Neural circuits for the adaptive regulation of fear and extinction memory

Abstract

The regulation of fear memories is critical for adaptive behaviors and dysregulation of these processes is implicated in trauma- and stress-related disorders. Treatments for these disorders include pharmacological interventions as well as exposure-based therapies, which rely upon extinction learning. Considerable attention has been directed toward elucidating the neural mechanisms underlying fear and extinction learning. In this review, we will discuss historic discoveries and emerging evidence on the neural mechanisms of the adaptive regulation of fear and extinction memories. We will focus on neural circuits regulating the acquisition and extinction of Pavlovian fear conditioning in rodent models, particularly the role of the medial prefrontal cortex and hippocampus in the contextual control of extinguished fear memories. We will also consider new work revealing an important role for the thalamic nucleus reuniens in the modulation of prefrontal-hippocampal interactions in extinction learning and memory. Finally, we will explore the effects of stress on this circuit and the clinical implications of these findings.

Keywords: amygdala; extinction; fear memory; hippocampus; prefrontal cortex; rat.

FIGURE 1

Neural circuits for extinction, retrieval and retrieval under stress. During extinction the IL exerts inhibitory control over the BLA and CeA, particularly through its inputs into the ITCs, thus suppressing the expression of the conditioned fear response. Concurrently, the HPC is encoding a configural representation of the extinction context, allowing for the contextual regulation of extinction learning and retrieval. Under retrieval conditions, the RE facilitates information flow from the mPFC to the HPC so that the mPFC can exert top-down control of the HPC, allowing for suppression of context inappropriate memories and retrieval of context appropriate memories. The IL also exerts inhibitory control of the BLA and CeA, suppressing the conditioned fear response. However, stress can impact these processes, resulting in impaired extinction retrieval. In the case of the immediate extinction deficit (IED), stress engages the LC-NE system, which excites the BLA through activation of β-adrenergic receptors. IL projecting BLA neurons drive feedforward inhibition of the IL through synapses on parvalbumin INT of the IL, impairing extinction retrieval. Other models of stress have demonstrated a role for the HPC in stress-induced extinction retrieval deficits, although the mechanisms and projections are not as clear. mPFC, Medial prefrontal cortex; PL, prelimbic; IL, infralimbic; INT, interneurons; BLA, basolateral amygdala; CeA, central amygdala; ITC, intercalated cells; RE, nucleus reuniens; HPC, hippocampus; LC, locus coeruleus. Created with BioRender.com.