Re-valuing the amygdala
Introduction
For many years, the amygdala was thought of primarily as a center for fear in the brain. This perception was fueled by a wealth of experimental data, mainly from rodents, that emerged from the fear conditioning paradigm (summarized in [1, 2]). Classic lesion and inactivation studies established that the amygdala is essential for the perception of fear, the expression of fearful behavior, and the acquisition of fear in response to stimuli that had been paired with aversive outcomes (Pavlovian fear conditioning) (e.g. [3], reviewed in [4]). Neurophysiological studies, which also were mainly limited to rodents, showed that cells in the basolateral amygdala (BLA) had firing rates that were highly sensitive to stimuli that were associated with fear-inducing events, and also to the aversive events themselves [4, 5].
While new light continues to be shed on the detailed functioning of the amygdala with regard to fear learning and fearful behavior, in recent years, a surge of work in humans and non-human primates has led to an expanded conception of the amygdala's role. The anatomical connections of the amygdala in primates hint at a reason for this: especially compared to rodents, humans and non-human primates have a hugely elaborated prefrontal cortex (PFC) [6], many parts of which — especially medial and orbital areas — have extensive bidirectional connections with the amygdala [7, 8, 9, 10]. The amygdala receives input from a full range of higher sensory and poly-sensory areas, and projects back to them in turn, even to primary sensory targets (connections that may be unique to primates) [11, 12, 13]. Other targets of amygdala output include the hippocampus, basal ganglia, perirhinal and entorhinal cortices, the basal forebrain, and subcortical structures such as the hypothalamus [14]. In sum, the anatomical situation of the amygdala seems to imply the potential for a far more wide-ranging role than ‘danger alarm.’
Using a combination of new techniques and innovative extensions of old ones, neuroscientists have uncovered a role for the amygdala in a wide variety of tasks with an emotional component, whether appetitive or aversive [15]. Emotional responses frequently occur in reaction to stimuli that predict impending rewarding or aversive reinforcement, and they are often described within a framework that uses two axes to characterize emotions: arousal (from calm to excited) and valence (from extremely negative to extremely positive) [16]. As we discuss below, recent data implicate the amygdala in processing information related to both arousal and valence; we will focus mainly, but not exclusively, on processing related to valence.
The concept of positive and negative valence is related to recent work by neuroscientists seeking to understand the neural basis of economic choice. According to neuroeconomic theory, a ‘universal currency’ of value should be encoded in the brain in order to effectively compare different economic options [17, 18, 19]; moreover, the values of stimuli, the values of actions, and ‘state value’ — the value of the overall situation of an organism at a given moment — are essential variables in theoretical accounts of learning [20, 21]. Using decision-making tasks, scientists have characterized neural signals correlated with value, where value is defined within an economic framework (reviewed in [18, 19]). In contrast, most studies focused on the amygdala have not used decision-making tasks; rather, they used classical or instrumental conditioning tasks, in which subjects learn the association between conditioned stimuli (CSs) and appetitive or aversive unconditioned stimuli (USs). Many types of associations between a CS and US may be formed during conditioning [22] — such as those between the CS and the motor response elicited by the US, or the sensory properties of the US — but, as we will discuss, considerable evidence now indicates that amygdala neurons encode information about the overall affective or motivational significance of USs associated with CSs. Therefore, we would argue that information about ‘valence’ encoded by the amygdala probably corresponds to ‘value’ as it is studied in decision-making tasks; we will use the terms ‘value’ and ‘valence’ interchangeably.
This review will examine recent progress in our understanding of whether and how value — in all its multifaceted senses — is encoded by the amygdala in rodents, humans, and non-human primates. We will consider the small but growing body of neurophysiological evidence concerning how the activity of individual amygdala neurons encodes the value of stimuli, and perhaps more general quantities, such as state value; and we will examine how this view of amygdala function may be supported by recent evidence from lesions and inactivation of the amygdala, and from observation of amygdala activity using functional imaging. Along the way, we will consider emerging ideas about how a representation of value might be ‘read out’ and used by other brain areas such as the orbitofrontal cortex (OFC). Overall, recent work paints a compelling picture of the amygdala as a key brain area for the processing and propagation of signals pertaining to value, and therefore as an essential part of the neural foundation of motivated behavior and emotion.
