Neural circuits for the adaptive regulation of fear and extinction memory.

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.

Parvalbumin-Positive Interneurons in the Medial Prefrontal Cortex Regulate Stress-Induced Fear Extinction Impairments in Male and Female Rats.

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 PV+ and PV- neurons in the prelimbic (PL) and infralimbic (IL) cortices. Footshock stress increased the proportion of PV+ cells expressing Fos in both male and female rats; this effect was more pronounced in IL compared with PL. To determine whether PV+ 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.SIGNIFICANCE STATEMENT Stress significantly impairs the memory of fear extinction, a type of learning that is central to behavioral therapies for trauma-based and anxiety-based disorders (e.g., post-traumatic stress disorder). Here we show that acute footshock stress recruits parvalbumin (PV) interneurons in the medial prefrontal cortex (mPFC) of male and female rats. Silencing mPFC PV interneurons or mPFC-projecting amygdala neurons during immediate extinction influenced extinction retrieval in a sex-dependent manner. This work highlights the role for PV-containing mPFC interneurons in stress-induced impairments in extinction learning.

Dispersion and Aggregation Fate of Individual and Co-Existing Metal Nanoparticles under Environmental Aqueous Suspension Conditions.

The use of diverse metal nanoparticles (MNPs) in a wide range of commercial products has led to their co-existence in the aqueous environment. The current study explores the dispersion and aggregation fate of five prominent MNPs (silver, copper, iron, nickel, and titanium), in both their individual and co-existing forms. We address a knowledge gap regarding their environmental fate under turbulent condition akin to flowing rivers. We present tandem analytical techniques based on dynamic light scattering, ultraviolet-visible spectroscopy, and inductively coupled plasma atomic emission spectroscopy for discerning their dispersion behavior under residence times of turbulence, ranging from 0.25 to 4 h. The MNPs displayed a multimodal trend for dispersion and aggregation behavior with suspension time in aqueous samples. The extent of dispersion was variable and depended upon intrinsic properties of MNPs. However, the co-existing MNPs displayed a dominant hetero-aggregation effect, independent of the residence times. Further research with use of real-world environmental samples can provide additional insights on the effects of sample chemistry on MNPs fate.