The Influence of Stress Hormones on Fear Circuitry

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The Influence of StressHormones on Fear CircuitrySarina M. Rodrigues,1 Joseph E. LeDoux,2,∗

and Robert M. Sapolsky3,∗

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] 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] 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 onMarch 24, 2009

The Annual Review of Neuroscience is online atneuro.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

AbstractFear arousal, initiated by an environmental threat, leads to activation ofthe stress response, a state of alarm that promotes an array of autonomicand endocrine changes designed to aid self-preservation. The stress re-sponse includes the release of glucocorticoids from the adrenal cortexand 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 illustratethis influence, we focus on how it impacts fear conditioning, a behavioralparadigm widely used to study the neural mechanisms underlying theacquisition, expression, consolidation, reconsolidation, and extinctionof emotional memories. We also discuss how stress and the endocrinemediators of the stress response influence the morphological and elec-trophysiological properties of neurons in brain areas that are crucialfor fear-conditioning processes, including the amygdala, hippocampus,and prefrontal cortex. The information in this review illuminates thebehavioral and cellular events that underlie the feedforward and feed-back networks that mediate states of fear and stress and their interactionin the brain.

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Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . 291WHAT IS FEAR, AND HOW IS IT

ORGANIZED IN THE BRAIN? . . 291Studying Fear in the Laboratory

with Fear Conditioning . . . . . . . . . 291Phases of Fear Conditioning . . . . . . . . 292Neural Circuitry Underlying

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

STRESS RESPONSE:OVERVIEW OF THISFEEDFORWARD ANDFEEDBACK NETWORK . . . . . . . . . 294

HOW DO STRESS,NOREPINEPHRINE, ANDGLUCOCORTICOIDSINFLUENCE DIFFERENTPHASES OF FEARCONDITIONING?. . . . . . . . . . . . . . . 295

ACQUISITION OF FEARCONDITIONING. . . . . . . . . . . . . . . . 297The Effects of Stress on the

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

The Effects of NE on theAcquisition of FearConditioning . . . . . . . . . . . . . . . . . . . 297

The Effects of GCs on theAcquisition of FearConditioning . . . . . . . . . . . . . . . . . . . 297

CONSOLIDATION OFLONG-TERM MEMORY . . . . . . . . 297The Effects of Stress on the

Consolidation of LTM ofFear Conditioning . . . . . . . . . . . . . . 297

The Effects of NE on theConsolidation of LTMof Fear Conditioning . . . . . . . . . . . . 298

The Effects of GCs on the

Consolidation of LTMof Fear Conditioning . . . . . . . . . . . . 298

RECONSOLIDATION . . . . . . . . . . . . . . 299The Effects of Stress on the

Reconsolidation of FearConditioning . . . . . . . . . . . . . . . . . . . 299

The Effects of NE Manipulationon the Reconsolidation of FearConditioning . . . . . . . . . . . . . . . . . . . 299

The Effects of GC Manipulationon the Reconsolidationof Fear Conditioning . . . . . . . . . . . . 299

EXTINCTION . . . . . . . . . . . . . . . . . . . . . . 299The Effects of Stress on the

Extinction of FearConditioning . . . . . . . . . . . . . . . . . . . 299

Involvement of NE in the Extinctionof Fear Conditioning . . . . . . . . . . . . 299

Involvement of GCs in theExtinction of FearConditioning . . . . . . . . . . . . . . . . . . . 300

SUMMARY OF THE EFFECTSON FEAR CONDITIONING . . . . 300

HOW STRESS AFFECTSFEAR CIRCUITRY ONA CELLULAR LEVEL. . . . . . . . . . . . 300The Influence of Stress on

the Morphology of Neuronsin Fear Circuitry . . . . . . . . . . . . . . . . 300

The Influence of Stress on theElectrophysiological Propertiesof Neurons in Fear Circuitry . . . . 302

The Influence of NE on theElectrophysiological Propertiesof Neurons in Fear Circuitry . . . . 304

The Influence of GCs on theElectrophysiological Propertiesof Neurons in Fear Circuitry . . . . 304

CONCLUSIONS . . . . . . . . . . . . . . . . . . . . 304

“The oldest and strongest emotion of mankind isfear.”

—H.P. Lovecraft

“A crust eaten in peace is better than a banqueteaten 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 helporganisms cope with environmental threatsand other challenges to safety and well-being.Skunks spray offensive odors, blowfish inflate tolook bigger than they actually are, and roachesscurry away into crevices for safety. Althoughhumans in modern societies usually have theluxury 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 tosave us from peril both in everyday situationsas well as under rare but hazardous conditions:We duck for cover, slam on the brakes, run forthe hills, or scream for help.

Fear arousal is one of the most reliableroutes 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 theway emotional and cognitive systems processinformation. Although such responses enhancesurvival in the short run, chronic activationof 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 howfear 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 coversome important topics, including how early-lifeexperiences, genetics, or gender might inter-act with stress in altering fear (DeRijk & deKloet 2005, Kalin & Shelton 2003, Luine 2002,Lyons & Parker 2007, Meaney 2001, Weinstock2007).

