rodrigues ledoux sapolsky arn 2009

8/18/2019 Rodrigues Ledoux Sapolsky Arn 2009

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The Influence of StressHormones on Fear Circuitry

Sarina M. Rodrigues,1 Joseph E. LeDoux,2,∗

and Robert M. Sapolsky 3,∗

1Institute of Personality and Social Research, University of California, Berkeley,California 94720; Address correspondence to Department of Psychology, Oregon StateUniversity, Corvallis, Oregon 97331; email: [email protected]

2Center for Neural Science and Department of Psychology, New York University,New York, New York 10003; Emotional Brain Institute Labs of the Nathan Kline Institut

Orangeburg, New York 10962; email: [email protected] 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

First published online as a Review in Advance on March 24, 2009

The Annual Review of Neuroscience is online at neuro.annualreviews.org

This article’s doi:10.1146/annurev.neuro.051508.135620

Copyright c 2009 by Annual Reviews. All rights reserved

0147-006X/09/0721-0289$20.00

∗ These authors contributed equally to this work.

Key Words

fear conditioning, glucocorticoids, norepinephrine

Abstract

Fear arousal, initiated by an environmental threat, leads to activation othe stress response, a state of alarm that promotes an array of autonomi

and endocrine changes designed to aid self-preservation. The stress response includes the release of glucocorticoids from the adrenal corte

and catecholamines from the adrenal medulla and sympathetic nerves These stress hormones, in turn, provide feedback to the brain and influ

ence neural structures that control emotion and cognition. To illustratthis influence, we focus on howit impacts fear conditioning, a behaviora

paradigm widely used to study the neural mechanisms underlying thacquisition, expression, consolidation, reconsolidation, and extinction

of emotional memories. We also discuss how stress and the endocrinmediators of the stress response influence the morphological and elec

trophysiological properties of neurons in brain areas that are cruciafor fear-conditioning processes, including the amygdala, hippocampus

and prefrontal cortex. The information in this review illuminates th

behavioral and cellular events that underlie the feedforward and feedback networks that mediate states of fear and stress and their interaction

in the brain.

289


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Contents

INTRODUCTION .. . . . . . . . . . . . . . . . . 291

WHAT IS FEAR, AND HOW IS ITORGANIZED IN THE BRAIN? . . 291

Studying Fear in the Laboratory with Fear Conditioning . . . . . . . . . 291

Phases of Fear Conditioning. . . . . . . . 292Neural Circuitry Underlying

Fear Conditioning . . . . . . . . . . . . . . 292FEAR AROUSAL AND THE

STRESS RESPONSE:OVERVIEW OF THIS

FEEDFORWARD AND

FEEDBACK NETWORK. . . . . . . . . 294HOW DO STRESS,

NOREPINEPHRINE, ANDGLUCOCORTICOIDS

INFLUENCE DIFFERENTPHASES OF FEAR

CONDITIONING?. . . . . . . . . . . . . . . 295 ACQUISITION OF FEAR

CONDITIONING... . . . . . . . . . . . . . 297 The Effects of Stress on the

Acquisition of FearConditioning . . . . . . . . . . . . . . . . . . . 297

The Effects of NE on the

Acquisition of FearConditioning . . . . . . . . . . . . . . . . . . . 297

The Effects of GCs on the Acquisition of Fear

Conditioning . . . . . . . . . . . . . . . . . . . 297CONSOLIDATION OF

LONG-TERM MEMORY . . . . . . . . 297 The Effects of Stress on the

Consolidation of LTM of Fear Conditioning . . . . . . . . . . . . . . 297

The Effects of NE on theConsolidation of LTM

of Fear Conditioning............ 298

The Effects of GCs on the

Consolidation of LTM

of Fear Conditioning............ 29RECONSOLIDATION . . . . . . . . . . . . . . 29

The Effects of Stress on theReconsolidation of Fear

Conditioning . . . . . . . . . . . . . . . . . . . 29 The Effects of NE Manipulation

on the Reconsolidation of FearConditioning . . . . . . . . . . . . . . . . . . . 29

The Effects of GC Manipulationon the Reconsolidation

of Fear Conditioning............ 29EXTINCTION . . . . . . . . . . . . . . . . . . . . . . 29

The Effects of Stress on the

Extinction of FearConditioning . . . . . . . . . . . . . . . . . . . 29

Involvement of NE in the Extinctionof Fear Conditioning............ 29

Involvement of GCs in theExtinction of Fear

Conditioning . . . . . . . . . . . . . . . . . . . 30SUMMARY OF THE EFFECTS

ON FEAR CONDITIONING . . . . 30HOW STRESS AFFECTS

FEAR CIRCUITRY ON A CELLULAR LEVEL. . . . . . . . . . . . 30

The Influence of Stress on

the Morphology of Neuronsin Fear Circuitry. . . . . . . . . . . . . . . . 30

The Influence of Stress on theElectrophysiological Properties

of Neurons in Fear Circuitry . . . . 30 The Influence of NE on the

Electrophysiological Propertiesof Neurons in Fear Circuitry . . . . 30

The Influence of GCs on theElectrophysiological Properties

of Neurons in Fear Circuitry . . . . 30

CONCLUSIONS . . . . . . . . . . . . . . . . . . . . 30

“The oldest and strongest emotion of mankind is

fear.”

—H.P. Lovecraft

“A crust eaten in peace is better than a banquet

eaten in fear.”

