrapolated largely on the basis
of appetitive conditioning findings and needs
to be studied more systematically in aversive
conditioning.
The expression of fear responses can be regulated by the medial prefrontal cortex (mPFC)
via projections to the LA, B, and ITC. The infralimbic subregion (IL) of the mPFC is especially important for fear extinction (Quirk
et al. 2006, Rosenkranz et al. 2003, SotresBayon et al. 2004) because it inhibits amygdala
output (Vidal-Gonzalez et al. 2006). However,
investigators have debated the nature of the
role of prefrontal amygdala interactions in extinction (Quirk et al. 2006, Rosenkranz et al.
2003, Sotres-Bayon et al. 2004). The various
sensory and higher-order influences on the
amygdala are shown in Figure 1.
B: basal nucleus of the
amygdala
mPFC: medial
prefrontal cortex
IL: infralimic
subregion of the
mPFC
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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)
B
Polymodal
association cortex
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 specific amygdala nuclei. Asterisk (∗ ) denotes species difference in connectivity. (Bottom)
Outputs of some specific 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.
FEAR AROUSAL AND THE
STRESS RESPONSE: OVERVIEW
OF THIS FEEDFORWARD AND
FEEDBACK NETWORK
The presence of an environmental threat, in
effect a stressor, leads to the activation of the
brain’s fear system, thus initiating the stress
response in both the brain and the body. A key
structure in the fear system, as we have just reviewed, is the amygdala. It is responsible for
the detection of threat and the orchestration of
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stress responses in the brain and the body (see
Figure 2).
Once the amygdala detects a threat, its
outputs lead to the activation of a variety of
target areas that control both behavioral and
physiological responses designed to address
the threat (Lang & Davis 2006; LeDoux 1996,
2002). In addition to the expression of defensive behaviors, such as freezing (Blanchard
& Blanchard 1969, Fendt & Fanselow 1999),
amygdala activation leads to responses in the
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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-affinity mineralocorticoid
receptor (MR) and the low-affinity 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 influenced 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, Paré 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) influence 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 influence 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 difficult to com-
a
pare stress manipulations directly across studies, we make distinctions between acute and
chronic stress throughout.
b
Functional connectivity
Processing threat stimulus
Environmental
threat
Sensory
thalamus
PFC
Sensory
thalamus
Sensory
cortex
Sensory
cortex
(fast)
(slow)
Amygdala
Hippocampus
c
Release of stress hormones
d
Feedback loop
PVN
Pituitary
Adrenal
gland
ACTH
Adrenal
Ad
dren gland
Monoamine
systems
SNS
Kidney
Medulla
Cortex
NTS
Glucocorticoids
Epinephrine and
norepinephrine
Glucocorticoids
• Increase in cardiovascular tone
• Increase in blood pressure
• Mobilization of stored energy to muscle
• Transient enhancement of immunity
• Inhibition of costly, long-term processes
such as growth and reproduction
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Vagus
nerve
MRs and GRs
ARs
Epinephrine and
norepinephrine
Sapolsky
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ACQUISITION OF FEAR
CONDITIONING
Acquisition of Fear Conditioning
Although many studies have looked at the effects of pretraining stress on the LTM of fear
conditioning (see below), influences of pretraining stress on acquisition, as tested in STM,
have not been formally assessed. However,
postshock freezing levels during fear conditioning are greater in chronically stressed rats
that are classified as highly reactive, as indexed
by their locomotion in a novel environment
(Cordero et al. 2003a). This classification suggests that at least in some conditions, stress may
influence behavior during the learning process. However, this possibility needs further
study because postshock freezing during acquisition reflects contextual conditioning as much
as cued.
viral vector into the amygdala prior to training.
Although more STM evaluations are needed to
determine the precise time course of GCs on
fear, adrenalectomized rats show reduced contextual LTM but no immediate memory impairments (Pugh et al. 1997b). Likewise, GR
blockade in the amygdala (LA/B) or hippocampus disrupts contextual LTM but leaves postshock levels of freezing intact (Donley et al.
