Although damage to most limbic areas does not have the effects on emotional behavior predicted by the limbic system theory, one limbic area was consistently shown to be involved in emotion. This area is the amygdala.
Studies of Avoidance Conditioning First Implicated the Amygdala in Fear Responses
In the mid-1950s Lawrence Weiskrantz sought to understand which region of the temporal lobe was responsible for the emotional changes characteristic of the Klüver-Bucy syndrome. To do this, he used avoidance conditioning, a form of instrumental conditioning.
In avoidance conditioning an animal learns to perform responses that successfully avoid an aversive shock, the unconditioned stimulus (US). Successful avoidance of shock reinforces the response, ie, it increases the probability of the response. Normal monkeys learn instrumental responses (ie, pressing a lever) to avoid the shock, but monkeys with lesions of the amygdala do not. Weiskrantz concluded that a key function of the amgydala was to connect external stimuli with their aversive (punishing) or rewarding consequences.
Fear has been a popular emotion in neuroscience research because it is so important for survival and also because excellent behavioral protocols are available for studying fear in animals. Following Weiskrantz's discovery, many researchers used avoidance conditioning to study the neural mechanisms of fear. However fear can also be studied using Pavlovian conditioning and by the early 1980s had become the preferred protocol.
Pavlovian Conditioning Is Used Extensively to Study the Contribution of the Amygdala to Learned Fear
In Pavlovian fear conditioning an association is learned between the US (eg, shock) and the conditioned stimuli (CS) that predict the US. For example, an emotionally neutral CS (a tone) is presented for several seconds and the animal is shocked during the final second of the CS. After several pairings of tone and shock, presentation of the tone alone elicits defensive freezing and associated changes in autonomic and endocrine activity. In addition, many defensive reflexes, such as eyeblink and startle, are facilitated by the tone alone.
Pavlovian fear conditioning is actually the first phase of avoidance conditioning. The pairing of US and CS initially results in the conditioning of a response, but in the second phase the animal learns to perform an instrumental response to avoid the shock. By the early 1980s neuroscientists began to realize that a more efficient way to study fear learning is to focus on the first stage of avoidance conditioning—Pavlovian fear conditioning—and not extend the experimental design to the second phase.
Research carried out in a variety of laboratories established that lesions of the amygdala prevent Pavlovian fear conditioning from occurring. Animals with amygdala damage fail to learn the association between the CS and the US and thus do not express fear when the CS is later presented alone.
The amygdala consists of approximately 12 nuclei, but the lateral and central nuclei are especially important in fear conditioning (Figure 48–5). Damage to either nucleus, but not other regions, prevents fear conditioning. The lateral nucleus is the input nucleus receiving information about the CS (eg, a tone) from the thalamus. The central nucleus is the output region; neurons here project to brain stem areas involved in the control of defensive behaviors and associated autonomic and humoral responses (see Chapter 47). The lateral and central nuclei are connected by way of several intra-amygdala circuits, including connections in the basal and intercalated nuclei.
Neural circuits engaged during fear conditioning.
The conditioned stimulus (CS) and unconditioned stimulus (US) are relayed to the lateral nucleus of the amygdala from the auditory and somatosensory regions of the thalamus and cerebral cortex. Convergence of the CS and US pathways in the lateral nucleus is believed to underlie the synaptic changes that mediate learning (see Figure 48–6). The lateral nucleus communicates with the central nucleus both directly and through intra-amygdala pathways (not shown) involving the basal and intercalated nuclei. The central nucleus then connects with regions that control various motor responses, including the central gray region (CG), which controls freezing behavior, the lateral hypothalamus (LH), which controls autonomic responses, and the paraventricular hypothalamus (PVN), which controls stress hormone secretion by the pituitary-adrenal axis. (Reproduced, with permission, from Medina et al. 2002.)
