160 LeDOUX What is Fear Conditioning Since Pavlov (1927),it has been known that an initially neutral stimulus [a con- ant event nd heha e under the control of the CS(Figure 1).For example,if a rat is given a tone ollowed by an electric shock US.after a few tone-shock pairings (one is e pres es that are brought under the contro of the CS include defensive behaviors (such as freezing)and autonomic (e.g.heart rate,blood pressure)and endocrine (hormone release)responses,as well as alterations in pain sensitivity (analgesia) ghout the ng be ed in flies. snails,fish,pigeons,rabbits,rats,cats,dogs,monkeys,and humans. STMULUS ICS) NTIONED STIMULUS (US) HREATENING STIMULI FEAR RESPONSES 三 a wide range of behavioral and physiological responses that characteristically occu threat (i.e.a cat)
160 LeDOUX defensive behavior autonomic arousal hypoalgesia reflex potentiation stress hormones CONDITIONED STIMULUS (CS) (tone or light) UNCONDITIONED STIMULUS (US) (footshock) time Natural Threat Cond Stimulus THREATENING STIMULI FEAR RESPONSES A B Figure 1 Fear conditioning involves the presentation of a noxious unconditioned stimulus, typically footshock, at the end of the occurrence of a relatively neutral conditioned stimulus (CS), such as a light or tone (top). After conditioning, the CS elicits a wide range of behavioral and physiological responses that characteristically occur when an animal encounters a threatening or fear-arousing stimulus (bottom). Thus, a rat that has been fear conditioned will express the same responses to a CS as to a natural threat (i.e. a cat). What is Fear Conditioning Since Pavlov (1927), it has been known that an initially neutral stimulus [a conditioned stimulus (CS)] can acquire affective properties on repeated temporal pairings with a biologically significant event [the unconditioned stimulus (US)]. As the CS-US relation is learned, innate physiological and behavioral responses come under the control of the CS (Figure 1). For example, if a rat is given a tone CS followed by an electric shock US, after a few tone-shock pairings (one is often sufficient), defensive responses (responses that typically occur in the presence of danger) will be elicited by the tone. Examples of species-typical defensive responses that are brought under the control of the CS include defensive behaviors (such as freezing) and autonomic (e.g. heart rate, blood pressure) and endocrine (hormone release) responses, as well as alterations in pain sensitivity (analgesia) and reflex expression (fear-potentiated startle and eyeblink responses). This form of conditioning works throughout the phyla, having been observed in flies, worms, snails, fish, pigeons, rabbits, rats, cats, dogs, monkeys, and humans
EMOTION AND THE BRAIN 161 Neuroanatomy of Fear Conditioning tioned fear is mediated by the transmission of information about the CS and US to the amygdala,and the control of fear reactions by way of output projections from the o the behavio autonomic,and esponse contro as the connections within the amvgdala that link inputs and outputs ae described The focus is on findings from rodents and other small mammals,as most of the Rol1s199219991 ely 12 ent n c no severa to label amygdala areas (see Krettek&Price 1978.de Olmos etal 1985.Amaral et al 1992),the scheme adopted by Amaral et al(1992)for the primate brain and applied to the rat rain by Pitkanen et a1997）1s1o ere.The areas o ),a other classification schemes b is known as the basolateral nucleus and ab as the (an AB.and CE (see Pitkanen et al 997.Pare et al 1995.Amaral et al 1992.Cassell et al 1999).In brief,LA projects to B.AB,and CE.and both B and AB also project to CE.However. is important to recognize th at the connections of the l1997 a s (see pitka for the most part we focus below on nuclei rather than subnuclei c Much involved the Auditory and other sensory inputs to the amygdala terminate mainly in LA (see LeDoux et al 1990b,Romanski&LeDoux 1993,Mascagni et al 1993. 1992 LA inte ampeau