2005). A similar pattern emerges from pretraining intra-amygdala (LA/B) administration of a
viral vector expressing a gene to blunt GR signaling, which effectively disrupts both cued and
contextual LTM without affecting acquisition
or postshock levels of freezing (Rodrigues &
Sapolsky 2009). These studies suggest that GCs
may not be involved in acquisition so much as
in the consolidation of fear LTM. We discuss
additional results that support this claim in the
following section.
The Effects of NE on the Acquisition
of Fear Conditioning
CONSOLIDATION OF
LONG-TERM MEMORY
Locus coeruleus lesions or pretraining infusion of propranolol, a beta adrenergic receptor
antagonist, into the amygdala (LA/B) blocks
STM, and consequently LTM (Bush et al. 2006;
Neophytou et al. 2001). This finding is consistent with an effect on acquisition and its expression in STM.
Studies assessing memory consolidation typically administer manipulations immediately
after training (Dudai 2004, McGaugh 2000,
Rodrigues et al. 2004). If such manipulations
fail to disrupt STM but do disrupt LTM, consolidation (conversion of STM to LTM) is said
to be affected.
The Effects of GCs on the Acquisition
Consolidation of LTM of
Fear Conditioning
The contribution of GCs to fear acquisition
has been studied by either removing their effects via adrenalectomy, blocking GRs in the
amygdala with an antagonist, or infusing a
Pretraining exposure to both acute and chronic
stressors can enhance LTM of both cued
and contextual fear conditioning for at least
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
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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3 months (Conrad et al. 1999; Cordero et al.
2003a,b; Kohda et al. 2007; Rau et al. 2005; Rau
& Fanselow 2008). Acute posttraining stress
also enhances LTM for cued fear conditioning
(Hui et al. 2006). Furthermore, preexposure
to stress sensitizes fear-conditioning responses
such that less-intense stressors can produce robust fear behaviors, which may help explain
why individuals with PTSD react strongly to
mild stimuli and quickly form new fears (Rau
et al. 2005). Because measurements of pretraining stress on acquisition and STM are lacking
in the literature, more research is needed to address the temporal dynamics of stress on fear
conditioning.
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Central NE depletion or pretraining infusions of propranolol into the LA/B prior
to conditioning impair auditory fear LTM
(Bush et al. 2006, Selden et al. 1990). In
addition, systemic injections of epinephrine,
which leads to the release of NE in the brain
(McGaugh 2003), enhance contextual fear
LTM (Frankland et al. 2004, Hu et al. 2007) via
a facilitation of AMPA (α-amino-3-hydroxyl5-methyl-4-isoxazole-propionate) receptor insertion in the hippocampus (Hu et al. 2007).
However, posttraining administration of propranolol systemically or into the LA/B does not
affect LTM consolidation of auditory or contextual fear conditioning (Bush et al. 2006, Debiec
& Ledoux 2004, Lee et al. 2001). Thus, NE
in the amygdala does not seem critical for the
consolidation of fear conditioning, but it does
seem to interact with GCs to fortify memories
(Roozendaal et al. 2006).
Posttraining intrahippocampal propranolol
infusions given immediately, but not six hours
after training, block LTM, but not STM, of
contextual fear conditioning ( Ji et al. 2003).
Furthermore, systemic or intrahippocampal infusions given before testing one day after conditioning impair the retrieval of contextual memories (Murchison et al. 2004).
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In humans, systemic NE blockade disrupts the consolidation of contextual, but not
cued, fear conditioning LTM (Grillon et al.
2004). Studies involving avoidance conditioning, an indirect means of measuring fear, show
that posttraining systemic and intra-amygdala
(LA/B) pharmacological manipulations show
that NE is crucial to consolidate avoidance
learning (Ferry & McGaugh 1999, Gallagher
et al. 1977, Liang et al. 1986, Quirarte et al.
1997, Roozendaal & McGaugh 1997). Moreover, NE levels following avoidance training
correlate with subsequent retention (McGaugh
et al. 2002, McIntyre et al. 2002). Thus, direct
measurement of fear responses with fear conditioning gives a different pattern of results than
do indirect measures with avoidance conditioning. More work systematically examining these
effects is needed.