—Aesop

290 Rodrigues · LeDoux· Sapolsky


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INTRODUCTION

Evolution has endowed each species with an ar-ray of instinctual defense mechanisms to help

organisms cope with environmental threatsand other challenges to safety and well-being.

Skunksspray offensive odors, blowfish inflate tolook bigger than they actually are, and roaches

scurry away into crevices for safety. Althoughhumans in modern societies usually have the

luxury of not having to worry about escapingfrom predators (except for the odd shark, bear,

or axe murderer), the emotion of fear and thedefensive 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 au-

tonomic and neuroendocrine changes that aidsurvival (McEwen 2003, Sapolsky et al. 2000).

At the same time, the peripheral changes in-duced by fear impact the brain, altering the

way emotional and cognitive systems processinformation. Although such responses enhance

survival in the short run, chronic activation

of stress responses contributes to the devel-opment of pathological states such as anxiety,

phobias, depression, and post-traumatic stressdisorder (PTSD), as well as a host of physi-

cal ailments, including compromised immunefunction, hypertension, and insulin resistance

(McEwen 2003, Sapolsky et al. 2000). The aim of this article is to explore how

fear arousal, manifested on the neurobiologicallevel, leads to activation of peripheral stress re-

sponses and how stress responses, in turn, alterbrain systems that control emotion and cogni-

tion. In the interest of space, we cannot cover

some important topics, including howearly-lifeexperiences, genetics, or gender might inter-

act with stress in altering fear (DeRijk & deKloet 2005, Kalin & Shelton 2003, Luine 2002,

Lyons&Parker2007,Meaney2001,Weinstock 2007).

CS: neutralconditioned stimulu

US: aversiveunconditionedstimulus

NE: norepinephrinGC: glucocorticoid

CR: conditionedresponse

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 occurin 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 fo-cus on here (Fanselow & Poulos 2005; Lang &

Davis 2006; LeDoux 1995, 1996, 2007; Maren2001, 2005; Par ´ e et al. 2004; Rodrigues et al.

2004). There are a variety of ways to assesslearned fear besides measuring Pavlovian con-

ditioned response effects. For example, a num-

berofstudieshaveexaminedtheroleofbrainar-eas 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 instrumentalbehaviors that avoid danger. Because studies of

avoidance conditioning have not led to a co-herent view of the neural system that mediates

avoidance (Cain & LeDoux 2008), we empha-size the effects of stress on fear conditioning in

this review. However, we mention some find-ings from other procedures where relevant.

Studying Fear in the Laboratory

with Fear Conditioning Pavlovian fear conditioning is a behavioral pro-

cedure in which an emotionally neutral condi-tioned stimulus (CS), such as an auditory tone,

is paired with an aversive conditioned stimu-lus (US), typically a foot shock. After one or

several pairings, the CS comes to elicit de-fensive behaviors, including freezing behav-

ior, as well as increased arousal in the brain

and secretion of norepinephrine (NE) andglucocorticoids (GCs) peripherally. These

conditioned responses (CRs) are hard-wiredand 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 suchresponses.

www.annualreviews.org • Stress Hormones and Fear Circuitry 291


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STM: short-termmemory

LTM: long-termmemory

LA: lateral nucleus of

the amygdalaCE: central nucleus of the amygdala

Phases of Fear Conditioning

In studies of fear conditioning, responseselicited by the CS are often measured during

acquisition andretrievaltests. Acquisition is ini-tial learning of the association between the CS

and US during the training portion of fear con-ditioning, when the animal first learns to pair

the two. Retrieval involves a test of the CS-USassociation in which the CS is presented alone.

Retrieval tests that occur within a few hoursafter acquisition measure short-term memory

(STM), whereas those that occur later (typ-ically 24 hours after learning) measure long-

term memory (LTM). STM and LTM tests are

used to study memory consolidation, the pro-cess through which an unstable STM is con-

verted into a more stable and enduring LTMtrace (Dudai 2004, McGaugh 2000, Rodrigues

et al. 2004).Retrieval tests are also used to study recon-

solidation. Reconsolidation occurs when fearmemories are retrieved and enter a new la-

bile state that requires stabilization via proteinsynthesis to persist as an enduring LTM trace

(Dudai2006,Nader2003,Naderetal.2000).Inaddition, 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 ab-

sence of the US (Quirk & Mueller 2008, Sotres-Bayon et al. 2004). Unlike the disruption of re-

consolidation, which is robust and long lasting,extinction involves a new learning process. As

a result, after extinction training, the CS canspontaneously produce CRs again after the an-

imal is reexposed to the US or is placed in anovel context (Bouton et al. 2006, Ji & Maren

2007).

Neural Circuitry Underlying Fear Conditioning

Fear conditioning is especially useful for study-ing the neural basis of fear because the cir-

cuit can be described in terms of pathwaysprocessing the CS and controlling the CRs. In-

deed, the pathways have been mapped from the

CS sensory processing to the CR motor co

trol systems. A key link in this circuitry is tamygdala, which sits between the sensory

put systems on one hand and the motor outsystems on the other (Fanselow & Poulos 20

Lang & Davis 2006; LeDoux 1995, 1996, 20 Maren 2001, 2005; Par ´ e et al. 2004; Rodrig

et al. 2004). However, other brain structualso contribute to fear conditioning.

Amygdala contributions to fear conditio

ing. The amygdala contains a heterogeneity

distinct nuclei, differing by cell type, densneurochemical composition, and connectiv

(LeDoux 2007, Pitkanen et al. 2000, Swans2003).