EMOTION AND THE BRAIN 161 Neuroanatomy of Fear Conditioning Research from several laboratories combined in the 1980s to paint a relatively simple and remarkably clear picture of the neuroanatomy of conditioned fear (see Kapp et al 1992, LeDoux 1992, Davis 1992, Fanselow 1994). In short, conditioned fear is mediated by the transmission of information about the CS and US to the amygdala, and the control of fear reactions by way of output projections from the amygdala to the behavioral, autonomic, and endocrine response control systems located in the brainstem. Below, the input and output pathways, as well as the connections within the amygdala that link inputs and outputs, are described. The focus is on findings from rodents and other small mammals, as most of the work on fear conditioning has involved these species (for the contribution of the primate amygdala to fear and other emotions see Pribram et al 1979, Pribram & Melges 1969, Aggleton & Mishkin 1986, Ono & Nishijo 1992, Gaffan 1992, Rolls 1992, 1999). Amygdala Terminology and Connections The amygdala consists of approximately 12 different regions, each of which can be further divided into several subregions (Figure 2). Although a number of different schemes have been used to label amygdala areas (see Krettek & Price 1978, de Olmos et al 1985, Amaral et al 1992), the scheme adopted by Amaral et al (1992) for the primate brain and applied to the rat brain by Pitka¨nen et al (1997) is followed here. The areas of most relevance to fear conditioning are the lateral (LA), basal (B), accessory basal (AB), and central (CE) nuclei and the connections between these (Figure 2). In other classification schemes, B is known as the basolateral nucleus and AB as the basomedial nucleus. The term basolateral complex is sometimes used to refer to LA and B (and sometimes AB) together. Studies in several species, including rats, cats, and primates, are in close agreement about the connections of LA, B, AB, and CE (see Pitka¨nen et al 1997, Pare´ et al 1995, Amaral et al 1992, Cassell et al 1999). In brief, LA projects to B, AB, and CE, and both B and AB also project to CE. However, it is important to recognize that the connections of these areas are organzied at the level of subnuclei within each region rather than at the level of the nuclei themselves (see Pitka¨nen et al 1997). For simplicity, though, for the most part we focus below on nuclei rather than subnuclei. CS Pathways The pathways through which CS inputs reach the amygdala have been studied extensively in recent years. Much of the work has involved the auditory modality, which is focused on here. Auditory and other sensory inputs to the amygdala terminate mainly in LA (see LeDoux et al 1990b, Romanski & LeDoux 1993, Mascagni et al 1993, Amaral et al 1992, McDonald 1998), and damage to LA interferes with fear conditioning to an acoustic CS (LeDoux et al 1990a, Campeau & Davis 1995)
162 LeDOUX Figure The amygdala consists fr regions.Those of mo relevance to nuclei.The piriform corex (PIR)lies lateral to the amy dala and the I to it, mparison of the N I-stained s on oper lefr)and athwa con mel).(Lower right)A blowup of the ical studi ather than the ing system is in general organized and see ears that the et oorly understo
162 LeDOUX Figure 2 The amygdala consists of a number of different regions. Those of most relevance to the pathways of fear conditioning are the lateral (LA), basal (B), accessory basal (AB), and central (CE) nuclei. The piriform cortex (PIR) lies lateral to the amygdala, and the caudate-putamen (CPU) is just dorsal to it. Comparison of the Nissl-stained section (upper left) and an adjacent section stained for acetylcholinesterase (upper right) helps identify the different nuclei. The major pathways connecting LA, B, AB, and CE are shown (lower left panel). (Lower right) A blowup of the LA, emphasizing the fact that each nucleus can be divided into subnuclei. Although anatomical studies have shown that the pathways are organized at the level of the subnuclei, rather than the nuclei (see Pitka¨nen et al 1997), the nuclear connections (lower left panel) provide a sufficiently detailed approximation of the connections for the purposes of considering how the fear conditioning system is, in general, organized. Auditory inputs to LA come from both the auditory thalamus and the auditory cortex (see LeDoux et al 1990b, Romanski & LeDoux 1993, Mascagni et al 1993), and fear conditioning to a simple auditory CS can be mediated by either of these pathways (Romanski & LeDoux 1992) (Figure 3). It appears that the projection to LA from the auditory cortex is involved with a more complex auditory stimulus pattern (Jarrell et al 1987), but the exact conditions that require the cortex are poorly understood (Armony et al 1997). Although some lesion studies have ques-