Pretraining systemic, intrahippocampal, or
intra-amygdala (LA/B) manipulation of GCs
influences the LTM of fear conditioning; contextual memories are more vulnerable (Conrad
et al. 2004; Cordero et al. 2002; Donley et al.
2005; Pugh et al. 1997a,b) likely because contextual fear memory is generally weaker (i.e.,
harder to learn and easier to disrupt) than cued
fear memory (Phillips & LeDoux 1992).
Posttraining systemic manipulations of GCs
also impact both auditory and contextual
fear memory consolidation (Corodimas et al.
1994, Hui et al. 2004, Pugh et al. 1997a,
Zorawski & Killcross 2002). Moreover, posttraining GR blockade in the LA/B affects auditory fear LTM but not STM ( Jin et al.
2007), providing more evidence that GCs are
most important for consolidation processes.
Furthermore, posttraining GCs administered
immediately, but not 3 hours, after auditory
fear conditioning facilitates freezing to a tone
previously paired with a US but does not alter responses to unpaired tones or to tone
or shock alone, suggesting a selective and
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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
Reconsolidation of Fear Conditioning
The Effects of Stress on the Extinction
Preliminary evidence suggests that acute stress
before, but not after, memory reactivation disrupts auditory fear reconsolidation LTM (Bush
et al. 2004). It would be interesting to see how
chronic stress or intra-amygdala manipulations
influence this phenomenon and the time course
of reconsolidation processes.
Chronic stress prior to conditioning impairs
the LTM of auditory and contextual extinction
LTM (Garcia et al. 2008, Miracle et al. 2006);
similarly, patients with PTSD show impaired
cued fear extinction (Blechert et al. 2007, Wessa
& Flor 2007). However, reports conflict regarding the influence of stress on the learning of
extinction (Izquierdo et al. 2006, Miracle et al.
2006), perhaps because of differences in stress
types or protocols or species (mice versus rats).
Stress induction after fear conditioning but before extinction does not influence extinction
LTM (G. Quirk, unpublished results). If a stressor is controllable, the mPFC inhibits activation
of brainstem nuclei (Amat et al. 2005). Moreover, stress and environmental enrichment produce opposite effects on fear renewal in a new
context; the influence of enrichment outweighs
that of stress (Mitra & Sapolsky 2009).
The Effects of NE Manipulation
on the Reconsolidation of Fear
Conditioning
Although the effects of prereactivation NE manipulations on reconsolidation are unknown,
systemic or intra-amygdala (LA/B) administration of propranolol after reactivation disrupts reconsolidation of auditory and contextual fear LTM in rats (Abrari et al. 2008,
Debiec & Ledoux 2004). The same trend holds
true for avoidance conditioning (Przybyslawski
et al. 1999). These findings are consonant with
reports that propranolol can effectively treat
PTSD when administered after aversive memory activation (Brunet et al. 2008, Orr et al.
2006, Pitman & Delahanty 2005, Pitman et al.
2002).
The Effects of GC Manipulation
on the Reconsolidation
How alterations of GC activity before reactivation might influence reconsolidation has yet to
Involvement of NE in the Extinction
NE in the LA/B after extinction training enhances the consolidation of extinction
memories of contextual fear LTM (Berlau &
McGaugh 2006). Furthermore, NE efflux increases in the PFC during presentation of a
CS previously paired with a US (Feenstra et al.
2001). Similarly, administration of propranolol
in the IL subregion of the mPFC before, but
299
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not after, extinction training impairs retrieval
of extinction the following day while leaving
within-session extinction intact. Furthermore,
NE signaling in the IL strengthens extinction
memory (Mueller et al. 2008).
Involvement of GCs in the Extinction
Chronic GC exposure, which decreases
endogenous GC secretion, prior to fear conditioning impairs contextual extinction LTM but
not STM and results in a decrease of NMDA
(N-methyl-d-aspartate) and AMPA (α-amino3-hydroxyl-5-methyl-4-isoxazole-propionate)
excitatory receptor subunits in the mPFC
(Gourley et al. 2008). In addition, systemic
and intra-amygdala (LA/B) GC manipulations
prior to extinction training suggest that GR
activation is key for extinction learning in a
fear-potentiated startle paradigm (Yang et al.