CS: neutralconditioned stimulus

US: aversiveunconditionedstimulus

NE: norepinephrine

GC: glucocorticoid

CR: conditionedresponse

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

The term fear refers to both a psychologicalstate and a set of bodily responses that occurin response to threat (LeDoux 1996). Muchprogress has been made in understanding howfear is organized in the brain through studiesof Pavlovian fear conditioning, which we fo-cus on here (Fanselow & Poulos 2005; Lang &Davis 2006; LeDoux 1995, 1996, 2007; Maren2001, 2005; Pare 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-ber of studies have examined the role of brain ar-eas in passive and active avoidance conditioning(Gabriel et al. 2003, McGaugh 2003, Sarter &Markowitsch 1985). In such studies, fear ismeasured indirectly in terms of instrumentalbehaviors that avoid danger. Because studies ofavoidance conditioning have not led to a co-herent view of the neural system that mediatesavoidance (Cain & LeDoux 2008), we empha-size the effects of stress on fear conditioning inthis review. However, we mention some find-ings from other procedures where relevant.

Studying Fear in the Laboratorywith 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 orseveral pairings, the CS comes to elicit de-fensive behaviors, including freezing behav-ior, as well as increased arousal in the brainand secretion of norepinephrine (NE) andglucocorticoids (GCs) peripherally. Theseconditioned responses (CRs) are hard-wiredand occur in response to both innate andlearned threats. Thus, fear learning does notcreate conditioned fear responses but allowsenvironmental 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 ofthe amygdala

CE: central nucleus ofthe amygdala

Phases of Fear Conditioning

In studies of fear conditioning, responseselicited by the CS are often measured duringacquisition and retrieval tests. Acquisition is ini-tial learning of the association between the CSand US during the training portion of fear con-ditioning, when the animal first learns to pairthe 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 areused 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, Rodrigueset 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(Dudai 2006, Nader 2003, Nader et al. 2000). Inaddition, retrieval tests are utilized to measureextinction, which is the gradual reduction in theability of the CS to elicit fear CRs that occurwhen 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. Asa 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 & Maren2007).

Neural Circuitry UnderlyingFear 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 con-trol systems. A key link in this circuitry is theamygdala, which sits between the sensory in-put systems on one hand and the motor outputsystems on the other (Fanselow & Poulos 2005;Lang & Davis 2006; LeDoux 1995, 1996, 2007;Maren 2001, 2005; Pare et al. 2004; Rodrigueset al. 2004). However, other brain structuresalso contribute to fear conditioning.

Amygdala contributions to fear condition-ing. The amygdala contains a heterogeneity ofdistinct nuclei, differing by cell type, density,neurochemical composition, and connectivity(LeDoux 2007, Pitkanen et al. 2000, Swanson2003).

The lateral nucleus (LA) is typically viewedas the sensory gateway to the amygdala be-cause it receives auditory, visual, gustatory,olfactory, and somatosensory (including pain)information from the thalamus and the cor-tex (olfactory and taste information is transmit-ted to other nuclei, as well). The LA receivessensory information about the CS from tha-lamic and cortical projections. The thalamo-amygdala pathway is a shortcut of sorts, trans-mitting rapid and crude information about thefear-eliciting stimulus without the opportu-nity for filtering by conscious control (LeDoux1995, 1996). The cortico-amygdala pathway, incontrast, provides slower, but more detailed andsophisticated sensory information. Neurons inthe LA respond to both the CS and the US,and damage to, or a disruption of, the LA pre-vents fear conditioning. It appears that the con-vergence takes place in the dorsal half of theLA (Romanski et al. 1993), and indeed single-unit recordings show that cellular plasticity oc-curs in the dorsal LA during fear conditioning(LeDoux 2007, Maren & Quirk 2004). More-over, molecular changes in the LA consolidatethe fear memory, converting STM into LTMtraces (Dudai 2004, Rodrigues et al. 2004).

The central nucleus (CE), in contrast, isviewed as the major output region of theamygdala. The CE controls the expressionof the fear reaction, including behavioral,


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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; Pare et al. 2004; Rodrigueset al. 2004). Plasticity also occurs in the CE(Pare 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 amygdaloidnuclei 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 alsoproject to the intercalated region (ITC), an in-hibitory network that connects with the CE(Likhtik et al. 2008, Pare et al. 2004). Projec-tion neurons in the CE tend to be inhibitory,thus LA and B projections to the ITC maystimulate the ITC’s inhibition of CE neuronsto allow the expression fear responses (LeDoux2007). In addition, the B projects to the striatum(McDonald 1991) to orchestrate instrumentalbehaviors, such as escape to safety (LeDoux2007). Furthermore, CE neurons project to themedial peri-locus coeruleus dendritic region,resulting in increased NE release (Aston-Jones2004), as well as to other monoamine systems inthe brainstem and forebrain (Fudge & Emiliano2003, Gray 1993, Pare 2003).