Sensory inputs reach the lateral nucleus from the thalamus both directly and indirectly. Much as predicted by the Cannon-Bard hypothesis, sensory signals from thalamic relay nuclei are conveyed to sensory areas of cortex. As a result the amygdala and cortex are activated simultaneously. However, the amygdala is able to respond to a danger cue before the cortex can process the stimulus information. Given that cortical processing is required to consciously experience fear, the emotional state triggered by thalamic inputs is likely to be initiated before we consciously feel fear.
The lateral nucleus is thought to be a site of synaptic change during fear conditioning. The CS and US signals converge in the lateral nucleus; when the CS and US are paired, the effectiveness of the CS is enhanced (Figure 48–6). The lateral nucleus appears to be functionally divided. Neurons in the most dorsal part of the dorsal division appear to initiate learning when the CS and US are paired, whereas neurons in an adjacent ventral part of the dorsal division are thought to mediate the long-term memory of the CS–US association. Recent studies have also shown that synaptic plasticity occurs in specific central amygdala circuits. The central amygdala thus does not simply drive motor outputs but is also part of the circuitry through which fear associations are formed and stored, very likely by transmitting information about the CS and US from the lateral nucleus.
The responses of the lateral nucleus of the amygdala are enhanced by fear conditioning.
A. The blue dots indicate the placement of extracellular electrodes in the lateral nucleus. (AST, amygdalo-striatal transition area; AB, accessory basal nucleus of the amygdala; B, basal nucleus of the amygdala; CE, central nucleus of the amygdala; EN, endopiriform cortex; LAd, dorsal lateral nucleus; LAv, ventral lateral nucleus.)
B. Histograms show activity in four simultaneously recorded neurons in the lateral nucleus before and after conditioning. Each histogram represents the sum of 10 presentations of the conditioned stimulus (black bar). Representative spike waveforms are shown in insets.
C. After conditioning, the neurons in the dorsal lateral nucleus fire at shorter latencies than do neurons in the auditory cortex. They also fire at higher frequencies (not shown).
The emotional charge of a stimulus is evaluated by the amygdala to determine whether danger is present. If the amygdala detects danger, it orchestrates the expression of behavioral and physiological responses by way of connections to the hypothalamus and brain stem. For example, freezing behavior is mediated by connections from the central nucleus to the ventral periaqueductal gray region. But in addition, the amygdala has a variety of connections that allow it to also influence other cognitive functions. For example, through its widespread projections to cortical areas it can modulate attention, perception, memory, and decision-making. Its connections with the modulatory dopaminergic, noradrenergic, serotonergic, and cholinergic nuclei that project to cortical areas also influence cognitive processing (see Chapter 46).
The cellular and molecular mechanisms within the amygdala that underlie learned fear, especially in the lateral nucleus, have been elucidated in great detail (see Chapter 66). The findings support the view that the lateral nucleus is a site of memory storage in fear conditioning.
The Amygdala Has Been Implicated in Unconditioned (Innate) Fear in Animals
Many animals rely on innate (unconditioned) olfactory signals in the detection of threats, mates, food, and so forth. For example, rodents exhibit freezing and other defensive behaviors when fox urine is detected.
Recent studies have made considerable progress in uncovering the circuits underlying innate fear (see Chapter 47). In mammals unconditioned threats involving predator or conspecific odors are transmitted from the vermonasal component of the olfactory system (see Chapter 32) to medial amygdala. Outputs of the medial amygdala reach the ventromedial hypothalamus, which connects with the premammillary hypothalamic nucleus. In contrast to learned fear, which depends on the ventral periaqueductal gray region, unconditioned fear responses depend on connections from the hypothalamus to the dorsal peri-aqueductal gray region.
The Amygdala Is Also Important for Fear in Humans
The basic findings in animals regarding the role of the amygdala in emotion have been confirmed in studies of humans. Thus patients with damage to the amygdala fail to undergo fear conditioning when presented with a neutral CS paired with a US (electric shock or loud noise). Patients with damage to the amygdala also fail to recognize facial expressions of fear and do not generate autonomic fear responses to these.