2006). Although systemic GC administration
before extinction training does not produce
extinction learning or LTM impairments (G.
Quirk, unpublished results), metyrapone,
a GC synthesis inhibitor, affects extinction
LTM while leaving learning intact (Barrett &
Gonzalez-Lima 2004). Moreover, adrenergic
receptor (AR) blockade or GR activation after
retrieval disrupts recall of contextual fear conditioning, but only the effects of GR activation
are reversed by a reminder shock (Abrari et al.
2008). Along these same lines, GR-mediated
disruptions of fear memories show spontaneous recovery and renewal of CRs (Barrett
& Gonzalez-Lima 2004, Cai et al. 2006).
However, GR inactivation impairs CRs in an
avoidance task, and these do not reemerge
after strong reminders (Tronel & Alberini
2007), possibly because of the involvement of
other processes in this paradigm. Nonetheless,
the results from animal studies that show GC
activity may promote extinction (Barrett &
Gonzalez-Lima 2004, Cai et al. 2006) parallel
findings that PTSD and phobia symptoms,
but not general anxiety, can improve with GC
treatment (Aerni et al. 2004, de Quervain 2008,
Schelling et al. 2004, Soravia et al. 2006).
300
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SUMMARY OF THE EFFECTS
ON FEAR CONDITIONING
Table 1 summarizes results from animal studies presented in this review. This information
comes with a number of caveats: First, data were
often gathered from only a very small number of
papers for each topic; second, few studies examined both contextual and cued fear conditioning; third, it was rarely the case that both STM
and LTM were examined; fourth, little work
has examined effects of stress, NE, or GCs on
the expression of fear; and fifth, the important
modulatory effects of age, genetics, and gender
have not been discussed throughout this review
in the interest of space.
HOW STRESS AFFECTS
FEAR CIRCUITRY ON
A CELLULAR LEVEL
The Influence of Stress on
the Morphology of Neurons
in Fear Circuitry
Stress can alter the morphology of pyramidal
neurons in structures involved in fear circuitry
(see Figure 3). To begin, chronic stress causes
an increase in the dendritic arborization, spine
formation, and synaptic connectivity in principal neurons in the LA/B (Vyas et al. 2002, 2006)
but not in the CE (Vyas et al. 2003). Moreover,
chronic immobilization stress, but not chronic
unpredictable stress, induces this dendritic remodeling in the LA/B (Vyas & Chattarji 2004).
In addition, the duration of stress directly impacts the spatiotemporal patterns of spine formation such that both acute and chronic stressors increase spines in LA/B neurons, but only
the latter has an effect on dendritic arbors
(Mitra et al. 2005). Furthermore, a single, acute
dose of GCs is sufficient to produce anxiety
and hypertrophy of LA/B neurons (Mitra &
Sapolsky 2008). Contrasting with these effects, stress decreases dendritic branching and
spine count in the hippocampus (for review, see
McEwen & Magarinos 2001).
Neurons in the mPFC endure morphological changes due to stress and GCs, including
?
↑
LTM
LTM
↑
LTM
LTM
?
↑
×××
↑↑
↑
STM
LTM
Contextual
×
↑↑
×
×∗ ↑
STM
Cued
×
×↑
↑
STM
Contextual
?
×§ ×§
↑
↑↑
STM
Cued
?
+
STM
?
?
?
?
↑↑
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
↑
?
?
?
↑
×
↑
?
↑↑
?
?
?
×
?
Postreactivation
Reconsolidation
Prereactivation
↓
×
?
?
?
?
?
?
↓
?
↓
×∗
Preconditioning
Extinction
?
?
×∗
×
?
?
↑
×
?
?
×
×
Preextinction
training
↑
?
?
?
↑
?
×
×
?
?
?
?
Postextinction
training
b
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 influences at this time.
?, Effects unknown.
∗
, conflicting reports.
§ , effectively disrupts consolidation of avoidance learning, but not fear conditioning.
a
GCs
↑
↑
LTM
Contextual
?
?