Information about the context of a fear-ful situation is conveyed to the LA andB by the hippocampus ( Ji & Maren 2007,Kim & Fanselow 1992, Phillips & LeDoux1992, 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. TheLA and B are also interconnected to a variety ofcortical areas, such as the prefrontal and poly-modal association cortices (Amaral & Insausti1992, McDonald 1998, McDonald et al. 1996,

B: basal nucleus of theamygdala

mPFC: medialprefrontal cortex

IL: infralimicsubregion 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, toinfluence amygdala functions.

The LA, B, and accessory basal nuclei aresometimes 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 notdepend on the LA (Lee et al. 2005, Maren1999). With overtraining, weak connectionsto the CE appear to induce fear conditioning(Zimmerman et al. 2007), but such pathwaysare not normally used. Moreover, although theB is not required for conditioning, it neverthe-less appears to contribute to the appearance ofthe fear response (Anglada-Figueroa & Quirk2005). Some authors suggest that under someconditions, especially those involving the useof instrumental responses to assess Pavlovianconditioning, the CE can mediate condition-ing independent of LA (Balleine & Killcross2006, Cardinal et al. 2002). However, this con-clusion is extrapolated largely on the basisof appetitive conditioning findings and needsto be studied more systematically in aversiveconditioning.

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 (Quirket 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 varioussensory 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 andentorhinal cortex

Polymodalassociation cortex

ITC

LA

B

CE

HPA axis(hypothalamus)

Freezing(central gray)

Modulatory systems:NE, 5HT, DA, ACh

(cell groups inforebrain and/or

brainstem)

Sympathetic andparasympathetic NS

(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. (Bottom)Outputs of some specific amygdala nuclei. 5HT, serotonin; Ach, acetylcholine; B, basal nucleus; CE, centralnucleus; DA, dopamine; ITC, intercalated cells; LA, lateral nucleus; NE, norepinephrine; NS, nervoussystem.

FEAR AROUSAL AND THESTRESS RESPONSE: OVERVIEWOF THIS FEEDFORWARD ANDFEEDBACK NETWORK

The presence of an environmental threat, ineffect a stressor, leads to the activation of thebrain’s fear system, thus initiating the stressresponse in both the brain and the body. A keystructure in the fear system, as we have just re-viewed, is the amygdala. It is responsible forthe detection of threat and the orchestration of

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

Once the amygdala detects a threat, itsoutputs lead to the activation of a variety oftarget areas that control both behavioral andphysiological responses designed to addressthe threat (Lang & Davis 2006; LeDoux 1996,2002). In addition to the expression of de-fensive 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 reac-tion. In the brain, monoaminergic systems areactivated, resulting in the release of neurotrans-mitters such as NE, acetylcholine, serotonin,and dopamine throughout the brain. Theseneurotransmitters lead to an increase in arousaland vigilance and, in general, an enhancementin 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 signalingcauses secretion of corticotropin-releasing hor-mone (CRH) from the periventricular nucleusof the hypothalamus. CRH, along with otherhypothalamic secretagogs, causes the release ofadrenocorticotropic hormone from the pitu-itary, which in turn stimulates the secretion ofGCs from the adrenal cortex. Circulating GCsbind to the high-affinity mineralocorticoidreceptor (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. Connectionsfrom 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 fromthe terminals of sympathetic nerves through-out the body. Adrenal medullary hormones andsympathetic nerves produce an array of effects,including increasing blood pressure and heartrate, 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 stressresponses. Thus, GCs travel in the circulationto the brain and affect the amygdala and a vari-ety of other structures. Although NE does notcross the blood-brain barrier, it may affect thebrain indirectly by binding to visceral afferentnerves, which transmit to the brain (McGaugh2003). Thus, the detection of threat and theconsequent activation of the fear system elicit avariety of effects that feed back onto the system

GR: glucocorticoidreceptor

that initiates and modulates emotional process-ing (McEwen 2003, Pare 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 mechanismsresponsible 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 highlightoverarching 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 drugstend to last beyond the short training sessionin such studies (sometimes only a single train-ing trial). If pretraining manipulations disruptSTM but posttraining manipulations do not,the effect is said to be on acquisition (thoughan effect on STM itself cannot be ruled out).If posttraining manipulations leave STM intactbut disrupt LTM, then the effect is said to be onLTM consolidation. Another important manip-ulation involves treatments given immediatelybefore testing LTM. This treatment is called anexpression test. However, many studies exam-ine pretraining or postraining effects only onLTM but not on STM or on acquisition. Sim-ilarly, relatively few studies observe effects onexpression. Therefore, more investigations areneeded to fully determine how stress, NE, andGCs 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. Althoughvariability in protocols makes it difficult to com-

pare stress manipulations directly across stud-ies, we make distinctions between acute andchronic stress throughout.

