Molecular specificity of multiple hippocampal processes governing fear extinction

Abstract

Over many years, fear extinction has been conceptualized as one dominant process, new inhibitory learning, which serves to dampen previously acquired fear. Here we present an alternative view, that brain region-specific processing of representations, expectations and emotional attributes of the fear-provoking event, recruits unique mechanisms that interdependently contribute to the conditioning and extinction of fear. The co-occurrence of these mechanisms within the fear circuit can thus be tracked and differentiated at a molecular and cellular level. Among others, the transcriptional regulators cFos, cAMP-dependent response element binding protein (CREB), Zif268, and extracellular signal-regulated kinases (Erk) stand out as hippocampal nuclear markers signaling novelty, arousal, retrieval, and prediction error, respectively. Consistent with evidence from human studies, these findings indicate that, beyond inhibitory learning, fear extinction requires modification of the emotional attributes and expectations that define the threatening context. Given the likely dysregulation of one or more of these processes in anxiety disorders, a key research challenge for the future is the identification and enhancement of individual extinction mechanisms to target the specific components of fear. Environmental stimuli lacking affective properties (conditioned stimuli, CS) rapidly become threatening if presented with stressful events (unconditioned stimuli, US). Consequently, based on a CS-US association, the presentation of the CS triggers species-specific fear responses until the US consistently stops occurring. At that point, new learning takes place and the fear response declines, a phenomenon termed extinction. The view that extinction occurs because a new, inhibitory CS-noUS association gains control over behavior, has remained dominant in the field. The implications of impaired fear regulation in the development of anxiety disorders have stimulated intense research in this area. Rodent studies identified the circuits involved in the conditioning and extinction of fear of salient cues, generating data that were confirmed in humans with brain imaging approaches. Nevertheless, research with experimental animals has not fully taken advantage of human data in order to better interpret extinction mechanisms in the framework of learning, expectation and emotion governing fear-motivated behavior. The present article aims to summarize recent molecular evidence on fear extinction, focusing on hippocampal mechanisms and experimental models of contextual fear, and compare the results with other relevant fear paradigms and human imaging studies. Instead of conceptualizing extinction learning as one process, such as CS-noUS association or inhibitory learning, we propose that fear extinction reflects the behavioral output of several region-specific learning processes that modify different components of the conditioning memory. The significance of these findings is discussed in the framework of fear regulation and anxiety disorders.

Fig. 1

Schematic representation of the conditioning and extinction procedures employed in passive avoidance (upper panel) and fear conditioning (lower panel) paradigms.

Fig. 2

Effect of reinforcement during conditioning on the rate of fear extinction. Schematic representation of different reinforcement schedules (left) and freezing behavior over multiple extinction trials (right). Note rapid extinction after continuous and lack of extinction after partial reinforcement. Adapted from Huh et al., 2009.

Fig. 3

Proposed processes of conditioning and extinction of fear. Continuous, single, and partial reinforcement are established similar contextual representations but different levels of associated expectancy and affective attributes. Successful extinction therefore needs to target the main fear-provoking component.

Fig. 4

Molecular changes triggered in the CA1 hippocampal area after short and long extinction trials. Neurons activated by fear conditioning are fluorescently labeled (green) as described in Tronson et al., 2009. Short and long extinction trials activate either ERK (left) or cFos (right), respectively. Scale bar = 5 μm. FDG, fluorescein-di-beta-D-galactopyranoside New contextual representations that are not associated with shock may thus preferentially contribute to extinction after long exposures

Fig. 5

Overview of hippocampal molecular mechanisms mediating or inhibiting contextual fear extinction.