Joseph E. LeDoux

Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.

The contribution of the amygdala and hippocampus to the acquisition of conditioned fear responses to a cue (a tone paired with footshock) and to context (background stimuli continuously present in the apparatus in which tone-shock pairings occurred) was examined in rats. In unoperated controls, responses to the cue conditioned faster and were more resistant to extinction than were responses to contextual stimuli. Lesions of the amygdala interfered with the conditioning of fear responses to both the cue and the context, whereas lesions of the hippocampus interfered with conditioning to the context but not to the cue. The amygdala is thus involved in the conditioning of fear responses to simple, modality-specific conditioned stimuli as well as to complex, polymodal stimuli, whereas the hippocampus is only involved in fear conditioning situations involving complex, polymodal events. These findings suggest an associative role for the amygdala and a sensory relay role for the hippocampus in fear conditioning.

Contributions of the Amygdala to Emotion Processing: From Animal Models to Human Behavior

Research on the neural systems underlying emotion in animal models over the past two decades has implicated the amygdala in fear and other emotional processes. This work stimulated interest in pursuing the brain mechanisms of emotion in humans. Here, we review research on the role of the amygdala in emotional processes in both animal models and humans. The review is not exhaustive, but it highlights five major research topics that illustrate parallel roles for the amygdala in humans and other animals, including implicit emotional learning and memory, emotional modulation of memory, emotional influences on attention and perception, emotion and social behavior, and emotion inhibition and regulation.

Extinction learning in humans: role of the amygdala and vmPFC.

Understanding how fears are acquired is an important step in translating basic research to the treatment of fear-related disorders. However, understanding how learned fears are diminished may be even more valuable. We explored the neural mechanisms of fear extinction in humans. Studies of extinction in nonhuman animals have focused on two interconnected brain regions: the amygdala and the ventral medial prefrontal cortex (vmPFC). Consistent with animal models suggesting that the amygdala is important for both the acquisition and extinction of conditioned fear, amygdala activation was correlated across subjects with the conditioned response in both acquisition and early extinction. Activation in the vmPFC (subgenual anterior cingulate) was primarily linked to the expression of fear learning during a delayed test of extinction, as might have been expected from studies demonstrating this region is critical for the retention of extinction. These results provide evidence that the mechanisms of extinction learning may be preserved across species.

Human Amygdala Activation during Conditioned Fear Acquisition and Extinction: a Mixed-Trial fMRI Study

Echoplanar functional magnetic resonance imaging (fMRI) was used in normal human subjects to investigate the role of the amygdala in conditioned fear acquisition and extinction. A simple discrimination procedure was employed in which activation to a visual cue predicting shock (CS+) was compared with activation to another cue presented alone (CS-). CS+ and CS- trial types were intermixed in a pseudorandom order. Functional images were acquired with an asymmetric spin echo pulse sequence from three coronal slices centered on the amygdala. Activation of the amygdala/periamygdaloid cortex was observed during conditioned fear acquisition and extinction. The extent of activation during acquisition was significantly correlated with autonomic indices of conditioning in individual subjects. Consistent with a recent electrophysiological recording study in the rat (Quirk et al., 1997), the profile of the amygdala response was temporally graded, although this dynamic was only statistically reliable during extinction. These results provide further evidence for the conservation of amygdala function across species and implicate an amygdalar contribution to both acquisition and extinction processes during associative emotional learning tasks.

The Emotional Brain, Fear, and the Amygdala

Abstract1. Considerable progress has been made over the past 20 years in relating specific circuits of the brain to emotional functions. Much of this work has involved studies of Pavlovian or classical fear conditioning, a behavioral procedure that is used to couple meaningless environmental stimuli to emotional (defense) response networks.2. The major conclusion from studies of fear conditioning is that the amygdala plays critical role in linking external stimuli to defense responses.3. Before describing research on the role of the amygdala in fear conditioning, though, it will be helpful to briefly examine the historical events that preceded modern research on conditioned fear.

Fear conditioning induces associative long-term potentiation in the amygdala

Long-term potentiation (LTP) is an experience-dependent form of neural plasticity believed to involve mechanisms that underlie memory formation. LTP has been studied most extensively in the hippocampus, but the relation between hippocampal LTP and memory has been difficult to establish. Here we explore the relation between LTP and memory in fear conditioning, an amygdala-dependent form of learning in which an innocuous conditioned stimulus (CS) elicits fear responses after being associatively paired with an aversive unconditioned stimulus (US). We have previously shown that LTP induction in pathways that transmit auditory CS information to the lateral nucleus of the amygdala (LA) increases auditory-evoked field potentials in this nucleus. Now we show that fear conditioning alters auditory CS-evoked responses in LA in the same way as LTP induction. The changes parallel the acquisition of CS-elicited fear behaviour, are enduring, and do not occur if the CS and US remain unpaired. LTP-like associative processes thus occur during fear conditioning, and these may underlie the long-term associative plasticity that constitutes memory of the conditioning experience.

