The neural circuitry of fear conditioning has been extensivelystudied and recently reviewed (63, 116, 141). In Pavlovianfear conditioning, a neutral conditioned stimulus (CS) is pairedwith an aversive unconditioned stimulus (US), such as a mildfoot-shock. CS-US pairings result in an association of theCS and US, whereby presentation of the CS subsequently elicitsa conditioned fear response (CR), such as freezing. The CScan be a discrete presentation of auditory, visual, olfactory,or tactile stimuli or the CS can be contextual, a collectionof numerous environmental features. Foot-shocks or loud noisesare typically used as unconditioned stimuli. In rats, lesionsto the amygdala disrupt Pavlovian fear conditioning regardlessof stimulus modality or response measures (17). Likewise, amygdalarlesions disrupt fear conditioning in non-human primates andhumans (11, 106). Studies over many years have clearly establishedthat within the amygdala, the basolateral complex and CeA playkey roles in the acquisition and expression of fear-relatedbehaviors. One prevailing view is that during fear conditioningsensory input reaches the basolateral complex via the LA, whichis the site for CS-US association. The basolateral complexthen controls the outputs of the CeA to evoke the behavioraland autonomic responses. The pathways involved in this modelof fear conditioning are outlined in Figure 10.
A. Basolateral Complex
A converging body of literature has implicated the basolateralcomplex in assigning affective value to stimuli (27, 43,82, 116). Anatomically, the basolateral complex is well positionedfor associative learning. Afferents conveying conditioned andunconditioned stimulus information from the neocortex, thalamus,and hippocampus converge on the basolateral complex (232).Lesions of the basolateral complex block acquisition and expressionof fear conditioning (24, 117, 142). Functional inactivationof the basolateral complex by infusion of muscimol, a GABAA agonist, into the basolateral complex disrupts fear conditioningwhen applied immediately before conditioning or during testing,but not when applied immediately after conditioning (77, 181, 294).
Different CS modalities are mediated by different amygdala afferents.Thalamic medial geniculate and auditory cortical afferentsare essential for conditioning to an auditory CS (24, 122,233), while projections from the perirhinal cortex are essentialfor conditioning to a visual CS (24, 236, 253). Foot-shockunconditioned information is conveyed to the basolateral complexby projections from the posterior parietal insula (IC) andthe posterior intralaminar nuclei of the thalamus (PoT/PIL)(253, 257). Combined, but not separate, lesions of the ICand PoT/PIL disrupt fear conditioning (234, 253, 257).
B. Central Nucleus
As described above, the basolateral complex receives both directand highly processed sensory information. This informationis processed locally and then transmitted to the central nucleuswhich projects to hypothalamic and brain stem areas that mediatethe autonomic and behavioral signs of fear. Lesions of theCeA block the expression of fear conditioned response usingvisual or auditory CS (24, 72, 76, 78, 79, 99, 298).Furthermore, stimulation of the CeA produces the constellationof conditioned fear responses even in the absence of priorfear conditioning (86, 97). These findings indicate thatthe complex behavioral pattern of the fear response is probablyhard wired. In fear conditioning, it is only necessary forthe conditioned stimulus to activate the CeA; the CS-US associationoccurs in or before the CeA. While the CeA is often consideredessential only for expression of the conditioned fear response(116), this view of the CeA is probably an oversimplification.There are no studies involving selective reversible inactivationof the CeA during conditioning. There is considerable evidenceshowing that CeA is not simply an output pathway of the basolateralcomplex. Data from other learning paradigms implicate the CeAin the modulation of attention, arousal, and vigilance duringconditioning (43, 82). These effects are mediated by the CeAvia striatal and basal forebrain connections (27, 74, 80,81). Finally, CeA activation of the cholinergic system modulatesneuronal processing in sensory and learning systems includingthe basolateral complex, which is highly enriched in cholinergicreceptors.
C. Where Is the Memory Stored?
Although there is general agreement about the circuitry thatparticipates in fear and fear conditioning, the exact roleplayed by the different amygdala regions has been questioned.One issue that has been at the forefront of discussion is whetherthe amygdala is involved in the acquisition and/or storageof fear-related memories or is its role largely in the expressionof fear responses. There is a large amount of literature showingthat the amygdala plays a role in memory formation in otherneural systems (168); however, it has been suggested thatthe same is also true for fear learning. Thus it has been arguedthat although the amygdala has a key role in the analysis ofemotional content, it largely modulates plasticity in otherbrain regions that are the substrates for memory storage (23,167). It has been shown that fear conditioning can cause synapticchanges in regions outside the amygdala. Furthermore, ratscan be fear conditioned even following complete lesions of the basolateral complex (22, 277).
There is abundant evidence that synaptic plasticity occurs inthe basolateral complex during fear conditioning (see below).However, the issue of whether these changes are necessary andsufficient for fear conditioning remains to be resolved. Thebasolateral complex, rather than simply controlling the CeA,has extensive projections to the striatum and prefrontal cortex(27, 53, 54), allowing it to influence complex behaviors.Studies demonstrating that inactivation of the basolateral complex (by infusion of lidocaine or tetrodotoxin) many hoursafter the conditioning can interfere with consolidation ofthe fear memory (242, 278) is consistent with the proposalthat while plasticity within the amygdala is associated withfear conditioning, changes in other brain regions, which requireamygdala activation, are also involved.
Apart from fear conditioning, the amygdala is involved in arange of memory tasks. It is well known that the amygdala isnecessary for fear-motivated operant conditioning. Unlike Pavlovianfear conditioning, in the instrumental-avoidance task animalsare able to avoid the aversive stimulus by making the appropriatebehavioral response. Amygdala lesions disrupt the acquisition,but not the retention, of both active avoidance (escape fromfear) (64, 212) and passive avoidance (124, 235, 271) conditionedresponses. These different learning tasks related to fear canbe double dissociated within the amygdala (99). In this study,one measure was a classical fear response measured as a reductionin ongoing behavior during CS presentation and was dependenton the CeA. This result is consistent with previous findingswith CeA lesions and agrees with the idea that CeA outputsmediate behavioral responses. The other behavior, measuredconcurrently with the first, involved an operant choice dependenton the predictive value of the CS. This behavior was independentof the CeA but required the basolateral complex (LA and B).It was notable that the classical fear responses were unaffectedby basolateral lesions, a finding that suggests that informationabout the CS need not require activity within the basolateralcomplex. Although the exact interpretation of these conclusionshas been debated (183), it seems clear that while the outputsof the CeA are involved in one type of emotional learning,the outputs of the basolateral complex need to be consideredin other types of learning that involve the amygdala (168).Despite these caveats, simple Pavlovian fear conditioning remainsthe single most tractable model in which to address the cellularsubstrates that might underlie these learned behaviors.