EMOTION AND THE BRAIN 163 Auditory Cortex TE1 TE3 PRh Auditory Pathways to Amygdala Circuits A CE Behavior ANS HPA CS tone s involved in fear d几 mulus.the of the eral amy ala (LA)fre ry pro ng areas mus [me (TE3)LA.in tun sion of the medial geniculate body.PRh perirhinal corex TE.primary auditory cortex. s1995.Shi D pathway learns more slowly over trils than does the thalamic pathway (Quirk et al 1995.1997).thus indicating that plasticity in the amygdala occurs initially through the thalamic pathway ent functional m but not the (Morris et al 1999),further emphasizing the importance of the direct thalamo- amygdala pathway. ed to expressing to the eCS,rats also exhibit the e wher in which shocks occur alone This is called contextual fear conditionin and requires both the amygdala and the 92.Maren et al 1997,Kim Fanselow 992.Franklandt
EMOTION AND THE BRAIN 163 CE Behavior ANS HPA Defense Responses LA MGm/ PIN Auditory Cortex TE1 TE3 MGv CS (tone) Auditory Pathways to Amygdala Circuits PRh Figure 3 The neural pathways involved in fear conditioning are well characterized. When the CS is an acoustic stimulus, the pathways involve transmission to the lateral nucleus of the lateral amygdala (LA) from auditory processing areas in the thalamus [medial division of the medial geniculate body (MGm/PIN)] and cortex [auditory association cortex (TE3)]. LA, in turn, projects to the central amygdala (CE), which controls the expression of fear responses by way of projections to brainstem areas. ANS, Autonomic nervous system; CS, conditioned stimulus; HPA, hypothalamic-pituitary axis; MGv, ventral division of the medial geniculate body; PRh, perirhinal cortex; TE1, primary auditory cortex. tioned the ability of the thalamic pathway to mediate conditioning (Campeau & Davis 1995, Shi & Davis 1998), single-unit recordings show that the cortical pathway learns more slowly over trials than does the thalamic pathway (Quirk et al 1995, 1997), thus indicating that plasticity in the amygdala occurs initially through the thalamic pathway. Recent functional magnetic resonance imaging studies in humans have found that the human amygdala shows activity changes during conditioning that correlate with activity in the thalamus but not the cortex (Morris et al 1999), further emphasizing the importance of the direct thalamoamygdala pathway. In addition to expressing fear responses to the CS, rats also exhibit these when returned to the chamber in which the tone and shock were paired, or a chamber in which shocks occur alone. This is called contextual fear conditioning and requires both the amygdala and the hippocampus (see Blanchard et al 1970, Phillips & LeDoux 1992, Maren et al 1997, Kim & Fanselow 1992, Frankland et al 1998). Areas of the ventral hippocampus (CA1 and subiculum) project to the B and AB nuclei of the amygdala (Canteras & Swanson 1992), and damage to these
164 LeDOUX areas interferes with contextual conditioning(Maren&Fanselow 1995.Majidi- shad et al 1996).Hippocampal projection to B and AB thus seem to be involved Tone CS Smui Context CS B Aa eus of the amygdala (CE).In con ning to the app ratus hy the hi and the hippocampus and the ba ur project to CE.As (Bd oning
164 LeDOUX LA CE B AB Auditory Stimulus Brainstem Fear Reaction LA CE B Brainstem Fear Reaction Contextual Stimulus Hippocampus Tone CS Context CS AB Figure 4 Conditioning to a tone [conditioned stimulus (CS)] involves projections from the auditory system to the lateral nucleus of the amygdala (LA) and from LA to the central nucleus of the amygdala (CE). In contrast, conditioning to the apparatus and other contextual cues present when the CS and unconditioned stimulus are paired involves the representation of the context by the hippocampus and the communication between the hippocampus and the basal (B) and accessory basal (B) nuclei of the amygdala, which in turn project to CE. As for tone conditioning, CE controls the expression of the responses. areas interferes with contextual conditioning (Maren & Fanselow 1995, Majidishad et al 1996). Hippocampal projection to B and AB thus seem to be involved in contextual conditioning (for a comparison of the amygdala pathways involved in conditioning to a tone CS and to a context, see Figure 4)