The lateral nucleus (LA) is typically viewas the sensory gateway to the amygdala b

cause it receives auditory, visual, gustatoolfactory, and somatosensory (including pa

information from the thalamus and the ctex (olfactory and taste information is transm

ted to other nuclei, as well). The LA receisensory information about the CS from th

lamic and cortical projections. The thalam

amygdala pathway is a shortcut of sorts, tramitting rapid and crude information about

fear-eliciting stimulus without the oppornity for filtering by conscious control (LeDo

1995, 1996). The cortico-amygdala pathwaycontrast, provides slower, butmore detailed a

sophisticated sensory information. Neuronsthe LA respond to both the CS and the U

and damage to, or a disruption of, the LA p vents fear conditioning. It appears that the co

vergence takes place in the dorsal half of LA (Romanski et al. 1993), and indeed sing

unit recordings show that cellular plasticity

curs in the dorsal LA during fear condition(LeDoux 2007, Maren & Quirk 2004). Mo

over, molecular changes in the LA consolidthe fear memory, converting STM into LT

traces (Dudai 2004, Rodrigues et al. 2004). The central nucleus (CE), in contrast

viewed as the major output region of amygdala. The CE controls the express

of the fear reaction, including behavio



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autonomic, and endocrine responses via projec-

tions to downstream areas, including hypotha-lamus, central gray, and the dorsal motor nu-

cleus of the vagus (Fanselow & Poulos 2005;Lang & Davis 2006; LeDoux 1995, 1996, 2007;

Maren 2001, 2005; Par ´ e et al. 2004; Rodrigueset al. 2004). Plasticity also occurs in the CE

(Par´ e et al. 2004, Wilensky et al. 2006), but thisis likely based on LA plasticity. The LA communicates with the CE directly,

but the connections between these two nucleiare somewhat modest and other amygdaloid

nuclei also help mediate between these two.For instance, the LA projects to the basal nu-

cleus (B), which in turn projects to CE (LeDoux2000, Pitkanen et al. 1997). The LA and B also

project to the intercalated region (ITC), an in-hibitory network that connects with the CE

(Likhtik et al. 2008, Par ´ e et al. 2004). Projec-tion neurons in the CE tend to be inhibitory,

thus LA and B projections to the ITC may

stimulate the ITC’s inhibition of CE neuronsto allow the expression fear responses (LeDoux

2007).Inaddition,theBprojectstothestriatum(McDonald 1991) to orchestrate instrumental

behaviors, such as escape to safety (LeDoux2007). 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 inthebrainstem andforebrain (Fudge& Emiliano

2003, Gray 1993, Par ´ e 2003).Information about the context of a fear-

ful 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, althoughfear conditioning to discrete sensory cues,

such as a tone or a light, are hippocam-pal independent, conditioning to contex-

tual information, including details about theenvironment, are hippocampal dependent. The

LA and B are also interconnected to a variety of cortical areas, such as the prefrontal and poly-

modal association cortices (Amaral & Insausti1992, McDonald 1998, McDonald et al. 1996,

B: basal nucleus of tamygdala

mPFC: medialprefrontal cortex

IL: infralimic

subregion of themPFC

Pitkanen et al 2000, Price 2003, Stefanacci &

Amaral 2002). These connections allow higher-order cognitive processes, such as emotion reg-

ulation, complex associations, imagination, andreactions 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 (baso-lateral amygdala). It is important to keep thesenuclei separate when possible.

Although the LA is required for fear con-ditioning under standard training conditions,

it appears that, with overtraining, fear condi-tioning can be mediated by circuits that do not

depend on the LA (Lee et al. 2005, Maren1999). 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 theB is not required for conditioning, it neverthe-

less 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 useof instrumental responses to assess Pavlovian

conditioning, the CE can mediate condition-ing independent of LA (Balleine & Killcross

2006, Cardinal et al. 2002). However, this con-clusion is extrapolated largely on the basis

of appetitive conditioning findings and needsto be studied more systematically in aversive

conditioning. The expression of fear responses can be reg-

ulated by the medial prefrontal cortex (mPFC)

via projections to the LA, B, and ITC. The in-fralimbic subregion (IL) of the mPFC is es-

pecially important for fear extinction (Quirk et al. 2006, Rosenkranz et al. 2003, Sotres-

Bayon et al. 2004) because it inhibits amygdalaoutput (Vidal-Gonzalez et al. 2006). However,

investigators have debated the nature of therole of prefrontal amygdala interactions in ex-

tinction (Quirk et al. 2006, Rosenkranz et al.2003, Sotres-Bayon et al. 2004). The various

sensory and higher-order influences on theamygdala are shown in Figure 1.



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ITC

LA

B

CE

Sensory thalamusand cortex

(auditory, visual,somatosensory,

gustatory, olfactory)

Viscero-sensorycortex

Sensory brainstem(pain, viscera)

Prefrontal cortex(medial)

Hippocampus and

entorhinal cortex

Polymodalassociation cortex

ITC

LA

B

CE

HPA axis(hypothalamus)

Freezing(central gray)

Modulatory systemNE, 5HT, DA, ACh

(cell groups inforebrain and/or

brainstem)

Sympathetic andparasympathetic N

(hypothalamus,brainstem)

Ventral striatum(instrumental behaviors)

Polymodal associationcortex (cognition)

Prefrontal cortex(regulation)

Figure 1

(Top) Inputs to some specific amygdala nuclei. Asterisk (∗) denotes species difference in connectivity. (BottOutputs of some specific amygdala nuclei. 5HT, serotonin; Ach, acetylcholine; B, basal nucleus; CE, centrnucleus; DA, dopamine; ITC, intercalated cells; LA, lateral nucleus; NE, norepinephrine; NS, nervoussystem.