ArticleExtinction Learning in Humans: Role of the Amygdala and vmPFC

Understanding how fears are acquired is an important step in translating basic research to the treatment of fear-related disorders. However, understanding how learned fears are diminished may be even more valuable. We explored the neural mechanisms of fear extinction in humans. Studies of extinction in nonhuman animals have focused on two interconnected brain regions: the amygdala and the ventral medial prefrontal cortex (vmPFC). Consistent with animal models suggesting that the amygdala is important for both the acquisition and extinction of conditioned fear, amygdala activation was correlated across subjects with the conditioned response in both acquisition and early extinction. Activation in the vmPFC (subgenual anterior cingulate) was primarily linked to the expression of fear learning during a delayed test of extinction, as might have been expected from studies demonstrating this region is critical for the retention of extinction. These results provide evidence that the mechanisms of extinction learning may be preserved across species.

Organization of intra-amygdaloid circuitries in the rat : an emerging framework for understanding functions of the amygdala

The amygdala is located in the medial aspects of the temporal lobe. In spite of the fact that the amygdala has been implicated in a variety of functions, ranging from attention to memory to emotion, it has not attracted neuroscientists to the same extent as its laminated neighbours, in particular the hippocampus and surrounding cortex. However, recently, principles of information processing within the amygdala, particularly in the rat, have begun to emerge from anatomical, physiological and behavioral studies. These findings suggest that after the stimulus enters the amygdala, the highly organized intra-amygdaloid circuitries provide a pathway by which the representation of a stimulus becomes distributed in parallel to various amygdaloid nuclei. As a consequence, the stimulus representation may become modulated by different functional systems, such as those mediating memories from past experience or knowledge about ongoing homeostatic states. The amygdaloid output nuclei, especially the central nucleus, receive convergent information from several other amygdaloid regions and generate behavioral responses that presumably reflect the sum of neuronal activity produced by different amygdaloid nuclei.

Extinction of emotional learning: contribution of medial prefrontal cortex.

Stimuli associated with painful or otherwise unpleasant events acquire aversive emotional properties in animals and humans. Subsequent presentation of the stimulus alone (in the absence of the unpleasant event) leads to the eventual extinction of the aversive reaction. Although the neural basis of emotional learning has been studied extensively, considerably less is known about the neural basis of emotional extinction. In the present study, we show that the medial prefrontal cortex plays an important role in the regulation of fear extinction in rats, a finding that may help elucidate the mechanisms and, possibly, the treatment of disorders of uncontrolled fear, such as anxiety, phobic, panic and posttraumatic stress disorders in humans.

Why We Think Plasticity Underlying Pavlovian Fear Conditioning Occurs in the Basolateral Amygdala

The encoding view provides a parsimonious account of the multiple convergent lines of evidence for the ABL’s role in fear conditioning. We do not dispute the notion that activation of the ABL can facilitate consolidation of information in other structures, such as the hippocampus, other cortical areas, or the striatum (4xMechanisms of emotional arousal and lasting declarative memory. Cahill, L and McGaugh, J.L. Trends Neurosci. 1998; 21: 294–299Abstract | Full Text | Full Text PDF | PubMed | Scopus (952)See all References, 27xAmygdala modulation of multiple memory systems (hippocampus and caudate-putamen) . Packard, M.G and Teather, L.A. Neurobiol. Learn. Mem. 1998; 69: 163–203Crossref | PubMed | Scopus (214)See all References). Rather, we argue that the ABL is involved in the encoding of fear memory and the modulation of memory functions of other structures.While we believe that the ABL is essential to the implicit learning that constitutes fear conditioning, we are not proposing that all of the plasticity relevant to fear conditioning necessarily occurs within the ABL. It seems possible that the ABL, while essential, is also part of a distributed network that encodes the fear memory. For example, as noted, there is compelling evidence that plastic changes occur in regions that are afferent to the ABL, such as thalamic and cortical sensory systems that process CSs (see Weinberger 1995xRetuning the brain by fear conditioning. Weinberger, N.M. See all ReferencesWeinberger 1995). Additionally, cortical areas that are both afferent and efferent to the ABL (e.g., perirhinal cortex, the hippocampal formation, and sensory cortex) may participate with the ABL in the long-term encoding of fear. It remains for future research to determine whether these distributed representations exist and, if so, to unravel their nature.‡To whom correspondence should be addressed (e-mail: fanselow@ucla.edu).