Human Amygdala Activity During the Expression of Fear Responses

Neuron, 1996

portantly, loss of fear. Later work indicated that the reduced fear in resected monkeys was due specifically Los Angeles, California 90095 to damage in the amygdala. Consistent with its general role in fear, reports began to emerge that the amygdala was also required for aversive learning, including the Pavlovian fear conditioning is a ubiquitous form of learnacquisition of conditioned avoidance responses in cats ing that involves the association of stimuli and their and conditioned emotional responses in rats. Together, aversive consequences. Perhaps the quintessential exthese reports provided a strong foundation for amygample of Pavlovian fear conditioning is Watson and daloid involvement in fear and aversively motivated Rayner's (1920) experiment with "Little Albert." In this learning. experiment, Albert, a normal and healthy child attending Building upon this foundation, considerable progress day care, was shown a white rat by Rayner. Not surprishas been made in the last decade further defining the ingly, Albert's first reaction to the white rat was curiosity, anatomy of the amygdaloid fear system (Figure 1). It is and when presented with the rat he reached out to touch now apparent that within the amygdala there are two it. In response to Albert's attempt to touch the rat, Watsubsystems that have unique roles with regard to fear son, who had been closely observing Albert's interaction conditioning (Davis et al., 1994; Fanselow, 1994; Lewith the rat, sounded a loud and frightening noise by Doux, 1995). The basolateral complex of the amygdala hammering an iron rail. Albert, startled and scared by the (BLA; comprised of the lateral [LA], basolateral [BL], noise, quickly withdrew from the rat and began crying. and basomedial [BM] nuclei) is a substrate for sensory Watson and Rayner continued the procedure, and after convergence from both cortical and subcortical areas, a few more presentations of the white rat followed by and is considered a putative locus for CS-US associanoise, Albert began to show an intense fear of the rat. tion during fear conditioning. In contrast, the central Evidently, Albert had associated the frightening noise nucleus of the amygdala (CE), which receives projecwith the white rat. Indeed, Little Albert had been conditions from the BLA, projects to brain areas involved in tioned to fear white rats! the generation of fear responses, such as the lateral In recent years, the process by which the brain medihypothalamus (LH) and periaqueductal gray (PAG). It is ates Pavlovian fear conditioning has come under intense therefore thought to be a final common output pathway examination. In the laboratory, Pavlovian fear conditionfor the generation of fear CRs. Consistent with these ing is typically studied in the object of Albert's fear, the roles, destruction of neurons in either the BLA or CE is rat. In this model, rats receive pairings of an innocuous detrimental to both the acquisition and expression of conditioned stimulus (CS), such as a tone or the context conditional fear (Campeau and Davis, 1995; Maren et of the conditioning chamber, and a noxious uncondial., 1996), regardless of the exact stimuli used to train tioned stimulus (US), such as a footshock. After a few fear or the response measure used to assess it. Thus, such pairings, the CS comes to elicit a constellation of the amygdala is ideally situated to both integrate and conditioned responses (CRs) that are characteristic of associate sensory information and to execute motor fear, including changes in heart rate and arterial blood programs during fear conditioning. pressure, somatomotor immobility (freezing), hypoalge-Associative Neuronal Firing sia, potentiated acoustic startle, and pupillary dilation. in the Amygdala In this minireview, we will present recent work that has It has been known for years that amygdaloid neurons advanced our understanding of the basic neurobiologirespond to conditional reinforcers. However, the recent cal mechanisms involved in fear conditioning. This work delineation of the amygdaloid circuits underlying fear includes the elucidation of anatomical circuits underlyconditioning has opened the door for fine-grained studing fear conditioning, the characterization of neuronal ies of physiological plasticity in these circuits during and synaptic plasticity in fear conditioning circuits, and learning. For example, investigations of neuronal firing the analysis of humans with damage in brain structures in the amygdala during aversive learning using multiplerequired for fear conditioning. Altogether, it has become unit recording techniques have revealed learningapparent that neurons in the amygdala, an almondinduced changes in both the CE (Applegate et al., 1982) shaped group of nuclei buried deep within the temporal and BL (Maren et al., 1991). In both cases, neuronal lobes, are critical for Pavlovian fear conditioning. Hence, discharges were significantly greater to an auditory CS it is the amygdala that is likely to have been responsible that was paired with a shock US than those to a different for Little Albert's fear of rats. CS that was not paired with shock. Neuroanatomy of Fear Although neuronal discrimination suggests that the Although the neural substrates of fear conditioning have changes in neuronal firing in the amygdala were associa-received considerable attention in the last decade, they tive in nature, it is not clear whether the associative have been under study for over 50 years. Perhaps the activity was generated at the recording site or relayed first clues to the neural substrates of fear came from the from an afferent region. Indeed, within the amygdala, studies of Kluver and Bucy (1937). These investigators found that temporal lobe resections in monkeys pro-the first locus of convergence for auditory CSs and footshock USs is in the LA. In recent experiments, duced an eclectic deficit, appropriately termed the