FEAR AROUSAL AND THESTRESS RESPONSE: OVERVIEW OF THIS FEEDFORWARD ANDFEEDBACK NETWORK

The presence of an environmental threat, ineffect a stressor, leads to the activation of the

brain’s fear system, thus initiating the stressresponse in both the brain and the body. A key

structure in the fear system, as we have just re- viewed, is the amygdala. It is responsible for

the detection of threat and the orchestration of

stress responses in the brain and the body (Figure 2).

Once the amygdala detects a threat, outputs lead to the activation of a variety

target areas that control both behavioral aphysiological responses designed to addr

the threat (Lang & Davis 2006; LeDoux 192002). In addition to the expression of

fensive behaviors, such as freezing (Blanch& Blanchard 1969, Fendt & Fanselow 199

amygdala activation leads to responses in



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brain and the body that support the fear reac-

tion. In the brain, monoaminergic systems areactivated, resulting in the releaseof neurotrans-

mitters such as NE, acetylcholine, serotonin,and dopamine throughout the brain. These

neurotransmitters lead to an increase in arousaland 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 hasendocrine consequences. Amygdaloid signaling

causes secretion of corticotropin-releasing hor-mone (CRH) from the periventricular nucleus

of the hypothalamus. CRH, along with otherhypothalamic secretagogs, causes the release of

adrenocorticotropic hormone from the pitu-itary, which in turn stimulates the secretion of

GCs from the adrenal cortex. Circulating GCsbind to the high-affinity mineralocorticoid

receptor (MR) and the low-affinity glucocor-

ticoid receptor (GR) in tissues throughout thebody and the brain (de Kloet 2004, Korte 2001).

Finally, detection of threat by the amyg-dala has autonomic consequences. Connections

from the amygdala to the brainstem lead tothe activation of the sympathetic nervous sys-

tem, involving the release of epinephrine andNE from the adrenal medulla and NE from

the terminals of sympathetic nerves through-out 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 mus-

cle, and inhibiting digestion (Goldstein 2003, McCarty & Gold 1996, Sapolsky 2004). Com-

ing full circle, fear circuitry is profoundly influ-enced by these endocrine and autonomic stress

responses. Thus, GCs travel in the circulationto the brain and affect the amygdala and a vari-

ety 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 theconsequent activation of the fear system elicit a

variety of effects that feed back onto the system

GR: glucocorticoidreceptor

that initiates and modulates emotional process-

ing (McEwen 2003, Par´ e 2003, Sapolsky 2003). With this overview we now turn to a more de-

tailed consideration of how the fear system in-teracts with stress.

HOW DO STRESS, NOREPINEPHRINE, AND GLUCOCORTICOIDSINFLUENCE DIFFERENT PHASESOF FEAR CONDITIONING?

In the remainder of this review we examinehow stress and its biochemical concomitants

(Charmandari et al. 2005, Sapolsky 2004) in-fluence the acquisition, consolidation, recon-

solidation, and extinction of conditioned fear,as well as the underlying neural mechanisms

responsible for different elements of fear pro-cessing. Throughout, we compare animal andhuman studies and their implications for stress-

induced psychopathology. Instead of an exhaus-tive survey of all pertinent studies, we highlight

overarching trends in the literature. To distin-guish effects on acquisition from consolidation,

it is necessary to compare pretraining manipu-lations with immediate posttraining manipula-

tions (Rodrigues et al. 2004). This comparisonis necessary because the effects of stress or drugs

tend to last beyond the short training sessionin such studies (sometimes only a single train-

ing 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 onLTM consolidation. Another important manip-

ulation involves treatments given immediately before testing LTM. This treatment is called an

expression test. However, many studies exam-ine pretraining or postraining effects only on

LTM but not on STM or on acquisition. Sim-ilarly, relatively few studies observe effects on

expression. Therefore, more investigations areneeded 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 dis-

cuss what has been discovered so far. Although variability in protocols makes it difficult to com-

pare stress manipulations directly across stu

ies, we make distinctions between acute achronic stress throughout.

Amygdala

Hippocampus

PFCFC

Sensoryensorythalamushalamus

Sensoryensorycortexortex

PFC

Sensorythalamus

Release of stress hormones

Environmental

threat

(slowslow(slow

Monoamineonoaminesystemsystems

Monoaminesystems

Feedback loop

MedullaCortex

PVNVNPVN

ACTH

SNS

Epinephrine andnorepinephrine

Epinephrine annorepinephrin

• Increase in cardiovascular tone

• Increase in blood pressure

• Mobilization of stored energy to muscle

• Transient enhancement of immunity

• Inhibition of costly, long-term processessuch as growth and reproduction

Glucocorticoids

Glucocorticoids

Pituitary

Functional connectivity Processing threat stimulus

c d

a b

ARs

(fast)fast)(fast)

Sensoryensorythalamushalamus

Sensoryensorycortexortex

Sensorythalamus

Sensorycortex

Sensorycortex

Vagunerv

NTSTSNTS

MRs and GRs

Kidney

Adrenalgland

Adrenal gland



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ACQUISITION OF FEAR CONDITIONING

The Effects of Stress on the Acquisition of Fear Conditioning

Although many studies have looked at the ef-

fects of pretraining stress on the LTM of fear

conditioning (see below), influences of pre-training stress on acquisition, as tested in STM,have not been formally assessed. However,

postshock freezing levels during fear condi-

tioning are greater in chronically stressed ratsthat are classified as highly reactive, as indexed

by their locomotion in a novel environment (Cordero et al. 2003a). This classification sug-

gests that at least in some conditions, stress may influence behavior during the learning pro-

cess. However, this possibility needs further

study because postshock freezing during acqui-sition reflects contextual conditioning as muchas cued.