Amygdala

Hippocampus

PFCPFC

Sensory Sensory thalamus thalamus

Sensory Sensory cortexcortex

PFC

Sensory thalamus

Release of stress hormones

Environmentalthreat

(slow)(slow)(slow)

MonoamineMonoaminesystemssystems

Monoaminesystems

Feedback loop

MedullaCortex

PVN PVN PVN

ACTH

SNS

Epinephrine andnorepinephrine

Epinephrine andnorepinephrine

• 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

Glucocorticoids

Glucocorticoids

Pituitary

Functional connectivity Processing threat stimulus

c d

a b

ARs

(fast)(fast)(fast)

Sensory Sensory thalamus thalamus

Sensory Sensory cortexcortex

Sensory thalamus

Sensory cortex

Sensory cortex

Vagusnerve

NTSNTSNTS

MRs and GRs

Kidney

Adrenalgland

Adrenal glandAddren


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ACQUISITION OF FEARCONDITIONING

The Effects of Stress on theAcquisition of Fear Conditioning

Although many studies have looked at the ef-fects of pretraining stress on the LTM of fearconditioning (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 indexedby their locomotion in a novel environment(Cordero et al. 2003a). This classification sug-gests that at least in some conditions, stress mayinfluence behavior during the learning pro-cess. However, this possibility needs furtherstudy because postshock freezing during acqui-sition reflects contextual conditioning as muchas cued.

The Effects of NE on the Acquisitionof Fear Conditioning

Locus coeruleus lesions or pretraining infu-sion of propranolol, a beta adrenergic receptorantagonist, into the amygdala (LA/B) blocksSTM, and consequently 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 Acquisitionof Fear Conditioning

The contribution of GCs to fear acquisitionhas been studied by either removing their ef-fects via adrenalectomy, blocking GRs in theamygdala 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 onfear, adrenalectomized rats show reduced con-textual LTM but no immediate memory im-pairments (Pugh et al. 1997b). Likewise, GRblockade 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 aviral vector expressing a gene to blunt GR sig-naling, which effectively disrupts both cued andcontextual LTM without affecting acquisitionor postshock levels of freezing (Rodrigues &Sapolsky 2009). These studies suggest that GCsmay not be involved in acquisition so much asin the consolidation of fear LTM. We discussadditional results that support this claim in thefollowing section.

CONSOLIDATION OFLONG-TERM MEMORY

Studies assessing memory consolidation typ-ically administer manipulations immediatelyafter 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 ofFear Conditioning

Pretraining exposure to both acute and chronicstressors can enhance LTM of both cuedand contextual fear conditioning for at least

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−Figure 2Overview 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 ofthreatening 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 stressalso enhances LTM for cued fear conditioning(Hui et al. 2006). Furthermore, preexposureto stress sensitizes fear-conditioning responsessuch that less-intense stressors can produce ro-bust fear behaviors, which may help explainwhy individuals with PTSD react strongly tomild stimuli and quickly form new fears (Rauet al. 2005). Because measurements of pretrain-ing stress on acquisition and STM are lackingin the literature, more research is needed to ad-dress the temporal dynamics of stress on fearconditioning.

The Effects of NE on theConsolidation of LTMof 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 fearLTM (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 notaffect LTM consolidation of auditory or contex-tual fear conditioning (Bush et al. 2006, Debiec& Ledoux 2004, Lee et al. 2001). Thus, NEin the amygdala does not seem critical for theconsolidation of fear conditioning, but it doesseem to interact with GCs to fortify memories(Roozendaal et al. 2006).

Posttraining intrahippocampal propranololinfusions given immediately, but not six hoursafter training, block LTM, but not STM, ofcontextual fear conditioning ( Ji et al. 2003).Furthermore, systemic or intrahippocampal in-fusions given before testing one day after condi-tioning impair the retrieval of contextual mem-ories (Murchison et al. 2004).

In humans, systemic NE blockade dis-rupts the consolidation of contextual, but notcued, fear conditioning LTM (Grillon et al.2004). Studies involving avoidance condition-ing, an indirect means of measuring fear, showthat posttraining systemic and intra-amygdala(LA/B) pharmacological manipulations showthat NE is crucial to consolidate avoidancelearning (Ferry & McGaugh 1999, Gallagheret al. 1977, Liang et al. 1986, Quirarte et al.1997, Roozendaal & McGaugh 1997). More-over, NE levels following avoidance trainingcorrelate with subsequent retention (McGaughet al. 2002, McIntyre et al. 2002). Thus, directmeasurement of fear responses with fear condi-tioning gives a different pattern of results thando indirect measures with avoidance condition-ing. More work systematically examining theseeffects is needed.

The Effects of GCs on theConsolidation of LTMof Fear Conditioning

Pretraining systemic, intrahippocampal, orintra-amygdala (LA/B) manipulation of GCsinfluences the LTM of fear conditioning; con-textual memories are more vulnerable (Conradet al. 2004; Cordero et al. 2002; Donley et al.2005; Pugh et al. 1997a,b) likely because con-textual fear memory is generally weaker (i.e.,harder to learn and easier to disrupt) than cuedfear memory (Phillips & LeDoux 1992).