The Journal of Physiology, 2013

Fear conditioning and fear extinction are Pavlovian conditioning paradigms extensively used to study the mechanisms that underlie learning and memory formation. The neural circuits that mediate this learning are evolutionarily conserved, and seen in virtually all species from flies to humans. In mammals, the amygdala and medial prefrontal cortex are two structures that play a key role in the acquisition, consolidation and retrieval of fear memory, as well extinction of fear. These two regions have extensive bidirectional connections, and in recent years, the neural circuits that mediate fear learning and fear extinction are beginning to be elucidated. In this review, we provide an overview of our current understanding of the neural architecture within the amygdala and medial prefrontal cortex. We describe how sensory information is processed in these two structures and the neural circuits between them thought to mediate different aspects of fear learning. Finally, we discuss how changes in circuits within these structures may mediate fear responses following fear conditioning and extinction.

Behavioral Neuroscience, 2003

Although laboratory animal studies have shown that the amygdala plays multiple roles in conditional fear, less is known about the human amygdala. Human subjects were trained in a Pavlovian fear conditioning paradigm during functional magnetic resonance imaging (fMRI). Brain activity maps correlated with reference waveforms representing the temporal pattern of visual conditional stimuli (CSs) and subject-derived autonomic responses were compared. Subjects receiving paired CS-shock presentations showed greater amygdala activity than subjects receiving unpaired CS-shock presentations when their brain activity was correlated with a waveform generated from their behavioral responses. Stimulusbased waveforms revealed learning differences in the visual cortex, but not in the amygdala. These data support the view that the amygdala is important for the expression of learned behavioral responses during Pavlovian fear conditioning.

Fear and anxiety are evolutionarily developed responses to perceived or anticipated threat. They involve behavioral, autonomic, and endocrine alterations aimed at increasing an organism's chances of survival. Excessive or uncontrolled fear and anxiety may lead to anxiety disorders. Animal and human studies indicate the critical role of the amygdala in adaptive and maladaptive fear. Recent advances elucidating the organization of the neural circuitry and molecular mechanisms of fear provide new insights in normal as well as pathological fear. In this chapter, we review the microcircuitry of the amygdala with a special emphasis on its relevance to fear processing and fear learning. We also discuss recent developments in understanding the basic molecular mechanism of fear. Finally, we address some of the implications of amygdala research for developing novel therapeutic approaches to maladaptive fear and anxiety.

2009

Fear and anxiety are evolutionarily developed responses to perceived or anticipated threat. They involve behavioral, autonomic, and endocrine alterations aimed at increasing an organism's chances of survival. Excessive or uncontrolled fear and anxiety may lead to anxiety disorders. Animal and human studies indicate the critical role of the amygdala in adaptive and maladaptive fear. Recent advances elucidating the organization of the neural circuitry and molecular mechanisms of fear provide new insights in normal as well as pathological fear. In this chapter, we review the microcircuitry of the amygdala with a special emphasis on its relevance to fear processing and fear learning. We also discuss recent developments in understanding the basic molecular mechanism of fear. Finally, we address some of the implications of amygdala research for developing novel therapeutic approaches to maladaptive fear and anxiety.