The Effects of NE on the Acquisition of Fear Conditioning

Locus coeruleus lesions or pretraining infu-sion of propranolol, a beta adrenergic receptor

antagonist, into the amygdala (LA/B) blocks

STM, andconsequently LTM (Bush et al. 2006;Neophytou et al. 2001). This finding is consis-

tent with an effect on acquisition and its expres-sion in STM.

The Effects of GCs on the Acquisition of Fear Conditioning

The contribution of GCs to fear acquisition

has been studied by either removing their ef-fects via adrenalectomy, blocking GRs in the

amygdala with an antagonist, or infusing a

viral vector into the amygdala prior to training.

Although more STM evaluations are needed todetermine the precise time course of GCs on

fear, adrenalectomized rats show reduced con-textual LTM but no immediate memory im-

pairments (Pugh et al. 1997b). Likewise, GR blockade in the amygdala (LA/B) or hippocam-

pus disrupts contextual LTM but leaves post-shock levels of freezing intact (Donley et al.2005). A similar pattern emerges from pretrain-

ing intra-amygdala (LA/B) administration of a viral vector expressing a gene to blunt GR sig-

naling, which effectively disrupts both cued andcontextual LTM without affecting acquisition

or postshock levels of freezing (Rodrigues &Sapolsky 2009). These studiessuggest that GCs

may not be involved in acquisition so much asin the consolidation of fear LTM. We discuss

additional results that support this claim in thefollowing section.

CONSOLIDATION OF LONG-TERM MEMORY

Studies assessing memory consolidation typ-

ically administer manipulations immediately after training (Dudai 2004, McGaugh 2000,

Rodrigues et al. 2004). If such manipulationsfail to disrupt STM but do disrupt LTM, con-

solidation (conversion of STM to LTM) is saidto be affected.

The Effects of Stress on theConsolidation of LTM of Fear Conditioning

Pretraining exposure to both acute and chronicstressors 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 structuresinvolved 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 indicatefeedback 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 responsessuch that less-intense stressors can produce ro-

bust fear behaviors, which may help explain why individuals with PTSD react strongly tomild stimuli and quickly form new fears (Rau

et al. 2005). Because measurements of pretrain-ing stress on acquisition and STM are lacking

in the literature, more research is needed to ad-dress the temporal dynamics of stress on fear

conditioning.

The Effects of NE on theConsolidation of LTM

of Fear Conditioning

Central NE depletion or pretraining infu-

sions of propranolol into the LA/B priorto conditioning impair auditory fear LTM

(Bush et al. 2006, Selden et al. 1990). Inaddition, 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) viaa facilitation of AMPA (α -amino-3-hydroxyl-

5-methyl-4-isoxazole-propionate) receptor in-sertion in the hippocampus (Hu et al. 2007).

However, posttraining administration of pro-

pranolol systemically or into the LA/B does not affectLTMconsolidationofauditoryorcontex-

tual fear conditioning (Bush et al. 2006, Debiec& Ledoux 2004, Lee et al. 2001). Thus, NE

in the amygdala does not seem critical for theconsolidation of fear conditioning, but it does

seem to interact with GCs to fortify memories(Roozendaal et al. 2006).

Posttraining intrahippocampal propranololinfusions 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 in-

fusions given before testing oneday after condi-tioning impair the retrieval of contextual mem-

ories (Murchison et al. 2004).

In humans, systemic NE blockade d

rupts the consolidation of contextual, but ncued, fear conditioning LTM (Grillon et

2004). Studies involving avoidance conditioing, an indirect means of measuring fear, sh

that posttraining systemic and intra-amygd(LA/B) pharmacological manipulations sh

that NE is crucial to consolidate avoidanlearning (Ferry & McGaugh 1999, Gallagh

et al. 1977, Liang et al. 1986, Quirarte et

1997, Roozendaal & McGaugh 1997). Moover, NE levels following avoidance traini

correlate with subsequent retention (McGauet al. 2002, McIntyre et al. 2002). Thus, dir

measurement of fear responses with fear contioning gives a different pattern of results th

do indirect measures with avoidance conditioing. More work systematically examining th

effects is needed.

The Effects of GCs on theConsolidation of LTMof Fear Conditioning

Pretraining systemic, intrahippocampal,

intra-amygdala (LA/B) manipulation of Ginfluences the LTM of fear conditioning; co

textual memories are more vulnerable (Conet al. 2004; Cordero et al. 2002; Donley et

2005; Pugh et al. 1997a,b) likely because cotextual fear memory is generally weaker (i

harder to learn and easier to disrupt) than cu

fear memory (Phillips & LeDoux 1992).Posttraining systemic manipulations of G

also impact both auditory and contextfear memory consolidation (Corodimas et

1994, Hui et al. 2004, Pugh et al. 199Zorawski & Killcross 2002). Moreover, po

training GR blockade in the LA/B affects aditory fear LTM but not STM ( Jin et

2007), providing more evidence that GCs most important for consolidation process

Furthermore, posttraining GCs administerimmediately, but not 3 hours, after audito

fear conditioning facilitates freezing to a to

previously paired with a US but does not ter responses to unpaired tones or to to

or shock alone, suggesting a selective a



11/27

time-dependent role for GC-facilitated mem-

ory of the tone-shock association (Hui et al.2004). In addition, elevation of GCs sys-

temically or in the LA/B enhances the re-trievalof fear memories in avoidance paradigms

(Izquierdo et al. 2002, Roozendaal & McGaugh1997), 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).