Posttraining systemic manipulations of GCsalso impact both auditory and contextualfear memory consolidation (Corodimas et al.1994, Hui et al. 2004, Pugh et al. 1997a,Zorawski & Killcross 2002). Moreover, post-training GR blockade in the LA/B affects au-ditory fear LTM but not STM ( Jin et al.2007), providing more evidence that GCs aremost important for consolidation processes.Furthermore, posttraining GCs administeredimmediately, but not 3 hours, after auditoryfear conditioning facilitates freezing to a tonepreviously paired with a US but does not al-ter responses to unpaired tones or to toneor shock alone, suggesting a selective and


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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-trieval of fear memories in avoidance paradigms(Izquierdo et al. 2002, Roozendaal & McGaugh1997), and this enhancement can be effectivefor memories acquired from one day to manymonths before (Izquierdo et al. 2002). Finally,in humans, high GC levels positively correlatewith fear memory consolidation (Zorawski et al.2006).

RECONSOLIDATION

The Effects of Stress on theReconsolidation of Fear ConditioningPreliminary evidence suggests that acute stressbefore, but not after, memory reactivation dis-rupts auditory fear reconsolidation LTM (Bushet al. 2004). It would be interesting to see howchronic stress or intra-amygdala manipulationsinfluence this phenomenon and the time courseof reconsolidation processes.

The Effects of NE Manipulationon the Reconsolidation of FearConditioningAlthough 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 holdstrue for avoidance conditioning (Przybyslawskiet al. 1999). These findings are consonant withreports that propranolol can effectively treatPTSD 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 Manipulationon the Reconsolidationof Fear ConditioningHow 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 & Alberini2007).

EXTINCTION

The Effects of Stress on the Extinctionof Fear Conditioning

Chronic stress prior to conditioning impairsthe LTM of auditory and contextual extinctionLTM (Garcia et al. 2008, Miracle et al. 2006);similarly, patients with PTSD show impairedcued fear extinction (Blechert et al. 2007, Wessa& Flor 2007). However, reports conflict regard-ing the influence of stress on the learning ofextinction (Izquierdo et al. 2006, Miracle et al.2006), perhaps because of differences in stresstypes or protocols or species (mice versus rats).Stress induction after fear conditioning but be-fore extinction does not influence extinctionLTM (G. Quirk, unpublished results). If a stres-sor is controllable, the mPFC inhibits activationof brainstem nuclei (Amat et al. 2005). More-over, stress and environmental enrichment pro-duce opposite effects on fear renewal in a newcontext; the influence of enrichment outweighsthat of stress (Mitra & Sapolsky 2009).

Involvement of NE in the Extinctionof Fear Conditioning

NE in the LA/B after extinction train-ing enhances the consolidation of extinctionmemories of contextual fear LTM (Berlau &McGaugh 2006). Furthermore, NE efflux in-creases in the PFC during presentation of aCS previously paired with a US (Feenstra et al.2001). Similarly, administration of propranololin the IL subregion of the mPFC before, but


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not after, extinction training impairs retrievalof extinction the following day while leavingwithin-session extinction intact. Furthermore,NE signaling in the IL strengthens extinctionmemory (Mueller et al. 2008).

Involvement of GCs in the Extinctionof Fear Conditioning

Chronic GC exposure, which decreasesendogenous GC secretion, prior to fear condi-tioning impairs contextual extinction LTM butnot STM and results in a decrease of NMDA(N-methyl-d-aspartate) and AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate)excitatory receptor subunits in the mPFC(Gourley et al. 2008). In addition, systemicand intra-amygdala (LA/B) GC manipulationsprior to extinction training suggest that GRactivation is key for extinction learning in afear-potentiated startle paradigm (Yang et al.2006). Although systemic GC administrationbefore extinction training does not produceextinction learning or LTM impairments (G.Quirk, unpublished results), metyrapone,a GC synthesis inhibitor, affects extinctionLTM while leaving learning intact (Barrett &Gonzalez-Lima 2004). Moreover, adrenergicreceptor (AR) blockade or GR activation afterretrieval disrupts recall of contextual fear con-ditioning, but only the effects of GR activationare reversed by a reminder shock (Abrari et al.2008). Along these same lines, GR-mediateddisruptions of fear memories show sponta-neous recovery and renewal of CRs (Barrett& Gonzalez-Lima 2004, Cai et al. 2006).However, GR inactivation impairs CRs in anavoidance task, and these do not reemergeafter strong reminders (Tronel & Alberini2007), possibly because of the involvement ofother processes in this paradigm. Nonetheless,the results from animal studies that show GCactivity may promote extinction (Barrett &Gonzalez-Lima 2004, Cai et al. 2006) parallelfindings that PTSD and phobia symptoms,but not general anxiety, can improve with GCtreatment (Aerni et al. 2004, de Quervain 2008,Schelling et al. 2004, Soravia et al. 2006).

