Neural circuits via which single prolonged stress exposure leads to fear extinction retention deficits

Abstract

Single prolonged stress (SPS) has been used to examine mechanisms via which stress exposure leads to post-traumatic stress disorder symptoms. SPS induces fear extinction retention deficits, but neural circuits critical for mediating these deficits are unknown. To address this gap, we examined the effect of SPS on neural activity in brain regions critical for extinction retention (i.e., fear extinction circuit). These were the ventral hippocampus (vHipp), dorsal hippocampus (dHipp), basolateral amygdala (BLA), prelimbic cortex (PL), and infralimbic cortex (IL). SPS or control rats were fear conditioned then subjected to extinction training and testing. Subsets of rats were euthanized after extinction training, extinction testing, or immediate removal from the housing colony (baseline condition) to assay c-Fos levels (measure of neural activity) in respective brain region. SPS induced extinction retention deficits. During extinction training SPS disrupted enhanced IL neural activity and inhibited BLA neural activity. SPS also disrupted inhibited BLA and vHipp neural activity during extinction testing. Statistical analyses suggested that SPS disrupted functional connectivity within the dHipp during extinction training and increased functional connectivity between the BLA and vHipp during extinction testing. Our findings suggest that SPS induces extinction retention deficits by disrupting both excitatory and inhibitory changes in neural activity within the fear extinction circuit and inducing changes in functional connectivity within the Hipp and BLA.

Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD

“…Habituation and/or extinction resulting from repeated testing of anxiety, arousal, and fear reaction to SPS cues might attenuate PL and BLA activation without preventing the expression of fear which could be mediated by other nodes in the fear circuitry. This possibility is supported by the recent identification of novel neural substrates in the regulation of fear memory expression 55 . It is worth noting that while in our conditions, vulnerable rats were not able to activate the BLA and the PL in response to trauma reminders, emotional remodeling with oxytocin, which had no effect on control and resilient rats, not only reversed PTSD behavioral symptoms but also rendered the pattern of BLA and PL activation of vulnerable rats similar to the one of saline-injected resilient rats.…”

Combined brain‐derived neurotrophic factor with extinction training alleviate impaired fear extinction in an animal model of post‐traumatic stress disorder

“…49 reported that administration of SPS attenuated increases in ILC neural activity and failed to inhibit basolateral amygdala (BLA) neural activity in rats. 50 Third, the difference in cellular structure between naïve and SPS rats may play a role, since SPS has been reported to induce apoptosis in the ventral mPFC of rats. 51,52 Thus, in SPS rats, infusion of BDNF may be insufficient to reduce freezing behavior during extinction training or reexposure to context without any extinction training 48 hours after infusion.…”

“…Second, differences in neuronal activity in the ILC between naïve and SPS rats could also be involved, as indicated in a study byKnox and associates, which reported that administration of SPS attenuated increases in ILC neural activity and failed to inhibit basolateral amygdala (BLA) neural activity in rats 50. In addition, they showed that BDNF infusion per se significantly decreased freezing behavior during the reexposure to context 48 hours after infusion without any extinction training.…”

Using the Single Prolonged Stress Model to Examine the Pathophysiology of PTSD

“…Many findings suggest that SPS produces behavioral and physiological symptoms that are similar to those observed in PTSD ( Liberzon et al, 1997 ; Kohda et al, 2007 ; Yamamoto et al, 2010 ; Knox et al, 2016 ). Examples of behavioral effects of SPS are illustrated in Figure 1 .…”

“…SPS rats demonstrate sleep abnormalities ( Vanderheyden et al, 2015 ) enhanced anxiety ( Han et al, 2014 ; Liu et al, 2016 ), arousal ( Khan and Liberzon, 2004 ), and fear learning ( Iwamoto et al, 2007 ; Keller et al, 2015b ) as well as impaired spatial and recognition memory, social interaction ( Kohda et al, 2007 ; Wen et al, 2016 ) and fear extinction ( Knox et al, 2012a ; Keller et al, 2015b ). Most changes are observed 7 days, but not 1 day, after exposure to the SPS procedure, suggesting that behavioral and cellular changes promoted by SPS are time-dependent ( Liberzon et al, 1999a ; Knox et al, 2016 ; Wu et al, 2016 ). Although it has been demonstrated that partial SPS does not generate extinction impairments ( Knox et al, 2012b ), the critical features of the SPS procedure for development of a PTSD-like phenotype remain unclear.…”