In normal human subjects activity in the amygdala increases during CS–US pairing (Figure 48–7). This activity is especially strong when the stimuli are presented subliminally. In normal subjects fearful facial expressions also activate the amygdala, even when presented subliminally. These findings emphasize the importance of the amygdala as a subconscious evaluator of the meaning of a stimulus.
Lesion and imaging results implicate the human amygdala in conditioned fear.
A. Left side: Three-dimensional magnetic resonance imaging (MRI) reconstructions of a normal brain seen from a medial perspective (right hemisphere on top, left hemisphere below). The amygdala (light blue) and the hippo-campus (dark blue), normally hidden by the parahippocampal gyrus, were traced and colored. Right side: Two coronal slices through the damaged amygdala of a patient with Urbach-Wiethe disease at the levels shown on the three-dimensional reconstruction. In such patients damage to the amygdala impairs fear responses and blocks fear conditioning. (Reproduced, with permission, from Hanna Damasio and Joel Bruss.)
B. Conditioned fear stimuli activate the human amygdala (arrow). Healthy volunteers underwent fear conditioning while their brains were scanned using functional MRI. Conditioning involved two conditioned stimuli, one paired with the unconditioned stimulus (CS+) and one not (CS–). Selective activation was assessed by subtracting the CS– scans from the CS+ scans. (Adapted, with permission, from LaBar et al. 1998.)
Certain forms of fear processing are unique to humans. For example, simply telling a human subject that the CS may be followed by a shock is enough to allow the CS to elicit fear responses. The CS elicits characteristic autonomic responses even though it was never associated with the delivery of the shock. Humans can also be conditioned by allowing them to observe someone else being conditioned—the observer learns to fear the CS even though the CS or US were never directly presented to the observing subject.
The emotional learning and memory capacities of the human amygdala fall into the category of implicit learning and memory (unconscious recall of perceptual and motor skills (see Chapter 65)). In situations of danger, however, the hippocampus and other components of the medial temporal lobe system concerned with explicit learning and memory (the conscious recall of people, places, and things) will encode the learning such that learned indicators of danger can also be recalled consciously.
Studies of patients with bilateral damage to the amygdala or hippocampus illustrate the separate contributions of the amygdala and the hippocampus to implicit and explicit memory, respectively. Patients with damage to the amygdala show no physiological responses to a CS (indicating no implicit learning) but have good memory of the conditioning experience (indicating explicit learning), whereas patients with hippocampal damage respond normally to the CS but have no conscious memory of the conditioning experience.
Amygdala function is altered in a number of psychiatric disorders in humans, especially disorders of fear and anxiety (see Chapter 63). In addition, the amygdala plays an important role in processing cues related to addictive drugs (see Chapter 49).
The Amygdala Is Involved in Positive Emotions in Animals and Humans
Although most work on the neural basis of emotion during the last half century has focused on aversive responses, especially fear, other studies have shown that the amygdala is also involved in positive emotions, in particular the processing of rewards. In monkeys and rats the amygdala is required for associating neutral stimuli with rewards.
Studies in nonhuman primates and rodents have followed up on Weiskrantz's suggestion that the amygdala connects stimulus rewards as well as punishers. For example, in a recent study monkeys were trained to associate abstract visual images with a reward or punisher. The meaning was then reversed (eg, by pairing a punisher with a stimulus that had previously been associated with a reward). In this way it was possible to separate the contributions of the amygdala to visual and value processing. Changes in the value of the images modulated neural activity in the amygdala, and the modulation occurred rapidly enough to account for behavioral learning.
A growing number of functional imaging studies of humans have also shown that the amygdala is involved in emotions. For example, the human amgydala is activated when subjects observe pictures of stimuli associated with food, sex, and money, or when people make decisions based on the reward value of stimuli.