SUMMARY OF THE EFFECTSON FEAR CONDITIONING

Table 1 summarizes results from animal stud-ies presented in this review. This informationcomes with a number of caveats: First, data wereoften gathered from only a very small number ofpapers for each topic; second, few studies exam-ined both contextual and cued fear condition-ing; third, it was rarely the case that both STMand LTM were examined; fourth, little workhas examined effects of stress, NE, or GCs onthe expression of fear; and fifth, the importantmodulatory effects of age, genetics, and genderhave not been discussed throughout this reviewin the interest of space.

HOW STRESS AFFECTSFEAR CIRCUITRY ONA CELLULAR LEVEL

The Influence of Stress onthe Morphology of Neuronsin Fear Circuitry

Stress can alter the morphology of pyramidalneurons in structures involved in fear circuitry(see Figure 3). To begin, chronic stress causesan increase in the dendritic arborization, spineformation, and synaptic connectivity in princi-pal 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 chronicunpredictable stress, induces this dendritic re-modeling in the LA/B (Vyas & Chattarji 2004).In addition, the duration of stress directly im-pacts the spatiotemporal patterns of spine for-mation such that both acute and chronic stres-sors increase spines in LA/B neurons, but onlythe latter has an effect on dendritic arbors(Mitra et al. 2005). Furthermore, a single, acutedose of GCs is sufficient to produce anxietyand hypertrophy of LA/B neurons (Mitra &Sapolsky 2008). Contrasting with these ef-fects, stress decreases dendritic branching andspine count in the hippocampus (for review, seeMcEwen & Magarinos 2001).

Neurons in the mPFC endure morpholog-ical changes due to stress and GCs, including


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Tab

le1

Loc

aliz

atio

nof

man

ipul

atio

ns:s

yste

mic

/bra

in-w

ide

(bla

ck),

LA

/B(r

ed),

hipp

ocam

pus

(blu

e),a

ndm

PFC

(gre

en)a,

b.P

osts

hock

free

zing

findi

ngs

incl

uded

inco

ntex

tual

STM

resu

lts

Con

diti

onin

gR

econ

solid

atio

nE

xtin

ctio

nP

retr

ain-

ing

Pos

ttra

in-

ing

Pre

test

-in

gP

rere

acti

va-

tion

Pos

trea

ctiv

a-ti

onP

reco

ndit

ion-

ing

Pre

exti

ncti

ontr

aini

ngP

oste

xtin

ctio

ntr

aini

ngST

RE

SSC

ued

STM

??

??

?×∗

×?

LTM

↑↑

?↑

×↓

×?

Con

text

ual

STM

+?

??

??

??

LTM

↑?

??

?↓

??

NE

Cue

dST

M↑

??

??

?×

×LT

M↑↑

×§×§

??

↑↑?

↑×

Con

text

ual

STM

↑×

??

??

??

LTM

↑×↑

↑↑?

↑?

?↑

GC

sC

ued

STM

××

??

×?

×?

LTM

×∗↑

↑↑?

?↑

?×∗

?C

onte

xtua

lST

M×

××

??

??

×?

?LT

M↑↑

↑?

??

↓?

↑↑

a Abb

revi

atio

ns:L

A/B

,lat

eral

/bas

alnu

cleu

sof

the

amyg

dala

;GC

,glu

coco

rtic

oids

;LT

M,l

ong-

term

mem

ory;

mP

FC,m

edia

lpre

fron

talc

orte

x;N

E,n

orep

inep

hrin

e;ST

M,s

hort

-ter

mm

emor

y.bK

ey:

↑,St

ress

,NE

,or

GC

sfa

cilit

ate

fear

mem

ory

here

.↓,

Stre

ssor

GC

sim

pair

fear

mem

ory

here

.×

,Str

ess,

NE

,or

GC

sm

anip

ulat

ions

prod

uce

noin

fluen

ces

atth

istim

e.?,

Eff

ects

unkn

own.

∗ ,con

flict

ing

repo

rts.

§,e

ffec

tivel

ydi

srup

tsco

nsol

idat

ion

ofav

oida

nce

lear

ning

,but

notf

ear

cond

ition

ing.


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Control Stress

500 nm

500 nm

500 nm

Amygdala (LA/B)

Hippocampus (CA3)

Prefrontal cortex (IL)

Figure 3Influences 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; Izquierdoet 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 extinction(Izquierdo et al. 2006). Stress-induced atrophyof hippocampal (Conrad et al. 1999, McEwen1999, Sousa et al. 2000) and mPFC neurons(Radley et al. 2005) reverses after a stress-free period. However, the same recovery perioddoes not rescue stress-induced hypertrophy ofamygdala neurons (Vyas et al. 2004).

The Influence of Stress on theElectrophysiological Propertiesof Neurons in Fear Circuitry

Stress and its accompanying biological effectsinfluence the electrophysiological activity ofneurons in fear circuitry (see Figure 4). Elec-trophysiological studies often explore neuronalexcitability, as well as long-term potentiation(LTP), an artificial means of inducing synap-tic connectivity between two brain areas, andthus a physiological model of fear learning andmemory (Blair et al. 2001, Rodrigues et al. 2004,Schafe et al. 2001). Stress has differential effectson the amygdala, hippocampus, and prefrontalcortex, which we now review.