STM
Cued
Pretesting
13 May 2009
NE
STRESS
Posttraining
Conditioning
ARI
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
accompanied by a resistance to fear extinction
(Izquierdo et al. 2006). Stress-induced atrophy
of hippocampal (Conrad et al. 1999, McEwen
1999, Sousa et al. 2000) and mPFC neurons
(Radley et al. 2005) reverses after a stressfree period. However, the same recovery period
does not rescue stress-induced hypertrophy of
amygdala neurons (Vyas et al. 2004).
Stress
Amygdala (LA/B)
500 nm
Hippocampus (CA3)
500 nm
Prefrontal cortex (IL)
500 nm
Figure 3
Influences of stress on the morphology of neurons in fear circuitry. LA/B,
lateral/basal nucleus of the amygdala; CA3, cornu ammonis subfield 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).
atrophy and spine loss (Brown et al. 2005; Cook
& Wellman 2004; Czeh et al. 2008; Izquierdo
et al. 2006; Radley et al. 2004, 2006, 2008;
Wellman 2001). Furthermore, atrophy in IL
neurons through brief uncontrollable stress is
302
Rodrigues
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Sapolsky
The Influence of Stress on the
of Neurons in Fear Circuitry
Stress and its accompanying biological effects
influence the electrophysiological activity of
neurons in fear circuitry (see Figure 4). Electrophysiological studies often explore neuronal
excitability, as well as long-term potentiation
(LTP), an artificial means of inducing synaptic connectivity between two brain areas, and
thus a physiological model of fear learning and
memory (Blair et al. 2001, Rodrigues et al. 2004,
Schafe et al. 2001). Stress has differential effects
on the amygdala, hippocampus, and prefrontal
cortex, which we now review.
LA/B neurons from stressed animals display
increased firing rates and greater responsiveness (Garcia et al. 1998, Kavushansky
et al. 2006, Kavushansky & Richter-Levin
2006, Rodrı́guez Manzanares et al. 2005).
Although some stress paradigms, especially
acute inductions, enhance LTP in the LA/B
(Rodrı́guez Manzanares et al. 2005, Vouimba
et al. 2004, 2006), other stress protocols
suppress it (Kavushansky & Richter-Levin
2006, Kavushansky et al. 2006, Kohda et al.
2007). Along these same lines, the type of
stress is also a critical factor in the influence
of stress on hippocampal plasticity such that
chronic, but not acute, stress suppresses
hippocampal LTP (Pavlides et al. 2002).
Temporal qualities of stressors have opposite
influences on the hippocampus, boosting LTP
when the tetanizing stimulation is in close
proximity to emotional processing and disrupting LTP when there is a substantial delay
between the stimulation and initiation of stress.
Furthermore, amygdala (LA/B) stimulation
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patterns of firing rates that encode fast and
slow responses to stress. Whereas some mPFC
neurons respond phasically during the duration
of a stressor, others show activity that persists
after the stress ceases, and yet others respond
during the initiation and termination of stress
( Jackson & Moghaddam 2006). Furthermore,
stress reduces LTP induction in projections
from both the LA/B (Maroun & RichterLevin 2003) and hippocampus (Cerqueira
et al. 2007, Rocher et al. 2004) to the
PFC.
Dendrite
Alteration of plasticity that
underlies fear learning
Decrease of GABAmediated inhibition
GABA
Cl-
Axon
Enhancement of neuronal
responses and excitability
GABA-A
receptor
Percent of control
mimics this emotion-induced influence on
hippocampal plasticity (LA/B) (Diamond et al.
2007, Richter-Levin 2004, Richter-Levin &
Akirav 2003). Hippocampal stimulation after
fear extinction training disrupts the recall of
extinction (Garcia et al. 2008). Furthermore,
uncontrollable stress drastically impairs hippocampal LTP relative to the influence of the
same amount of controllable stress (Shors et al.
1989). The mPFC seems to play a role in
determining the controllability of stress (Amat
et al. 2005), and neurons here display unique
200
100
LTP induction
0
Time (min)
50
LA/B neuron
cell body
Figure 4
Influence 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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The Influence of NE on the
NE increases the spiking of neurons in the LA
and facilitates the induction of LTP (Tully et al.
2007). What’s more, fear conditioning increases
depolarization-evoked NE release (Liu et al.
