▪ Abstract Learning the relationships between aversive events and the environmental stimuli that predict such events is essential to the survival of organisms throughout the animal kingdom. Pavlovian fear conditioning is an exemplar of this form of learning that is exhibited by both rats and humans. Recent years have seen an incredible surge in interest in the neurobiology of fear conditioning. Neural circuits underlying fear conditioning have been mapped, synaptic plasticity in these circuits has been identified, and biochemical and genetic manipulations are beginning to unravel the molecular machinery responsible for the storage of fear memories. These advances represent an important step in understanding the neural substrates of a rapidly acquired and adaptive form of associative learning and memory in mammals.

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Neurobiology of Pavlovian fear conditioning.

Excessive fear and anxiety are hallmarks of a variety of disabling anxiety disorders that affect millions of people throughout the world. Hence, a greater understanding of the brain mechanisms involved in the inhibition of fear and anxiety is attracting increasing interest in the research community. In the laboratory, fear inhibition most often is studied through a procedure in which a previously fear conditioned organism is exposed to a fear-eliciting cue in the absence of any aversive event. This procedure results in a decline in conditioned fear responses that is attributed to a process called fear extinction. Extensive empirical work by behavioral psychologists has revealed basic behavioral characteristics of extinction, and theoretical accounts have emphasized extinction as a form of inhibitory learning as opposed to an erasure of acquired fear. Guided by this work, neuroscientists have begun to dissect the neural mechanisms involved, including the regions in which extinction-related plasticity occurs and the cellular and molecular processes that are engaged. The present paper will cover behavioral, theoretical and neurobiological work, and will conclude with a discussion of clinical implications.

Mechanisms of fear extinction

The involvement of dopamine in drug reinforcement is well recognized but its role in drug addiction is much less clear. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events. In addition, imaging studies have also documented a role of dopamine in motivation, which appears to be encoded both by fast as well as smooth DA increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient (driving attention, arousal conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells. Indeed, imaging studies have shown that in drug-addicted subjects, dopamine function is markedly disrupted (decreases in dopamine release and in dopamine D2 receptors in striatum) and this is associated with reduced activity of the orbitofrontal cortex (neuroanatomical region involved with salience attribution and motivation and implicated in compulsive behaviors) and the cingulate gyrus (neuroanatomical region involved with inhibitory control and attention and implicated in impulsivity). However, when addicted subjects are exposed to drug-related stimuli, these hypoactive regions become hyperactive in proportion to the expressed desire for the drug. We postulate that decreased dopamine function in addicted subjects results in decreased sensitivity to nondrug-related stimuli (including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control. These findings suggest new strategies for pharmacological and behavioral treatments, which focus on enhancing DA function and restoring brain circuits disrupted by chronic drug use to help motivate the addicted subject in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs and interfere with their compulsive administration.

Dopamine in drug abuse and addiction: results from imaging studies and treatment implications

Molecular Mechanisms of Fear Learning and Memory

It is currently believed that the acquisition of classically conditioned fear involves potentiation of conditioned thalamic inputs in the lateral amygdala (LA). In turn, LA cells would excite more neurons in the central nucleus (CE) that, via their projections to the brain stem and hypothalamus, evoke fear responses. However, LA neurons do not directly contact brain stem-projecting CE neurons. This is problematic because CE projections to the periaqueductal gray and pontine reticular formation are believed to generate conditioned freezing and fear-potentiated startle, respectively. Moreover, like LA, CE may receive direct thalamic inputs communicating information about the conditioned and unconditioned stimuli. Finally, recent evidence suggests that the CE itself may be a critical site of plasticity. This review attempts to reconcile the current model with these observations. We suggest that potentiated LA outputs disinhibit CE projection neurons via GABAergic intercalated neurons, thereby permitting associative plasticity in CE. Thus plasticity in both LA and CE would be necessary for acquisition of conditioned fear. This revised model also accounts for inhibition of conditioned fear after extinction.

https://www.physiology.org/doi/pdf/10.1152/jn.00153.2004

New vistas on amygdala networks in conditioned fear.

In this study, the role of mRNA synthesis in the amygdala was studied during the acquisition of conditional fear. Rats with cannulas placed in the basolateral region of the amygdala were trained with a series of noise-shock pairings in a distinctive observation chamber. One half of the rats were pretreated with the mRNA synthesis inhibitor actinomycin-D (act-D). Responding to the training context and the auditory stimulus in a novel context measured by defensive freezing was assessed. Pretreatment with act-D significantly attenuated fear responses to both stimuli. Animals receiving act-D injections exhibited normal reactions to the conditioned stimulus-unconditioned stimulus pairings in the initial training session and displayed normal learning when retrained 7 days after injections. These results indicate that the transcription of new mRNA and subsequent protein synthesis in the amygdala may be essential for neural plasticity during this form of associative learning.

David J. Bailey

Papers

Acquisition of fear conditioning in rats requires the synthesis of mRNA in the amygdala.

Effects of Hippocampal Injections of a Novel Ligand Selective for the α5β2γ2 Subunits of the GABA/Benzodiazepine Receptor on Pavlovian Conditioning

Down Regulating Mu Receptors in the Basolateral Complex of Amygdala Prevents Antinociception in the Rat