1. 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.

Brain Structure and Function, 2013

Do different brains forming a specific memory allocate the same groups of neurons to encode it? One way to test this question is to map neurons encoding the same memory and quantitatively compare their locations across individual brains. In a previous study, we used this strategy to uncover a common topography of neurons in the dorsolateral amygdala (LAd) that expressed a learning-induced and plasticity-related kinase (p42/44 mitogen-activated protein kinase; pMAPK), following auditory Pavlovian fear conditioning. In this series of experiments, we extend our initial findings to ask to what extent this functional topography depends upon intrinsic neuronal structure. We first showed that the majority (87 %) of pMAPK expression in the lateral amygdala was restricted to principal-type neurons. Next, we verified a neuroanatomical reference point for amygdala alignment using in vivo magnetic resonance imaging and in vitro morphometrics. We then determined that the topography of neurons encoding auditory fear conditioning was not exclusively governed by principal neuron cytoarchitecture. These data suggest that functional patterning of neurons undergoing plasticity in the amygdala following Pavlovian fear conditioning is specific to memory formation itself. Further, the spatial allocation of activated neurons in the LAd was specific to cued (auditory), but not contextual, fear conditioning. Spatial analyses conducted at another coronal plane revealed another spatial map unique to fear conditioning, providing additional evidence that the functional topography of fear memory storing cells in the LAd is non-random and stable. Overall, these data provide evidence for a spatial organizing principle governing the functional allocation of fear memory in the amygdala. Keywords Lateral amygdala Á Basal amygdala Á Lateral ventricle Á Network Á Neural circuit Á Fear Á Fear learning Á Memory Á Mitogen-activated protein kinase (MAPK) Á Calcium calmodulin-dependent protein kinase II (CAMKII) Á Magnetic resonance imaging (MRI) Á Principal components analysis (PCA) Á Multiple discriminant analysis (MDA) Á Multivariate ANOVA (MANOVA) Á Dual-labeling immunofluorescence Á Sprague-Dawley rat Á Consolidation Á Cytoarchitecture Á Principal cell-type Á Mapping Á Micro anatomy Á Stability Á Topography Á Organization Electronic supplementary material The online version of this article (

Physiology, 2015

The historically understood role of the central amygdala (CeA) in fear learning is to serve as a passive output station for processing and plasticity that occurs elsewhere in the brain. However, recent research has suggested that the CeA may play a more dynamic role in fear learning. In particular, there is growing evidence that the CeA is a site of plasticity and memory formation, and that its activity is subject to tight regulation. The following review examines the evidence for these three main roles of the CeA as they relate to fear learning. The classical role of the CeA as a routing station to fear effector brain structures like the periaqueductal gray, the lateral hypothalamus, and para- ventricular nucleus of the hypothalamus will be briefly reviewed, but specific emphasis is placed on recent literature suggesting that the CeA 1) has an important role in the plasticity underlying fear learning, 2) is involved in regulation of other amygdala subnuclei, and 3) is itself regulated by intra- and extra-amygdalar input. Finally, we discuss the parallels of human and mouse CeA involvement in fear disorders and fear conditioning, respectively.

Nature, 2010

The central amygdala (CEA), a nucleus predominantly composed of GABAergic inhibitory neurons, is essential for fear conditioning. How the acquisition and expression of conditioned fear are encoded within CEA inhibitory circuits is not understood. Using in vivo electrophysiological, optogenetic and pharmacological approaches in mice, we show that neuronal activity in the lateral subdivision of the central amygdala (CEl) is required for fear acquisition, whereas conditioned fear responses are driven by output neurons in the medial subdivision (CEm). Functional circuit analysis revealed that inhibitory CEA microcircuits are highly organized and that cell-type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization. Our results define the functional architecture of CEA microcircuits and their role in the acquisition and regulation of conditioned fear behaviour.