LA/B neurons from stressed animals displayincreased firing rates and greater respon-siveness (Garcia et al. 1998, Kavushanskyet al. 2006, Kavushansky & Richter-Levin2006, Rodrıguez Manzanares et al. 2005).Although some stress paradigms, especiallyacute inductions, enhance LTP in the LA/B(Rodrıguez Manzanares et al. 2005, Vouimbaet al. 2004, 2006), other stress protocolssuppress it (Kavushansky & Richter-Levin2006, Kavushansky et al. 2006, Kohda et al.2007). Along these same lines, the type ofstress is also a critical factor in the influenceof stress on hippocampal plasticity such thatchronic, but not acute, stress suppresseshippocampal LTP (Pavlides et al. 2002).Temporal qualities of stressors have oppositeinfluences on the hippocampus, boosting LTPwhen the tetanizing stimulation is in closeproximity to emotional processing and dis-rupting LTP when there is a substantial delaybetween the stimulation and initiation of stress.Furthermore, amygdala (LA/B) stimulation


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mimics this emotion-induced influence onhippocampal plasticity (LA/B) (Diamond et al.2007, Richter-Levin 2004, Richter-Levin &Akirav 2003). Hippocampal stimulation afterfear extinction training disrupts the recall ofextinction (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 indetermining the controllability of stress (Amatet al. 2005), and neurons here display unique

patterns of firing rates that encode fast andslow responses to stress. Whereas some mPFCneurons respond phasically during the durationof a stressor, others show activity that persistsafter the stress ceases, and yet others respondduring 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 (Cerqueiraet al. 2007, Rocher et al. 2004) to thePFC.

Dendrite

LA/B neuron

cell 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

Pe

rce

nt

of

con

tro

l

0 50

Figure 4Influence 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).


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The Influence of NE on theElectrophysiological Propertiesof Neurons in Fear Circuitry

NE increases the spiking of neurons in the LAand 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 persistsfor 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, Segalet al. 1991), and suppression of GC secretionincreases NE transmission here (Mizoguchiet al. 2008); the relevance of this to fear learningand memory processes is unclear. In the IL ofthe mPFC, fear conditioning decreases, and ex-tinction increases, neuronal excitability (Santiniet al. 2008). Pertinent to this, NE signaling inthis 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 & Pare 2007, Kavushansky & Richter-Levin 2006). In addition, GCs depolarize theresting potential, increase input resistance, andsignificantly decrease spike-frequency adapta-tion of LA/B neurons (Duvarci & Pare 2007).The influences of GCs are different on thehippocampus; there low concentrations (viaMR activation) are excitatory, whereas highconcentrations (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 onhippocampal LTP, respectively (Pavlides et al.1996, Pavlides & McEwen 1999). We do not

know how GCs directly influence the elec-trophysiological profiles of mPFC neurons.Therefore, more data are needed to illustratehow GCs interact with other factors to influ-ence plasticity in structures that modulate fearconditioning.

CONCLUSIONS

An extensive literature has demonstrated theways in which stress, and the endocrine media-tors of the stress response, can impact explicit,declarative memory processes (McEwen 1999).Though based on a smaller literature, this re-view highlights the ability of stress and arousal-triggered fear to impact emotional learningand memory, as assessed by fear condition-ing. Indeed, stressful experiences, NE, and GCsalter the morphological and electrophysiologi-cal characteristics of neurons in areas that play avital role in fear processing, including the amyg-dala (LA/B), hippocampus, and PFC. As a re-sult, they can have a powerful influence on fearconditioning.

In the laboratory, investigators use a num-ber of models to induce stress, includingexposure to predator odor, restraint, foot shock,forced swimming, saline injections, and coldtemperatures. Furthermore, the duration ofstress manipulations can be acute, moderate, orchronic. Although these differences make directcomparisons between studies difficult, stereo-typical responses to these various stressors dooccur and activate the brain’s fear system,thus initiating the stress response in both thebody and the brain. Nonetheless, because stressmagnitude and duration differentially impactthe morphological and electrophysiologicalproperties of fear circuitry neurons, it wouldbe important for future studies to compareand contrast the influence of different stressprotocols.

Existing studies show that stress before orafter training boosts LTM of fear condition-ing. 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 extinctionLTM. Altogether, these findings suggest thatduring initial learning, stress activates eventsthat can influence later consolidation and ex-tinction processes. Whether effects exist on theacquisition 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 forconsolidation. NE increases neuronal excitabil-ity and LTP in the LA, and its activity there isneeded for both STM and LTM of fear condi-tioning. NE also increases neuronal excitabilityin the IL of the mPFC and is important for theLTM of extinction. Because pretraining but notposttraining intra-amygdala (LA/B) or intra-mPFC infusions of propranolol block LTM offear 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 STMto LTM.

