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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. [ABSTRACT FROM AUTHOR]

Stress has profound effects on fear extinction, a form of learning that is essential to behavioral therapies for trauma-related and stressor-related disorders. Recent work reveals that acute footshock stress reduces medial prefrontal cortex (mPFC) activity that is critical for extinction learning. Reductions in mPFC activity may be mediated by parvalbumin (PV)-containing interneurons via feedforward inhibition imposed by amygdala afferents. To test this hypothesis, footshock stress-induced Fos expression was characterized in PV1 and PV-neurons in the prelimbic (PL) and infralimbic (IL) cortices. Footshock stress increased the proportion of PV1 cells expressing Fos in both male and female rats; this effect was more pronounced in IL compared with PL. To determine whether PV1 interneurons in the mPFC mediate stress-induced extinction impairments, we chemogenetically silenced these neurons before an immediate extinction procedure in PV-Cre rats. Clozapine-N-oxide (CNO) did not affect conditioned freezing during the extinction procedure. However, CNO exacerbated extinction retrieval in both male and female rats with relatively high PL expression of designer receptors exclusively activated by designer drugs (DREADD). In contrast, in rats with relatively high IL DREADD expression, CNO produced a modest facilitation of extinction in the earliest retrieval trials, but in male rats only. Conversely, excitation of IL PV interneurons was sufficient to impair delayed extinction in both male and female rats. Finally, chemogenetic inhibition of IL-projecting amygdala neurons reduced the immediate extinction deficit in male, but not female rats. These results reveal that PV interneurons regulate extinction learning under stress in a sex-dependent manner, and this effect is mediated by amygdaloprefrontal projections. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that cannabidiol (CBD), a substance present in the Cannabis sativa plant, has potential therapeutic value to regulate abnormal emotional memories associated with post-traumatic stress and drug use disorders. CBD can attenuate their valence after retrieval (i.e., during reconsolidation) or potentiate their suppression by extinction. Pharmacological research has now focused on elucidating how it acts. Systemic antagonism of cannabinoid type-1 (CB1) receptors has often prevented the abovementioned effects of CBD. However, it is unknown in which brain regions CBD stimulates CB1 receptors and how it interferes with local activity-related plasticity to produce these effects. The present study addressed these questions considering the reconsolidation of contextual fear memories in rats. We focused on the medial prefrontal cortex (mPFC), which comprises the anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) subregions, as local activity or plasticity has been associated with the process to-be-investigated. Animals that received post-retrieval systemic CBD treatment presented relatively fewer cells expressing Zif268/Egr1 protein, a proxy for synaptic plasticity related to reconsolidation, in the AC and PL. At the same time, there were no significant differences in the IL. Pretreatment with the CB1 receptor antagonist/inverse agonist AM251 into the AC, PL, or IL prevented the impairing effects of systemic CBD treatment on reconsolidation. CBD also caused reconsolidation impairments when injected directly into the AC or PL but not the IL. Together, these findings show complementary mechanisms through which CBD may hinder the reconsolidation of destabilized aversive memories along the dorsoventral axis of the mPFC. [Display omitted] • Systemic CBD administration attenuated contextual fear memory reconsolidation. • CBD reduced reconsolidation-associated plasticity in AC and PL but not IL cortex. • mPFC CB1 receptor antagonism prevented the CBD-induced effects on reconsolidation. • CBD infusion into the AC or PL but not IL reproduced the systemic effects. • CBD recruited complementary mPFC mechanisms to hinder a reactivated memory. [ABSTRACT FROM AUTHOR]

In both rodents and humans, the basolateral amygdala (BLA) is essential for encoding and retrieving conditioned fear memories. Although the BLA is a putative storage site for these memories, recent evidence suggests that they become independent of the BLA with the passage of time. We systematically examined the role for the BLA in the retrieval of recent (1 day) and remote (2 weeks) fear memory using optogenetic, electrophysiological, and calcium imaging methods in male and female Long-Evans rats. Critically, we used a behavioral design that permits within-subjects comparison of recent and remote memory at the same time point; freezing behavior served as the index of learned fear. We found that BLA c-Fos expression was similar after the retrieval of recent or remote fear memories. Extracellular single-unit recordings in awake, behaving animals revealed that single BLA neurons exhibit robust increases in spike firing to both recent and remote conditioned stimuli. Fiber photometry recordings revealed that these patterns of activity emerge from principal neurons. Consistent with these results, optogenetic inhibition of BLA principal neurons impaired conditioned freezing to both recent and remote conditioned stimuli. There were no sex differences in any of the measures or manipulations. These data reveal that BLA neurons encode both recent and remote fear memories, suggesting substantial overlap in the allocation of temporally distinct events. This may underlie the broad generalization of fear memories across both space and time. Ultimately, these results provide evidence that the BLA is a long-term storage site for emotional memories. [ABSTRACT FROM AUTHOR]