2007). Moreover, ARs seem particularly pivotal
for a late phase of LTP in the LA, which persists
for at least three hours and requires the synthesis of new mRNA and protein (Huang et al.
2000). The reactivity of the hippocampal neurons is enhanced by NE (Harley 2007, Segal
et al. 1991), and suppression of GC secretion
increases NE transmission here (Mizoguchi
et al. 2008); the relevance of this to fear learning
and memory processes is unclear. In the IL of
the mPFC, fear conditioning decreases, and extinction increases, neuronal excitability (Santini
et al. 2008). Pertinent to this, NE signaling in
this region increases neuron excitability (Barth
et al. 2007, Mueller et al. 2008) and strengthens the memory for extinction (Mueller et al.
2008).
The Influence of GCs on the
Both high and low GC concentrations enhance the excitability of LA/B neurons (Duvarci & Paré 2007, Kavushansky & RichterLevin 2006). In addition, GCs depolarize the
resting potential, increase input resistance, and
significantly decrease spike-frequency adaptation of LA/B neurons (Duvarci & Paré 2007).
The influences of GCs are different on the
hippocampus; there low concentrations (via
MR activation) are excitatory, whereas high
concentrations (via MR plus GR activation)
are inhibitory (de Kloet et al. 1999, Joels
& de Kloet 1992). A similar biphasic relationship of MR and GR activation exists for enhancing and suppressing effects of GCs on
hippocampal LTP, respectively (Pavlides et al.
1996, Pavlides & McEwen 1999). We do not
304
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·
Sapolsky
know how GCs directly influence the electrophysiological profiles of mPFC neurons.
Therefore, more data are needed to illustrate
how GCs interact with other factors to influence 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 influence 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 difficult, stereotypical responses to these various stressors do
occur and activate the brain’s 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 influence 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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extinction training, interferes with extinction
LTM. Altogether, these findings suggest that
during initial learning, stress activates events
that can influence later consolidation and extinction processes. Whether effects exist on the
acquisition and expression of fear is less clear
owing to the relative paucity of studies.
In regard to NE, cumulative evidence suggests that NE is important for fear conditioning, reconsolidation, and extinction, but not for
consolidation. NE increases neuronal excitability and LTP in the LA, and its activity there is
needed for both STM and LTM of fear conditioning. NE also increases neuronal excitability
in the IL of the mPFC and is important for the
LTM of extinction. Because pretraining but not
posttraining intra-amygdala (LA/B) or intramPFC infusions of propranolol block LTM of
fear conditioning and extinction, respectively,
it seems that NE must be tonically active during learning to promote rapid postlearning cascades in the LA and IL to facilitate STM retrieval and to promote the conversion of STM
to LTM.
Next, GCs appear to be particularly
crucial for LTM, but not the acquisition,
of fear conditioning. Therefore, the overall
trend of systemic or intra-amygdala (LA/B) GC
disrupting LTM is consonant with electrophysiological findings that GCs have long-term, but
not short-term, enhancing effects on neuronal
excitability in LA/B (Duvarci & Paré 2007).
GRs are located both at synaptic and at nuclear
sites in the LA. The classic actions of GR, as
a steroid receptor, involve binding GCs in the
cytoplasm and acting as a transcription factor
upon translocating to the nucleus, whereas
less traditional GR actions include rapid,
nongenomic effects. The fact that GRs seem
more important for fear consolidation than for
learning, and for enduring but not immediate
influences on the firing of LA/B neurons,
suggests that more traditional genomic effects
underlie these behavioral and electrophysiological findings.
Stress-induced enhancement of LTP in auditory inputs to the LA alongside disruption of
LTP in the projections to the PFC from the
hippocampus and the LA/B is congruent with
the notion that powerful fear inputs can facilitate strong emotional pathways at the cost of
activating more regulatory pathways. Indeed,
an abundant literature showing that NE is important particularly for hippocampal and PFC
function, in addition to LA/B activation, is in
line with NE’s role in arousal and cognition.