Section snippets
A neurophysiological representation of value
Until recent years, neurophysiological recording in the amygdala was mostly the province of rodents, with the exception of a few pioneering experiments in non-human primates [23, 24], and the majority of rodent studies were focused on fear conditioning. These studies helped to establish the viewpoint that the amygdala — particularly the lateral nucleus — is a key structure in Pavlovian conditioning, at least of the aversive valence, because it is a site of convergence for information about
Non-human primate studies
Lesions of the amygdala, which produce an extraordinarily wide range of behavioral and emotional effects, have historically provided a rich source of data about possible functions of the amygdala [45, 46] (reviewed in [47]). In recent years, neuroscientists working in rodents and non-human primates have used newer techniques — such as temporary pharmacological inactivation — to silence the amygdala, and those who work with lesions have increasingly used anatomically precise techniques that spare
The value signal in BOLD
Consistent with the historically prevalent view of the amygdala as a fear center, functional imaging studies in humans have often focused on the amygdala in the context of aversive events. Therefore, there is a large body of literature — including many ongoing research efforts — that connects increases in the blood-oxygenation level-dependent (BOLD) signal in the amygdala to stimuli that induce fear or apprehension. Many studies have shown that activation of the amygdala is correlated with fear
Conclusions
Here we have reviewed the latest progress toward understanding how value may be represented in the amygdala. In neuroscience, the terminology of ‘value’ is used in a variety of ways — motivational value, incentive value, economic value, stimulus value, and action value, among others; however, it might be said that the idea of ‘state value’ subsumes and encompasses all of these concepts. The value of a ‘state’ takes into account not only external stimuli (including all the CSs and USs we have
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by grants from NIMH (R01 MH082017 and RC1 MH088458), NIDA (R01 DA020656), NEI (R24 EY015634) and the James S McDonnell and Gatsby foundations. SEM received support from a National Science Foundation graduate fellowship and from an individual NIMH National Research Service Award (F31 MH081620). We wish to thank J Paton, M Belova, and members of the Salzman lab for helpful comments and discussions.
References (88)
- et al.
Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat
Neuron
(1995) Forward frontal fields: phylogeny and fundamental function
Trends Neurosci
(2008)- et al.
Pathways for emotion: interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey
Neuroscience
(2002) - et al.
Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala
Neuroimage
(2007) - et al.
Topographic organization of projections from the amygdala to the visual cortex in the macaque monkey
Neuroscience
(2003) Cortical pathways to the mammalian amygdala
Prog Neurobiol
(1998)The amygdala, reward and emotion
Trends Cogn Sci
(2007)- et al.
Neural economics and the biological substrates of valuation
Neuron
(2002) - et al.
Visual responses of neurons in the dorsolateral amygdala of the alert monkey
Exp Neurol
(1979) Synaptic mechanisms of associative memory in the amygdala
Neuron
(2005)
Flexible neural representations of value in the primate brain
Ann N Y Acad Sci
Emotional enhancement of memory via amygdala-driven facilitation of rhinal interactions
Nat Neurosci
Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning
Nature
Switching on and off fear by distinct neuronal circuits
Nature
Measuring reward assessment in a semi-naturalistic context: the effects of selective amygdala, orbital frontal or hippocampal lesions
Neuroscience
Orbitofrontal cortex and amygdala contributions to affect and action in primates
Ann N Y Acad Sci
Selective bilateral amygdala lesions in rhesus monkeys fail to disrupt object reversal learning
J Neurosci
Amygdala and orbitofrontal cortex lesions differentially influence choices during object reversal learning
J Neurosci
Learning fears by observing others: the neural systems of social fear transmission
Soc Cogn Affect Neurosci
Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis
Biol Psychiatry
The emotional brain, fear, and the amygdala
Cell Mol Neurobiol
New vistas on amygdala networks in conditioned fear
J Neurophysiol
Functional inactivation of the amygdala before but not after auditory fear conditioning prevents memory formation
J Neurosci
Emotion circuits in the brain
Ann Rev Neurosci
Topographic organization of cortical inputs to the lateral nucleus of the macaque monkey amygdala: a retrograde tracing study
J Comp Neurol
Some observations on cortical inputs to the macaque monkey amygdala: an anterograde tracing study
J Comp Neurol
The organization of projections from the amygdala to visual cortical areas TE and V1 in the macque monkey
J Comp Neurol
The role of the amygdala in conditioned and unconditioned fear and anxiety
A circumplex model of affect
J Personal Social Psychol
Choosing the greater of two goods: neural currencies for valuation and decision making
Nat Rev Neurosci
A framework for studying the neurobiology of value-based decision making
Nat Rev Neurosci
Reinforcement Learning
Theoretical Neuroscience
Learning about multiple attributes of reward in Pavlovian conditioning
Ann N Y Acad Sci
Single neuron responses in amygdala of alert monkey during complex sensory stimulation with affective significance
J Neurosci
The primate amygdala represents the positive and negative value of visual stimuli during learning
Nature
Moment-to-moment tracking of state value in the amygdala
J Neurosci
The convergence of information about rewarding and aversive stimuli in single neurons
J Neurosci
Expectation modulates neural responses to pleasant and aversive stimuli in primate amygdala
Neuron
Behavioral triggers of skin conductance responses and their neural correlates in the primate amygdala
J Neurophysiol
Neural responses to facial expression and face identity in the monkey amygdala
J Neurophysiol
Responses of single neurons in monkey amygdala to facial and vocal emotions
J Neurophysiol
Facial-expression and gaze-selective responses in the monkey amygdala
Curr Biol
Substantial similarity in amygdala neuronal activity during conditioned appetitive and aversive emotional arousal
Proc Natl Acad Sci U S A
Cited by (263)
Urbach-Wiethe disease in a young patient without apparent amygdala calcification
2023, NeuropsychologiaNeural computations underlying contextual processing in humans
2022, Cell ReportsThe role of the amygdala in processing social and affective touch
2022, Current Opinion in Behavioral SciencesRelations between lab indices of emotion dysregulation and negative affect reactivity in daily life in two independent studies
2022, Journal of Affective Disorders