The neuroanatomical and neurochemical basis of conditioned fear

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Abstract

After a few pairings of a threatening stimulus with a formerly neutral cue, animals and humans will experience a state of conditioned fear when only the cue is present. Conditioned fear provides a critical survival-related function in the face of threat by activating a range of protective behaviors. The present review summarizes and compares the results of different laboratories investigating the neuroanatomical and neurochemical basis of conditioned fear, focusing primarily on the behavioral models of freezing and fear-potentiated startle in rats. On the basis of these studies, we describe the pathways mediating and modulating fear. We identify several key unanswered questions and discuss possible implications for the understanding of human anxiety disorders.

Introduction

Acute fear can be one of the most potent emotional experiences of our lifetime. The strength of this subjective experience may be because fear serves a function that is critical to the survival of higher vertebrates. It can be thought of as activation of a defensive behavioral system [1] that protects animals or humans against potentially dangerous environmental threats. For a small vertebrate such as a rat, an example of such an environmental threat would be predation. These threats may be innately recognized or learned [2], [3]. For example, in the presence of a cat or a stimulus that predicts potential injury, a rat will become completely motionless and freeze, no movements except those associated with respiration are observable [4], [5], [6]. Furthermore, the rat shows a fear-potentiated startle response [7], [8], [9], analgesia [10], a host of autonomic changes [11], [12] and increased release of several hormones [13]. In humans, these responses are correlated with a subjective state of fear [14], [15], [16], [17]. The brain and body are dedicated to fast and effective defense to increase the chances of survival. Therefore, we use the term “fear” to refer to the activation of the defensive behavioral system that gives rise to this constellation of reactions to threatening stimuli.

There are three major reasons why scientists investigate the neuronal basis of fear. First, they use fear-modulated behaviors as models to understand how emotions influence behavior. Second, the investigation of the neuroanatomical and neurochemical basis of fear and anxiety is a prerequisite to develop strategies to treat and cure anxiety disorders. Anxiety disorders, such as specific phobias (agoraphobia, social phobia, etc.), panic disorder, post-traumatic stress disorder and generalized anxiety disorder are among the most common psychopathologies in the industrial states. Third, fearful experiences are rapidly learned about and long remembered. Hence, fear-conditioning has become an excellent model for trying to unravel the processes and mechanisms underlying learning and memory.

The development of several reliable behavioral tasks for investigating fear has led to major developments in our understanding of the neuronal basis of fear and anxiety in just the last decade. These behavioral tasks fall into two general classes: learned and unlearned. Tests of unlearned fear rely on stimuli that naturally provoke fear even when the animal has had no prior experience with the stimulus. The most frequently used stimuli in these tasks are natural predators (e.g. [18]) and exposure to a novel place (especially one that is brightly lighted [19] or elevated [20]). Approaches using learned fear examine conditioned behaviors provoked by stimuli that have become associated with something aversive, usually an electric footshock. These Pavlovian fear stimuli provoke many of the same behaviors that innate fear stimuli do. For example, rats freeze to both cats and conditioned stimuli associated with shock. To measure the conditioned fear, a number of specific responses can be easily quantified such as fear-potentiated startle [7], [8], freezing [3], [21], tachycardia [22], conditioned defensive burying [23] and ultrasonic vocalization [24], [25], [26]. Alternatively, conditioned fear can be measured as a disruption of ongoing behaviors (e.g. conditioned suppression [27], [28] and conflict tests [29], [30]).

Validity for this approach to fear is obtained when a variety of stimuli that present clear threats to the subject generate a consistent set of behaviors that are tailored to protect against the threat. Additionally, these perceptual-motor organizations should have a common neuronal basis that overlaps considerably with the neural systems that mediate human fear and anxiety. Furthermore, the potency of drugs that modulate human fear and anxiety should correlate with their effectiveness in altering the behavior in these animal models.

The present review will primarily compare two specific responses to learned fear, freezing and fear-potentiated startle because these are most clearly identified with specific neural mechanisms that mediate between environmental stimulus and behavioral response. We go on to describe a hypothetical neuronal circuit which characterizes conditioned fear and helps organize existing knowledge about several conditioned defensive behaviors. Finally, we indicate what we feel to be some of the most critical open questions remaining for the analysis of fear.

Section snippets

The fear-conditioning procedure

Fear-conditioning is a form of Pavlovian conditioning where a subject is trained to associate a neutral stimulus (e.g. a 10 s presentation of light) with an aversive, unconditioned stimulus (US), such as an electric footshock. After such pairings, the light alone predicts the occurrence of the shock and acts as a conditioned stimulus (CS), eliciting a state of fear. Tones, lights, odors and tactile stimuli have been used as CS in fear-conditioning experiments. These stimuli range from a few

The role of the amygdala

It is now well established that the amygdala plays a pivotal role in fear. The initial hints of this were provided by Brown and Schaffer [93] who reported that large lesions of the temporal lobe tamed previously ferocious monkeys. Kluver and Bucy [94] characterized the rather widespread emotional disturbance caused by such brain damage and this psychopathology became known as the Kluver–Bucy syndrome. Weiskrantz [95] reported that many aspects of the Kluver–Bucy syndrome could be produced by

The periaqueductal gray and fear-potentiated startle

Cassella and Davis [186] first showed that the PAG is involved in the modulation of startle responding. They reported that electrolytic lesions of the dorsal PAG enhanced baseline amplitude, habituation and sensitization of the startle response. Although these lesions increased the sensitization of the startle response, no influences on the potentiation of startle by conditioned fear could be observed [186]. Some of Cassella's and Davis’ data were supported later by Borszcz et al. [187],

Other brain regions

Although the amygdala and PAG play a central role in the acquisition and expression of fear-related behavior, certainly several other brain regions play an important role as well. In the ensuing paragraphs, we will discuss the two brain regions that have been shown to play a role in fear-potentiated startle and freezing, the tegmental area and the hippocampal formation, respectively.

Summary, a neural circuitry and open questions

The studies reviewed here suggest a certain neural circuitry and this is shown in Fig. 3. This circuit goes a long way in integrating and summarizing the extensive data on Pavlovian fear-conditioning.

As shown in the figure, the amygdala plays the central role in the acquisition and expression of fear to the conditioned stimulus [136], [213], [214], [215], [216]. The amygdala is the interface between the sensory system that carry information about the CS and US, and the different motor and

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (SFB 307/C2 and Fe 483/1-1) to M.F. and National Science Foundation (US) grant # IBN-9723295 to M.S.F. M.F. specially thanks Dr. Michael Koch for helpful discussions during the work on the manuscript.

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