RECONSOLIDATION

The Effects of Stress on theReconsolidation of Fear Conditioning

Preliminary evidence suggests that acute stress

before, but not after, memory reactivation dis-rupts 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 courseof reconsolidation processes.

The Effects of NE Manipulation on the Reconsolidation of Fear Conditioning

Although the effects of prereactivation NE ma-nipulations on reconsolidation are unknown,

systemic or intra-amygdala (LA/B) adminis-

tration of propranolol after reactivation dis-rupts reconsolidation of auditory and contex-

tual fear LTM in rats (Abrari et al. 2008,Debiec & Ledoux 2004). The same trend holds

true for avoidance conditioning (Przybyslawskiet al. 1999). These findings are consonant with

reports that propranolol can effectively treat PTSD when administered after aversive mem-

ory activation (Brunet et al. 2008, Orr et al.2006, Pitman & Delahanty 2005, Pitman et al.

2002).

The Effects of GC Manipulation on the Reconsolidation of Fear Conditioning

How alterations of GC activity before reactiva-tion might influence reconsolidation has yet to

be investigated. After reactivation, GR antago-

nism in the LA/B disrupts LTM but not STMof auditory fear reconsolidation; this effect oc-

curs if blockade is immediate, but not 6 hours,after reactivation. Furthermore, this immedi-

ate postreactivation blockade is effective both1 day and 10 days after conditioning ( Jin et al.

2007). Likewise, GR blockade in the LA/B im-mediately after retrieval blocks reconsolidationin an avoidance paradigm (Tronel & Alberini

2007).

EXTINCTION

The Effects of Stress on the Extinction of Fear Conditioning

Chronic stress prior to conditioning impairs

the LTM of auditory and contextual extinctionLTM (Garcia et al. 2008, Miracle et al. 2006);

similarly, patients with PTSD show impairedcued fearextinction (Blechert et al. 2007, Wessa

& Flor 2007). However, reports conflict regard-ing 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 be-

fore extinction does not influence extinction

LTM (G. Quirk, unpublished results). If a stres-soris controllable, themPFC inhibits activation

of brainstem nuclei (Amat et al. 2005). More-over, stress and environmental enrichment pro-

duce opposite effects on fear renewal in a new context; the influence of enrichment outweighs

that of stress (Mitra & Sapolsky 2009).

Involvement of NE in the Extinction of Fear Conditioning

NE in the LA/B after extinction train-ing enhances the consolidation of extinction

memories of contextual fear LTM (Berlau & McGaugh 2006). Furthermore, NE efflux in-

creases 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



12/27


13/27

T a b l e 1

L o c a l i z a t i o n o f m a n i p u l a t i o n s : s y s t e m i c / b r a i n - w

i d

e ( b l a c k ) , L A / B ( r e d ) , h i p p o c a m p u s (

b l u e

) , a n d m P F C ( g r e e n

) a ,

b .

P o s t s h o c

k f r e e z i n g fi n d i n g s

i n c l u d e d i n c o n t e x t u a l S T M r e s u l t s

C o n d i t i o n i n g

R e c o n s o l i d a t i o n

E x t i n c t i o n

P r e t r a i n -

i n g

P o s t t r a i n -

i n g

P r

e t e s t -

i n g

P r e r e a c t i v a -

t i o n

P o s t r e a c

t i v a -

t i o n

P r e c o n d i t i o n -

i n g

P r e e x t i n

c t i o n

t r a i n i n g

P o s t e x t i n c t i o n

t r a i n i n g

S T R E S S

C u e d

S T M

?

?

?

?

?

× ∗

×

?

L T M

↑

↑

?

↑

×

↓

×

?

C o n t e x t u a

l

S T M

+

?

?

?

?

?

?

?

L T M

↑

?

?

?

?

↓

?

?

N E

C u e d

S T M

↑

?

?

?

?

?

×

×

L T M

↑ ↑

× §

× §

?

?

↑ ↑

?

↑

×

C o n t e x t u a

l

S T M

↑

×

?

?

?

?

?

?

L T M

↑

× ↑

↑ ↑

?

↑

?

?

↑

G C s

C u e d

S T M

×

×

?

?

×

?

×

?

L T M

× ∗ ↑

↑ ↑

?

?

↑

?

× ∗

?

C o n t e x t u a

l

S T M

×

×

×

?

?

?

?

×

?

?

L T M

↑ ↑

↑

?

?

?

↓

?

↑

↑

a A b b r e v i a t i o n s : L A / B , l a t e r a

l / b a s a l n u c l e u s o f t h e a m y g d a l a ; G C , g l u c o c o

r t i c o i d s ; L T M , l o n g - t e r m m e m o r y ; m P F C , m

e d i a l p r e f r o n t a l c o r t e x ; N E , n o r e p i n e p h r i n e

; S T M , s h o r t - t e r m m e m o r y .

b K e y :

↑ , S t r e s s , N E , o r G C s f a c i l i t a t e f e a r m e m o r y h e r e .