Next, GCs appear to be particularlycrucial for LTM, but not the acquisition,of fear conditioning. Therefore, the overalltrend of systemic or intra-amygdala (LA/B) GCdisrupting LTM is consonant with electrophys-iological findings that GCs have long-term, butnot short-term, enhancing effects on neuronalexcitability in LA/B (Duvarci & Pare 2007).GRs are located both at synaptic and at nuclearsites in the LA. The classic actions of GR, asa steroid receptor, involve binding GCs in thecytoplasm and acting as a transcription factorupon translocating to the nucleus, whereasless traditional GR actions include rapid,nongenomic effects. The fact that GRs seemmore important for fear consolidation than forlearning, and for enduring but not immediateinfluences on the firing of LA/B neurons,

suggests that more traditional genomic effectsunderlie these behavioral and electrophysio-logical findings.

Stress-induced enhancement of LTP in au-ditory inputs to the LA alongside disruption ofLTP in the projections to the PFC from thehippocampus and the LA/B is congruent withthe notion that powerful fear inputs can facil-itate strong emotional pathways at the cost ofactivating more regulatory pathways. Indeed,an abundant literature showing that NE is im-portant particularly for hippocampal and PFCfunction, 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-textual ones? This answer might be explained bythe model of the hippocampus shifting from acognitive mode to a flashbulb memory modeunder intense stress, which explains why thecontextual memories of traumatic experiencesare vivid and endure for many years but tend tobe disjointed and fragmented (Diamond et al.2007).

In summary, stress, NE, and GCs appear tobe 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& Pare 2007, Rodriguez Manzanares et al.2005, Tully et al. 2007), thereby allowing forincreased excitability in LA/B, is harmoniouswith 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 “gowith our gut.” As this review highlights, ourbodies and our minds really are not separate,but instead mutually inform each other on howto process the emotional events of our lives.

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight 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 owingto space limitations. We extend our sincere gratitude to our many wonderful collaborators forthoughtful discussions pertaining to the topic and data of this review. Research by S.M.R. andR.M.S. on this topic supported by NIH Grant 5R01 AG020633. J.E.L. supported by NIH GrantsP50 MH058911, R01 MH046516, R37 MH037884, and K05 MH067048.

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Annual Review ofNeuroscience

Volume 32, 2009Contents

Neuropathic Pain: A Maladaptive Response of the NervousSystem to DamageMichael Costigan, Joachim Scholz, and Clifford J. Woolf � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Synaptic Mechanisms for Plasticity in NeocortexDaniel E. Feldman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �33

Neurocognitive Mechanisms in Depression: Implications forTreatmentLuke Clark, Samuel R. Chamberlain, and Barbara J. Sahakian � � � � � � � � � � � � � � � � � � � � � � � � � �57

Using Diffusion Imaging to Study Human Connectional AnatomyHeidi Johansen-Berg and Matthew F.S. Rushworth � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �75

Serotonin in Affective ControlPeter Dayan and Quentin J.M. Huys � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �95

Physiology and Pharmacology of Striatal NeuronsAnatol C. Kreitzer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 127

The Glial Nature of Embryonic and Adult Neural Stem CellsArnold Kriegstein and Arturo Alvarez-Buylla � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 149

Representation of Number in the BrainAndreas Nieder and Stanislas Dehaene � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 185

Neuronal Gamma-Band Synchronization as a Fundamental Processin Cortical ComputationPascal Fries � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 209

The Neurobiology of Individual Differences in ComplexBehavioral TraitsAhmad R. Hariri � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 225

The Science of Neural Interface SystemsNicholas G. Hatsopoulos and John P. Donoghue � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 249

The Neuropsychopharmacology of Fronto-Executive Function:Monoaminergic ModulationT.W. Robbins and A.F.T. Arnsten � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 267

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The Influence of Stress Hormones on Fear CircuitrySarina M. Rodrigues, Joseph E. LeDoux, and Robert M. Sapolsky � � � � � � � � � � � � � � � � � � � � � � � 289

The Primate Cortical Auditory System and Neural Representation ofConspecific VocalizationsLizabeth M. Romanski and Bruno B. Averbeck � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 315

Establishment of Axon-Dendrite Polarity in Developing NeuronsAnthony P. Barnes and Franck Polleux � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 347

Axon Growth and Guidance: Receptor Regulationand Signal TransductionMichael O’Donnell, Rebecca K. Chance, and Greg J. Bashaw � � � � � � � � � � � � � � � � � � � � � � � � � � � � 383

Cerebellum and Nonmotor FunctionPeter L. Strick, Richard P. Dum, and Julie A. Fiez � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 413

Advances in Light Microscopy for NeuroscienceBrian A. Wilt, Laurie D. Burns, Eric Tatt Wei Ho, Kunal K. Ghosh,Eran A. Mukamel, and Mark J. Schnitzer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 435

Indexes

Cumulative Index of Contributing Authors, Volumes 23–32 � � � � � � � � � � � � � � � � � � � � � � � � � � � 507

Cumulative Index of Chapter Titles, Volumes 23–32 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 511

Errata

An online log of corrections to Annual Review of Neuroscience articles may be found athttp://neuro.annualreviews.org/

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The Influence of Stress Hormones on Fear Circuitry

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