Given that hippocampal function is disrupted by major stressors or exposure to elevated levels of GCs, how might it play a pivotal
role in forming fear memories, particularly contextual ones? This answer might be explained by
the model of the hippocampus shifting from a
cognitive mode to a flashbulb memory mode
under intense stress, which explains why the
contextual memories of traumatic experiences
are vivid and endure for many years but tend to
be disjointed and fragmented (Diamond et al.
2007).
In summary, stress, NE, and GCs appear to
be potent modulators of fear memory formation. Furthermore, the ability of stress, NE,
and GCs to decrease GABA (γ -aminobutyric
acid)-A receptor-mediated inhibition (Duvarci
& Paré 2007, Rodriguez Manzanares et al.
2005, Tully et al. 2007), thereby allowing for
increased excitability in LA/B, is harmonious
with the fact that benzodiazepines act on this
receptor to decrease anxiety.
During difficult times, we are often advised
to “use our heads” or “follow our hearts” or “go
with our gut.” As this review highlights, our
bodies and our minds really are not separate,
but instead mutually inform each other on how
to process the emotional events of our lives.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial 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.
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Annual Review of
Neuroscience
Contents
Volume 32, 2009
Neuropathic Pain: A Maladaptive Response of the Nervous
System to Damage
Michael Costigan, Joachim Scholz, and Clifford J. Woolf p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Synaptic Mechanisms for Plasticity in Neocortex
Daniel E. Feldman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p33
Neurocognitive Mechanisms in Depression: Implications for
Treatment
Luke Clark, Samuel R. Chamberlain, and Barbara J. Sahakian p p p p p p p p p p p p p p p p p p p p p p p p p p57
Using Diffusion Imaging to Study Human Connectional Anatomy
Heidi Johansen-Berg and Matthew F.S. Rushworth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p75
Serotonin in Affective Control
Peter Dayan and Quentin J.M. Huys p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95
Physiology and Pharmacology of Striatal Neurons
Anatol C. Kreitzer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 127
The Glial Nature of Embryonic and Adult Neural Stem Cells
Arnold Kriegstein and Arturo Alvarez-Buylla p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 149
Representation of Number in the Brain
Andreas Nieder and Stanislas Dehaene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185
Neuronal Gamma-Band Synchronization as a Fundamental Process
in Cortical Computation
Pascal Fries p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 209
The Neurobiology of Individual Differences in Complex
Behavioral Traits
Ahmad R. Hariri p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 225
The Science of Neural Interface Systems
Nicholas G. Hatsopoulos and John P. Donoghue p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 249
The Neuropsychopharmacology of Fronto-Executive Function:
Monoaminergic Modulation
T.W. Robbins and A.F.T. Arnsten p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 267
v
AR379-FM
ARI
20 May 2009
14:8
The Influence of Stress Hormones on Fear Circuitry
Sarina M. Rodrigues, Joseph E. LeDoux, and Robert M. Sapolsky p p p p p p p p p p p p p p p p p p p p p p p 289
The Primate Cortical Auditory System and Neural Representation of
Conspecific Vocalizations
Lizabeth M. Romanski and Bruno B. Averbeck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 315
Establishment of Axon-Dendrite Polarity in Developing Neurons
Anthony P. Barnes and Franck Polleux p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 347
Axon Growth and Guidance: Receptor Regulation
and Signal Transduction
Michael O’Donnell, Rebecca K. Chance, and Greg J. Bashaw p p p p p p p p p p p p p p p p p p p p p p p p p p p p 383
Cerebellum and Nonmotor Function
Peter L. Strick, Richard P. Dum, and Julie A. Fiez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Advances in Light Microscopy for Neuroscience
Brian A. Wilt, Laurie D. Burns, Eric Tatt Wei Ho, Kunal K. Ghosh,
Eran A. Mukamel, and Mark J. Schnitzer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 435
Indexes
Cumulative Index of Contributing Authors, Volumes 23–32 p p p p p p p p p p p p p p p p p p p p p p p p p p p 507
Cumulative Index of Chapter Titles, Volumes 23–32 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511
Errata
An online log of corrections to Annual Review of Neuroscience articles may be found at
http://neuro.annualreviews.org/
vi
Contents

The Influence of Stress Hormones on Fear Circuitry

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