↓ , S t r e s s o r G C s i m p a i r f e a r

m e m o r y h e r e .

×

, S t r e s s , N E , o r G C s m a n

i p u l a t i o n s p r o d u c e n o i n fl u e n c e s a t t h i s t i m e .

? , E f f e c t s u n k n o w n .

∗ , c o n fl i c t i n g r e p o r t s .

§

, e f f e c t i v e l y d i s r u p t s c o n s o l i d a t i o n o f a v o i d a n c e l e a r n i n g , b u t n o t f e a r c o

n d i t i o n i n g .



14/27

Control Stress

500 nm

500 nm

500 nm

Amygdala (LA/B)

Hippocampus (CA3)

Prefrontal cortex (IL)

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 thehippocampus; IL, infralimbic subregion of the medial prefrontal cortex.

Reconstructed Golgi-impregnated neuron images reproduced with permissionfrom 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 ILneurons through brief uncontrollable stress is

accompanied by a resistance to fear extinct

(Izquierdo et al. 2006). Stress-induced atropof hippocampal (Conrad et al. 1999, McEw

1999, Sousa et al. 2000) and mPFC neuro(Radley et al. 2005) reverses after a stre

free period. However, the same recovery perdoes not rescue stress-induced hypertrophy

amygdala neurons (Vyas et al. 2004).

The Influence of Stress on theElectrophysiological Propertiesof Neurons in Fear Circuitry

Stress and its accompanying biological effe

influence the electrophysiological activityneurons in fear circuitry (see Figure 4). El

trophysiological studies often explore neuroexcitability, as well as long-term potentiati

(LTP), an artificial means of inducing syn

tic connectivity between two brain areas, athus a physiological model of fear learning a

memory(Blairetal.2001,Rodriguesetal.20Schafe et al. 2001). Stress has differential effe

on the amygdala, hippocampus, and prefroncortex, which we now review.

LA/B neurons from stressed animals dispincreased firing rates and greater respo

siveness (Garcia et al. 1998, Kavushanet al. 2006, Kavushansky & Richter-Le

2006, Rodr´ ıguez Manzanares et al. 200 Although some stress paradigms, especia

acute inductions, enhance LTP in the LA

(Rodr´ ıguez Manzanares et al. 2005, Vouimet al. 2004, 2006), other stress protoc

suppress it (Kavushansky & Richter-Le2006, Kavushansky et al. 2006, Kohda et

2007). Along these same lines, the typestress is also a critical factor in the influen

of stress on hippocampal plasticity such thchronic, but not acute, stress suppres

hippocampal LTP (Pavlides et al. 200 Temporal qualities of stressors have oppos

influences on the hippocampus, boosting LT when the tetanizing stimulation is in cl

proximity to emotional processing and d

rupting LTP when there is a substantial debetween the stimulation and initiation of stre

Furthermore, amygdala (LA/B) stimulat



15/27

mimics this emotion-induced influence on

hippocampal plasticity (LA/B) (Diamond et al.2007, Richter-Levin 2004, Richter-Levin &

Akirav 2003). Hippocampal stimulation afterfear extinction training disrupts the recall of

extinction (Garcia et al. 2008). Furthermore,uncontrollable stress drastically impairs hip-

pocampal LTP relative to the influence of thesame 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

patterns of firing rates that encode fast and

slow responses to stress. Whereas some mPFCneurons respond phasically during the duration

of a stressor, others show activity that persistsafter the stress ceases, and yet others respond

during the initiation and termination of stress( Jackson & Moghaddam 2006). Furthermore,

stress reduces LTP induction in projectionsfrom both the LA/B (Maroun & Richter-Levin 2003) and hippocampus (Cerqueira

et al. 2007, Rocher et al. 2004) to thePFC.

Dendrite

LA/B neuroncell body

Decrease of GABA-mediated inhibition

GABA-Areceptor

Axon

GABACl-

Enhancement of neuronalresponses and excitability

Alteration of plasticity thatunderlies fear learning

LTP induction

Time (min)

100

200

P e r

c e n t o f c o n t r o l

0 50

Figure 4

Influence of stress, norepinephrine (NE), and glucocorticoids (GCs) on the electrophysiological propertiesof 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).



16/27

The Influence of NE on theElectrophysiological Propertiesof Neurons in Fear Circuitry

NE increases the spiking of neurons in the LA and facilitates the induction of LTP (Tully et al.

2007). What’s more,fear conditioning increasesdepolarization-evoked NE release (Liu et al.

2007). Moreover, ARs seem particularly pivotalfor a late phase of LTP in the LA, which persists

for at least three hours and requires the synthe-sis of new mRNA and protein (Huang et al.

2000). The reactivity of the hippocampal neu-rons is enhanced by NE (Harley 2007, Segal

et al. 1991), and suppression of GC secretion

increases NE transmission here (Mizoguchiet al. 2008); the relevance of this to fear learning

and memory processes is unclear. In the IL of the mPFC, fear conditioning decreases, and ex-

tinction increases, neuronal excitability (Santiniet al. 2008). Pertinent to this, NE signaling in

this region increases neuron excitability (Barthet al. 2007, Mueller et al. 2008) and strength-

ens the memory for extinction (Mueller et al.2008).

The Influence of GCs on theElectrophysiological Propertiesof Neurons in Fear Circuitry

Both high and low GC concentrations en-

hance the excitability of LA/B neurons (Du-

varci & Par´ e 2007, Kavushansky & Richter-Levin 2006). In addition, GCs depolarize the

resting potential, increase input resistance, andsignificantly decrease spike-frequency adapta-

tion of LA/B neurons (Duvarci & Par ´ e 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 relation-ship of MR and GR activation exists for en-

hancing and suppressing effects of GCs on

hippocampal LTP, respectively (Pavlides et al.1996, Pavlides & McEwen 1999). We do not

know how GCs directly influence the el

trophysiological profiles of mPFC neuro Therefore, more data are needed to illustr

how GCs interact with other factors to inflence plasticity in structures that modulate f

conditioning.

CONCLUSIONS

An extensive literature has demonstrated

ways in which stress, and the endocrine medtors of the stress response, can impact expli

declarative memory processes (McEwen 199 Though based on a smaller literature, this

view highlights the ability of stress and aroustriggered fear to impact emotional learn

and memory, as assessed by fear conditioing. Indeed, stressful experiences, NE,and G

alter the morphological and electrophysiolocal characteristics of neurons in areas that pla vital role in fear processing, including the am

dala (LA/B), hippocampus, and PFC. As a sult, they can have a powerful influence on f

conditioning.In the laboratory, investigators use a nu

ber of models to induce stress, includexposure to predator odor, restraint, foot sho

forced swimming, saline injections, and ctemperatures. Furthermore, the duration

stress manipulations can be acute, moderatechronic. Although thesedifferencesmakedir

comparisons between studies difficult, ster

typical responses to these various stressorsoccur and activate the brain’s fear syste

thus initiating the stress response in both tbody and the brain. Nonetheless, because str

magnitude and duration differentially impthe morphological and electrophysiolog

properties of fear circuitry neurons, it wobe important for future studies to comp

and contrast the influence of different strprotocols.

Existing studies show that stress beforeafter training boosts LTM of fear conditio

ing. In addition, stress before, but not aftreactivation enhances reconsolidation. Fina

stress before fear conditioning, but not bef



17/27

extinction training, interferes with extinction

LTM. Altogether, these findings suggest that during initial learning, stress activates events

that can influence later consolidation and ex-tinction processes. Whether effects exist on the

acquisition and expression of fear is less clearowing to the relative paucity of studies.

In regard to NE, cumulative evidence sug-gests that NE is important for fear condition-ing, reconsolidation, and extinction, but not for

consolidation. NE increases neuronal excitabil-ity and LTP in the LA, and its activity there is

needed for both STM and LTM of fear condi-tioning. NE also increases neuronal excitability

in the IL of the mPFC and is important for theLTM of extinction. Because pretraining but not

posttraining intra-amygdala (LA/B) or intra-mPFC infusions of propranolol block LTM of

fear conditioning and extinction, respectively,it seems that NE must be tonically active dur-

ing learning to promote rapid postlearning cas-

cades in the LA and IL to facilitate STM re-trieval 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) GCdisrupting LTM is consonant with electrophys-

iological findings that GCs have long-term, but not short-term, enhancing effects on neuronal

excitability in LA/B (Duvarci & Par´ e 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 thecytoplasm and acting as a transcription factor

upon translocating to the nucleus, whereasless traditional GR actions include rapid,

nongenomic effects. The fact that GRs seemmore important for fear consolidation than for

learning, and for enduring but not immediateinfluences on the firing of LA/B neurons,

suggests that more traditional genomic effects

underlie these behavioral and electrophysio-logical findings.

Stress-induced enhancement of LTP in au-ditory inputs to the LA alongside disruption of

LTP in the projections to the PFC from thehippocampus and the LA/B is congruent with

the notion that powerful fear inputs can facil-itate strong emotional pathways at the cost of activating more regulatory pathways. Indeed,

an abundant literature showing that NE is im-portant particularly for hippocampal and PFC

function, in addition to LA/B activation, is inline with NE’s role in arousal and cognition.

Given that hippocampal function is dis-rupted by major stressors or exposure to ele-

vated levels of GCs, how might it play a pivotalrole in forming fear memories, particularly con-

textualones?Thisanswermightbeexplainedby the model of the hippocampus shifting from acognitive mode to a flashbulb memory mode

under intense stress, which explains why thecontextual memories of traumatic experiences

are vivid and endure for many years but tend tobe disjointed and fragmented (Diamond et al.

2007).In summary, stress, NE, and GCs appear to

be potent modulators of fear memory forma-tion. Furthermore, the ability of stress, NE,

and GCs to decrease GABA (γ

-aminobutyricacid)-A receptor-mediated inhibition (Duvarci

& Par´ e 2007, Rodriguez Manzanares et al.

2005, Tully et al. 2007), thereby allowing forincreased excitability in LA/B, is harmonious

with the fact that benzodiazepines act on thisreceptor to decrease anxiety.

During difficult times, we are often advisedto “use our heads” or “follow our hearts” or “go

with our gut.” As this review highlights, ourbodies 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.



18/27

ACKNOWLEDGMENTS

We apologize to all the investigators whose research could not be appropriately cited owto space limitations. We extend our sincere gratitude to our many wonderful collaborators

thoughtful discussions pertaining to the topic and data of this review. Research by S.M.R. aR.M.S. on this topic supported by NIH Grant 5R01 AG020633. J.E.L. supported by NIH Gra

P50 MH058911, R01 MH046516, R37 MH037884, and K05 MH067048.

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